Intravenous Vitamin K Solution for Oral Use
Amy Cook, PharmD1 and Alexis Crawford, PharmD, BCPS2
1PGY1 Resident, Bon Secours Memorial Regional Medical Center
2Critical Care Specialist, Bon Secours Memorial Regional Medical Center

Vitamin K, a fat soluble vitamin, is an important factor in the hepatic synthesis of coagulation and anticoagulation factors.  It is often used for the reversal of warfarin when the patient experiences elevated international normalized ratio (INR) or when they experience bleeding associated with the use of warfarin.  The use of oral vitamin K is recommended for reversal of warfarin when the patient has an elevated INR (4.5 -10) without major bleeding but is at high risk for bleeding or if the INR is greater than 10.1  Intravenous administration of vitamin K is recommended for patients who experience a major bleed associated with warfarin.  The objective of this article is to review and compare the different vitamin K administration routes and to provide information about using the intravenous (IV) solution for oral administration as a cost effective alternative to oral tablets.   
There are three administration routes routinely used for the administration of vitamin K; subcutaneous, intravenous, and oral.  The subcutaneous route of administration for vitamin K is the manufacturer’s recommended administration route for this medication.2   However, it has been noted in the literature that the subcutaneous administration has a highly variable absorption resulting in an inconsistent onset of action.3  In studies, a decrease in INR can occur anywhere from 24 to 72 hours after administration, which is not ideal when patients are experiencing a significant bleed or need to undergo surgery.4   The IV and oral routes provide more reliable and effective INR lowering and synthesis of hepatic clotting factors compared to the subcutaneous route.2  Based on these factors, IV and oral vitamin K administration is preferred over subcutaneous vitamin K administration.     
 Intravenous (IV) vitamin K is recommended for patients who experience significant bleeding associated with warfarin use.  With IV administration, there is an increase in coagulation factors within 1-2 hours, and a lowering of the INR can occur within 12-14 hours.2   Although IV vitamin K has the fastest onset of action and can lower the INR quickly, it does have risks associated with its use.  Anaphylaxis is a possible severe reaction that has been reported with the IV formulation and is therefore a black box warning.  In order to prevent patients from experiencing other adverse effects from IV vitamin K, it is recommended to dilute the dose in 50 mL of normal saline of dextrose 5% and infuse over 20 minutes.5  Intravenous vitamin K should not be administered faster than 1 mg/min.  The IV route does provide more reliable reversal of warfarin; however, it does have a risk for anaphylaxis and should be reserved for patients with significant bleeding.    
Oral vitamin K is recommended for use in patients with an elevated INR but without significant bleeding.  Administration of vitamin K through oral administration results in the synthesis of coagulation factors within 6-10 hours and a decrease in INR can be seen within 24-48 hours.  In a study comparing lower doses of oral vitamin K (1 mg and 2.5 mg), it was noted that these doses were effective at lowering INRs without making patients sub-therapeutic.6   Low dose oral vitamin K is ideal for management of patients with elevated INRs as it decreases the risk of bleeding without putting the patient at risk for thrombus formation.

 *Table 1: Overview of vitamin K administration routes

Route of Administration	Time to Increase of Coagulation Factors	Time to Decrease INR	Recommended Dose	Other Considerations
Subcutaneous	Variable	24-72 hours	2.5-10 mg	·         Unreliable pharmacokinetics ·         Should not be used
Intravenous	1-2 hours	12-14 hours	5-10 mg	·         Black Box Warning for anaphylaxis ·         Only for patients with significant bleeding associated with warfarin
Oral	6-10 hours	24-48 hours	1.25-5 mg	·         Reliable reversal of warfarin ·         Low doses decrease INR to goal range ·         Price of oral tablets has been rising

Multiple studies have compared the different administration routes of vitamin K in an attempt to determine the most effective route of administration for patients.  Table 2 below summarizes three of the most cited studies comparing the different administration routes of vitamin K.  In a study by Nee, et al. IV and subcutaneous vitamin K was compared in 55 patients on warfarin with an INR between 6 and 20.  Patients were randomized to receive either subcutaneous or IV vitamin K 0.5 mg (for INR 6-10) and 3 mg (for INR 10-20) with INR measurements taken 24 hours, 72 hours, and 7 days after administration. It was found that 95% of patients in the IV vitamin K group achieved an INR <5 within 24 hours after administration compared to only 45% of patients in the subcutaneous group.3 The researchers concluded that IV administration resulted in a faster reduction of INR compared to the subcutaneous route. 

 In a study by Crowther et al. subcutaneous vitamin K administration was compared to oral administration in 51 patients with an INR of 4.5-10 without significant bleeding.  Patients were randomized to receive 1 mg of subcutaneous or oral vitamin K with INR testing the day after reversal of warfarin.  The results of the study showed 57.7% of patients in the oral dose group achieved therapeutic INRs within 24 hours compared to 24% in the subcutaneous group.4   For patients who volunteered to have INRs checked after the first day, the researchers noted that the INRs in the subcutaneous group were, on average, higher than patients in the oral group at day 2 and 3 after vitamin K administration.  The authors concluded that oral vitamin K administration may be more effective than subcutaneous administration, as it was shown in the study that a similar oral dose decreased the INR faster than the subcutaneous route.
​
 A study by Lubetsky, et al. compared IV and oral administration of vitamin K in 61 subjects.  Patients with INRs of 6-10 were randomized to receive vitamin K either 0.5 mg IV or 2.5 mg oral and those with an INR greater than 10 were received vitamin K either 1 mg IV or 10 mg oral.  INR values were recorded at 2, 4, 6, 12, 48, and 72 hours after administration of vitamin K to determine how long it would take patients to reach a “safe zone” which was defined as an INR of 2-4.  It was found that oral vitamin K was as effective as IV at lowering INR within 24 hours, with the IV administration resulting in a faster decrease in INR than the oral administration. The researchers also noted that patients in the oral administration group had a lower incidence of sub-therapeutic INR values compared to those in the IV group.7  The authors concluded that for patients who do not require urgent INR normalization, oral administration of vitamin K is the preferred route when compared to the IV administration.    

