Safe practice recommendations for using vitamin K1 to reverse excessive warfarin anticoagulation

The route for administering phytonadione (vitamin K1) for excessive warfarin anticoagulation is controversial. Essentially, phytonadione promotes biosynthesis of certain clotting factors in the liver. Currently, there are two formulations available in the US: an oral 5 mg tablet (MEPHYTON) and an injectable preparation available in a 2 mg/mL or 10 mg/mL aqueous dispersion (AQUAMEPHYTON). With oral Mephyton, blood coagulation factors increase in 6-12 hours and INR values return to normal within 24 to 48 hours. With IV AquaMEPHYTON, coagulation factors increase in 1-2 hours, bleeding is controlled within 3-8 hours, and INR values return to normal after 12-14 hours. The IV route will produce the most rapid effect with progressively reduced effects seen in the following order: subcutaneous, intramuscular, and oral.^1-3 However, the desire for a more rapid onset of action must be carefully weighed against the risks of IV phytonadione administration and the availability of other alternatives to treat excessive anticoagulation.

AquaMEPHYTON contains polyoxyethylated fatty acid (CREMOPHOR EL) as a solubilizer, which is known to cause anaphylactic reactions. It's also possible that the drug itself or the total preparation (which also contains benzyl alcohol), not just the solubilizer, may be causing reported reactions.^4-6 AquaMEPHYTON product information includes a box warning that reads: "Severe reactions, including fatalities, have occurred during and immediately after INTRAVENOUS injection of AquaMEPHYTON, even when precautions have been taken to dilute the AquaMEPHYTON and to avoid rapid infusion." The warning also notes that the IV route should be restricted to those situations where other routes are not feasible and the serious risk involved is considered justified. Alternatively, administering the drug intramuscularly or subcutaneously may induce hemorrhage or hematoma at the injection site. It's also possible to overshoot anticoagulant reversal and cause warfarin resistance if too much phytonadione is administered. High doses of phytonadione can saturate body stores and significantly delay repeated warfarin treatment for up to two weeks or more, increasing the risk of thromboembolism.4 Some patients respond with fewer adverse effects and complications at IV doses less than 1 mg.^7-8

Last November, the American College of Chest Physicians identified only two clinical situations that justified use of IV phytonadione.⁹ For patients with a serious bleed or an INR over 20, the College recommends a 10 mg dose of phytonadione by slow IV infusion, supplemented with fresh plasma transfusion or prothrombin complex concentrate. Administration may have to be repeated every 12 hours. The College also recommends 10 mg of IV phytonadione and prothrombin complex concentrate for life-threatening bleeds. Still, these recommendations are based mainly upon observational studies and it's unknown whether the benefits outweigh the risks.

Researchers are searching for a safer intravenous formulation. Currently, a mixed micelle preparation and a liposomal product are in development.^10-11 Until then, oral administration is the safest route for phytonadione. Many patients with excessive anticoagulation respond very well by simply withholding warfarin and administering oral phytonadione. In the most severe cases where there is need for rapid reversal of warfarin's anticoagulant effect, fresh whole blood or fresh frozen plasma may be given (although use of blood products is not without risks). Products known to cause a potentially deadly reaction when used IV should not be used unnecessarily where other safe and effective options are available.

1.Udall J: Don't use the wrong vitamin K. Calif Med 1970; 112:65.

2. Wessler S: Anticoagulant therapy. JAMA 1974; 228:757.

3. Wessler S, Alexander B. Guide to anticoagulant therapy. American Heart Association, New York, 1970; 14.

4. Mattea EJ, Quinn K. Adverse reactions after intravenous phytonadione administration. Hosp Pharmacy 1981;16: 224, 231, 234-235.

5. Aziz NA, Kamaruddin Z, Hassan Y, Jaalam K. Vitamin K1-induced anaphylactic shock. J of Pharmacy Technology 1996;12:214-216.

6. Songy KA Jr, Layon AJ. Vitamin K-induced cardiovascular collapse. J of Clinical Anesthesia 1997; 9:514-519.

7. Whitling AM, Bussey JI, Lyons RM. Comparing different routes and doses of phytonadione for reversing excessive anticoagulation. Arch of Internal Med 1998;158:2136-2140.

8. Nee R, Doppenschmidt D, Donovan D, Andrews TC. Intravenous versus subcutaneous vitamin K in reversing excessive oral anticoagulation. Am J of Cardiology 1999; 83: 286-288.

9. Hirsch J et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998; 114(5):445S-469S.

10. Havel M, Muller M, Graninger W, Kurz R, Lindemayr H. Tolerability of a new vitamin K1 preparation for parenteral administration to adults: one case of anaphylactoid reaction. Clin Therapeutics 1987; 9(4): 373-379.

11. Personal communication: Dr. S. Belknap, University of Illinois, College of Medicine at Peoria, June 1998.

Other References

PDR 53rd edition, 1999. AquaMEPHYTON monograph.

Barrett JS, Hey EB Jr. Ventricular arrhythmias associated with the use of diazepam for cardioversion. JAMA 1970; 214: 1323-1234.

O'Reilly RA, Kearns P. Intravenous vitamin K injections: dangerous prophylaxis. Arch of Internal Med 1995; 155(19): 2127.

Oie S, Trenk D, Guentert TW, Mosberg H, Jahnchem E. Disposition of vitamin K1 after intravenous and oral administration to subjects on phenprocoumon therapy. International J of Pharmaceutics 1988; 48: 223-230.

Phytonadione-induced cardiovascular collapse. Micromedex Drug Consults. 1999; Volume 101.

AHFS 1999 Edition. Phytonadione monograph.

Drug Facts and Comparisons Updated monthly edition. Phytonadione monograph.

Taberner DA, Thompson JM, Poller L. Comparison of prothrombin complex concentrate and vitamin K1 in oral anticoagulant reversal. Brit Med J 1976; 2: 83-85.

Trissel L ed. Phytonadione monograph. Handbook for Injectable Drugs 10th edition, 1998.

Other reports of serious reactions

Barash P, Kitahata LM, Mandel S. Acute cardiovascular collapse after intravenous phytonadione. Anesthes Analg 1976; 55:304-306.

Corallo CE, Gillett M. Anaphylactic shock following intravenous vitamin K1. Australian J of Hosp Pharmacy 1997; 27:146-147.

Lefrer JJ. Acute cardiovascular collapse during intravenous vitamin K1 injection [letter]. Thromb Haemost 1987; 58:790.

Martin JC. Anaphylactoid reactions and vitamin K1 [letter]. Med J Austral 1991; 155: 851.

Martinez-Abad M, Delgado F, Palop V, Morales_Olivas FJ. Vitamin K1 and anaphylactic shock. Annals of Pharmacotherapy 1991; 25:871-872.

Anon. Slow down on parenteral vitamin K. Australian Adverse Drug Reactions Bulletin 1991; 10(3): Abstract 4.

Rich EC, Drage CW. Severe complications of intravenous phytonadione therapy. Postgraduate Med Journal 1982; 72:303-306.

Rubia J, Grau E, Montserrat I, Auzau I, Paya A. Anaphylactic shock with vitamin K1 [letter]. Annals of Inter Med 1989; 110:943.

Udall JA. Don't use the wrong vitamin K. California Medicine 1970; 112: 65-67.