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Frequently Asked Questions

Can the intravenous formulation of vitamin K be administered orally?

Background
Warfarin (Coumadin) is a vitamin K antagonist (VKA) that is widely used for oral anticoagulation, ranking at numbers 29 and 180 on the top 200 drugs of 2007 for generic and brand name medications, respectively.1 Warfarin inhibits the activation of vitamin K dependent clotting factors II, VII, IX, and X.2 Patients may require warfarin therapy for a variety of reasons including treatment or prevention of deep vein thrombosis (DVT) or pulmonary embolism (PE), stroke prevention for atrial fibrillation or prosthetic heart valves, or prevention of recurrent thromboembolic events. Dosing of warfarin is complicated by a number of drug-drug and drug-food interactions, which may enhance or diminish the anticoagulant effect. In order to optimize therapy and minimize dangerous side effects, such as bleeding, close monitoring of the degree of anticoagulation is required through blood testing of the international normalized ratio (INR). For most patients, a target INR of 2.0 to 3.0 is desired, but target INR varies depending on clinical indication. Although warfarin has been used for many years as an anticoagulant, there are still questions regarding the associated risks and management of an elevated INR, specifically with respect to vitamin K dosing.

There are a number of guidelines available regarding the management of an elevated INR in patients receiving VKAs. The American College of Chest Physicians (ACCP) updated their recommendations on the use of vitamin K in June of 2008.3 Oral vitamin K is preferred to subcutaneous (SC) for patients with elevated INRs in the absence of major bleeding. Along with suggestions to omit and reduce doses, the guidelines recommend vitamin K in the following situations when the patient does not have significant bleeding:

  • INR ≥5.0 and <9.0 – may give oral vitamin K 1 to 2.5 mg if the patient is at an increased risk for bleeding; up to 5 mg oral vitamin K may be given if more rapid reversal is required. Additional doses may be required.
  • INR ≥9.0 – give vitamin K 2.5 to 5 mg orally; additional doses may be required.

If the patient is experiencing serious or life-threatening bleeding, intravenous vitamin K 10 mg along with blood products should be administered.3

Guidelines are also available from the British Committee for Standards in Haematology (BCSH) and the Australasian Society of Thrombosis and Haemostasis (ASTH). All 3 guidelines recommend oral administration of low-dose vitamin K if there is no significant bleeding.3-5 These latter 2 guidelines also specify that the intravenous preparation of vitamin K should be administered orally as there is increased dosing flexibility as compared to the tablet formulation.

Literature Review
The efficacy of the intravenous preparation of vitamin K administered orally has been evaluated in 3 studies. Crowther and colleagues performed a multicenter, double-blind, placebo-controlled, randomized study in 2000 to determine the efficacy of low dose oral vitamin K for reversal of INR.6 The study included patients with a target INR of 2.0 to 3.0 who presented with INRs between 4.5 and 10.0. Main exclusion criteria were INR tested > 12 hours prior to screening, short life expectancy <10 days, required immediate reversal of INR, or liver dysfunction. Ninety-two participants were randomized to receive equal volumes of either saline placebo (n=44) or 1 mg of the intravenous formulation of vitamin K given orally (n=45). The INR was tested on the day following vitamin K administration and was optional thereafter for the following 4 days. Follow-up was conducted at a clinic visit or via telephone at 1 and 3 months following study enrollment to determine if patients had experienced thromboembolic or bleeding events.

The primary outcome was a comparison of the proportion of patients in each study group with INRs between 1.8 and 3.2 on the day following vitamin K administration. Twenty-five (56%) of 45 patients who received vitamin K and 9 (20%) of 44 people in the placebo group had INRs between 1.8 and 3.2 (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.07 to 0.57, p=0.001) at this time point. An INR value of less than 1.8 was found in 7 (16%) patients receiving vitamin K and in no patients receiving placebo (p=0.012). On follow-up at 3 months, bleeding was reported in 2 (4%) patients in the vitamin K group and 8 (17%) of the placebo recipients. Overall, there was a significantly higher rate of bleeding reported with placebo as compared to vitamin K (OR 0.187, 95% CI 0.019 to 0.999, p=0.0499). There was only 1 report of major bleeding, which occurred 3 days following administration of vitamin K in a patient with an INR value of 2.0. Two thrombotic events were also discovered upon follow-up: a myocardial infarction 3 days following administration of vitamin K and a DVT 22 days following placebo. Fourteen patients died during follow-up; however, none of the deaths was attributed to complications from either warfarin or vitamin K therapy. The authors concluded that low dose intravenous vitamin K administered orally is effective for reducing INR values of 4.5 to 10.0.

In 2002, Crowther and colleagues conducted a second trial, hypothesizing that oral vitamin K was more effective than SC vitamin K.7 Fifty-one patients were included in this multicenter, randomized, open-label, controlled trial. The study was conducted at 2 teaching hospitals in Ontario, Canada and Varese, Italy. The inclusion and exclusion criteria were identical to those used in aforementioned 2000 trial. At least 1 dose of warfarin was held and patients were randomly assigned to receive 1 mg of vitamin K either orally or subcutaneously.7 Reinitiation of warfarin therapy was left to the discretion of the treating physicians based on INR. In Canada, injectable phytonadione (vitamin K1) was used for both oral and SC administration; and in Italy, patients were given a 1 mg/ml oral solution of vitamin K. International normalized ratio testing was required on the day following administration of vitamin K, and was optional thereafter. Follow-up was conducted at a clinic visit or via telephone 1 month after study enrollment to determine if patients had experienced thrombotic or bleeding events.