 *Table 2: Comparison of different vitamin K administration routes

Study	Purpose	Groups	Primary Endpoint	Conclusions
Nee, et al.	Compare IV to subcutaneous vitamin K administration	·      INR 6-10 o   IV 0.5 mg (n=20) o   Subcutaneous 0.5 mg (n=20) ·      INR 10-20 o   IV 3 mg (n=2) o   Subcutaneous 3 mg (n=8)	INR <5 at 24 and 72 hours ·      95% IV administration ·      45% subcutaneous administration ·      p<0.001 All but one patient had an INR <5 at 72 hours in both groups	IV vitamin K administration achieved an INR < 5 faster than the subcutaneous route
Crowther, et al.	Compare subcutaneous to oral vitamin K administration	·      1 mg subcutaneous vitamin K (n=25) ·      1 mg oral vitamin K (n=26)	INR 1.8-3.2 one day after administration ·      58% oral administration ·      24% subcutaneous administration ·      OR 4.32, p=0.015	1 mg oral vitamin K decreases the INR faster than 1 mg subcutaneous vitamin K
Lubetsky, et al.	Compare IV to oral vitamin K administration	·      IV vitamin K o   INR 6-10: 0.5 mg (n=24) o   INR >10: 1 mg (n=10) ·      Oral vitamin K o   INR 6-10: 2.5 mg (n=23) o   INR >10: 5 mg (n=9)	INR 2-4 ·      6 hours: 35% IV group; 0% oral (p<0.001) ·      12 hours: 53% IV; 35% oral (p= 0.03) ·      24 hours: 68% IV; 81% oral (p>0.05) ·      INR <2: 20% IV; 13% oral (p>0.05)	Oral vitamin K is a better alternative compared with IV vitamin K when restoration of INR is not considered urgent

​Oral vitamin K is available currently as a 5 mg tablet; however, the price for the tablet has risen significantly in recent months.  It is important to note that the price for the IV solution has remained consistent.   A possible way to decrease the cost of providing vitamin K orally to patients in need is to use the IV solution for oral administration.8   In a study by Baker, et al. patients with elevated INRs without major bleeding who were given the IV solution of vitamin K orally at doses of 2.5 mg and 5 mg achieved effective INR lowering 1 day after administration.9  According to the literature, a formulation of IV vitamin K drawn up in an amber syringe with sterile water for injection or simple syrup to a 1 mg/mL suspension can be stored at room temperature for 3 months without decreasing its stability.10  After performing a medication use evaluation of oral vitamin K use at Bon Secours Memorial Regional Medical Center for a 6 month period, it was found that using the IV solution for oral use would save the hospital about $13,700 a year.  A recipe for using the IV formulation for oral administration adapted from the article from Vernier, et al. is provided below.   

 

Recipe Ingredients/equipment:   ·         Vitamin K 10 mg/mL ampoule ·         9 mL of sterile water for injection or simple syrup ·         Amber oral syringes with caps ·         Filter needle ·         Graduated cylinder ·         Beaker   Procedure: ·         Using a graduated cylinder, measure 9 mL of sterile water for injection or simple syrup. ·         Open ampoule and draw up IV solution using the filter needle ·         Mix the solution together in a beaker ·         Draw up either 2.5 mL (for 2.5 mg dose batch) or 5 mL for (for 5 mg dose batch) ·         Label as oral use only, room temperature, protect from light, and stable for 3 months

Vitamin K is known to be an effective reversal agent for bleeding associated with warfarin.  Although the IV formulation has the fastest onset of action for decreasing INR, it has been shown that oral use of vitamin K is as effective at decreasing INR within 24 hours.  It has even been shown that oral vitamin K at doses of 1.25 and 2.5 mg are sufficient at lowering the INR without causing the patient be sub-therapeutic.  With the recent price increase of vitamin K tablets, compounding the IV solution for oral administration is a possible option for providing sufficient INR lowering at a decreased cost. 
 
References:

1. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2012;141:e152S-184S
2. Vitamin K1(Phytonadione Injection) [package insert]. Lake Forest, IL: Hospira, Inc. 12/2013
3. Nee R, Doppenschmidt D, Donovan DJ, Andrews TC. Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation. American Journal of Cardiology. 1999;83:286-288
4. Crowther MA, Douketis JD, Schnurr T, Steidl L, Mera V, Ultori C, Venco A, Ageno W. Oral vitamin K lowers international normalized ratio more rapidly that subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Ann Intern Med.2002;137:251-254
5. Whitling AM, Bussey HI, Lyons RM. Comparing different routes and doses of phytonadione for reversing excessive anticoagulation. Arch Intern Med. 1998;158:2136-2140
6. Wilson SE, Watson HG, Crowther MA. Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review. CMAJ. 2004;170:821-824
7. Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Ann Intern Med.2003;163:2469-2473
8. Sewell GJ, Palmer AJ. The Formulation and stability of a unit-dose oral vitamin K preparation. Journal of Clinical Pharmacy and Therapeutics. 1988;13:73-76
9. Barker P, Gleghorn A, Tripp T, Paddon K, Eagleton H, Keeling D. Reversal of asymptomatic over-anticoagulation by orally administered vitamin K. BJH. 2006;133:331-336.
10. Vanier MC, Ngo TT. Reversal of Overanticoagulation with Vitamin K1: A Plea for Oral Administration. Can J Hosp Pharm.2006;59:125-135