As with the first study, the primary outcome was a comparison of the proportion of patients in each study group with INRs between 1.8 and 3.2 on the day after vitamin K administration.7 The group of 26 patients who were randomized to receive oral vitamin K had an initial mean INR of 5.8 and the 25 patients receiving SC vitamin K had a mean INR of 6.2. Following vitamin K administration, 15 (58%) of the 26 patients receiving oral vitamin K and 6 (24%) of 25 patients receiving SC vitamin K had INRs between 1.8 to 3.2 (OR 4.32, 95% CI 1.13 to 17.44, p = 0.015). Mean INR values were higher in the SC group compared to the oral group on the second and third days following vitamin K administration (p value not reported). Upon follow-up, there were no episodes of thromboembolism or bleeding reported, however, there were 5 deaths unrelated to complications of warfarin therapy. The authors concluded that oral vitamin K might be more effective than SC vitamin K in reestablishing therapeutic INR in patients presenting with INRs between 4.5 and 10.0, as oral administration decreased INR more quickly than SC administration. They suggest that 1 mg of oral vitamin K be considered for asymptomatic patients presenting with INRs of 4.5 to 10.0.

A retrospective analysis of 2 years of data by Baker and colleagues in 2006 employed a protocol based on the BCSH and ASTH recommendations in which the intravenous preparation of vitamin K (phytomenadione) was administered orally.8 Patients who were followed at a nurse-run anticoagulant service in the United Kingdom were included in the analysis if they presented with an INR > 8. Laboratory confirmation was requested for values > 8, and patients were contacted by nursing staff to check for significant bleeding and possible causes for increase in INR. If they had not already taken it, patients were instructed not to take their warfarin dose for that day. Vitamin K was administered orally according to the following regimen: for an INR > 8 but < 12 patients received 2.5 mg and 5 mg was administered for an INR > 12. Vitamin K was prepared as a 2 mg/mL liquid by the pharmacy and was administered to patients on the day of INR measurement. International normalized ratio measurements were repeated the following morning and daily until the INR was <5, at which point warfarin therapy was reinitiated.

Two hundred twenty three patients were included in this retrospective analysis and were divided into 3 groups based on INR at presentation – INR 8.0 to 11.9 (n=166), 12.0 to 20.0 (n=36), and >20.0 (n=21). On presentation, median INR for the first group was 9.2 and fell to 3.8 roughly 14 hours following the administration of vitamin K. One hundred twenty-seven (77%) of 166 patients had measured INRs between 2.0 and 4.9 on day 1, and 12 were over reversed with INRs between 1.5 to 1.9. The 36 patients presenting with INRs between 12.0 to 20.0 experienced decreases in INR to a median of 3.0 on day 1. Nineteen (52%) of the 36 patients had INRs between 2.0 and 4.9, 16 (17%) were subtherapeutic with INR <2, and 3 (9%) patients had INR values that remained between 8.0 and 11.9. Of the 21 patients originally presenting with an INR >20, following vitamin K administration, 9 (44%) had measured INR values between 2.0 and 4.9, 6 (29%) had INRs <1.9, and 2 (10%) patients had INRs that remained between 8.0 and 11.9. Baker and colleagues concluded that the oral administration of intravenous vitamin K dosed at 2.5 mg for INR values of 8.0 to 11.9 and 5 mg for INR levels >12 provides safe and predictable reversal of anticoagulation.

Conclusion
Based on the above studies and the recommendations made by the BCSH and ASTH guidelines, it appears that intravenous vitamin K is well tolerated when administered orally and works quickly to correct supratherapeutic INRs without over-correcting anticoagulation. The advantage of this formulation is that it allows for flexible dosing regimens when compared to tablets; it is easy to administer and does not require dilution.

References

  1. Drug Topics. Top 200 Drugs. http://drugtopics.modernmedicine.com/Top+200+Drugs. Accessed October 30, 2008.
  2. Coumadin [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
  3. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists. Chest. 2008;133(6 Suppl):160S-198S.
  4. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2004;181(9):492-497.
  5. Haemostasis and Thrombosis Task Force for the British Committee for Standards in Haematology. Guidelines on oral anticoagulation: third edition. Br J Haematol. 1998;101(2):374-387.
  6. Crowther MA, Julian J, McCarty D, et al. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet. 2000;356(9241):1551-1553.
  7. Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. Ann Intern Med. 2002;137(4):251-254.
  8. Baker P, Gleghorn A, Tripp T, Paddon K, Eagleton H, Keeling D. Reversal of asymptomatic over-anticoagulation by orally administered vitamin K. Br J Haematol. 2006;133(3):331-336.

By: Aura Platakis, PharmD