Update: Can the intravenous formulation of vitamin K be administered orally?

Introduction
Phytonadione (vitamin K) is commonly used for the reversal of coagulopathy due to vitamin K antagonists (warfarin).^1,2 Vitamin K is commercially available as an aqueous colloidal injection (2 mg/mL and 10 mg/mL) and oral tablets (5 mg).^3,4 Although vitamin K can be administered subcutaneously or intramuscularly, it is not preferred due to erratic or unpredictable absorption with subcutaneous use and risk of hematoma with intramuscular use.^1,5 The preferred routes of vitamin K administration are oral or intravenous (IV).¹ While IV vitamin K has a boxed warning related to the risk of anaphylaxis, it has generally been administered safely via this route.^1,4 Vitamin K is available orally as 5 mg tablets. However, there are several limitations with the use of the oral tablets, including the high cost, drug shortages, and single tablet size preventing the use of low doses.^1,6,7 Therefore, interest in the oral administration of the injectable formulation  has increased.

A frequently asked question (FAQ) was published in 2015 on the oral administration of injectable vitamin K.⁸ The FAQ is available here, and was later expanded into a review article in 2017 (available here).^1,8 The FAQ had concluded that the use of injectable vitamin K orally was both effective and safe. The purpose of this FAQ is to update the 2015 review.

Guideline recommendations
Like the 2012 American College of Chest Physicians (ACCP) guideline, the 2018 American Society of Hematology guideline suggested against oral vitamin K in patients with an international normalized ratio (INR) > 4.5 but  <10 without clinically relevant bleeding.^2,9 In the discussion of benefits and harms/burden, the guideline authors note that oral vitamin K did not reduce the risk of all-cause mortality or increase the number of patients who achieved target INR.². The guideline commentary states that oral vitamin K could be considered in patients at high risk of bleeding complications or if the INR is expected to be prolonged for an extended period. The use of injectable vitamin K orally was not discussed.

Literature review
In the 2015 FAQ and 2017 review article, multiple studies had found the use of injectable vitamin K orally to be safe and effective for supratherapeutic INR reversal.^1,8,10-15 Since that time, 1 study and 2 reports were identified that evaluated the injectable preparation of vitamin K administered orally.^7,16,17

A single-center, retrospective, cohort study evaluated the use of phytonadione IV given orally (n=116) compared to phytonadione tablets (n=84) in adult patients who required vitamin K.¹⁶ The institution compounded a 100 mcg/mL suspension using the 10 mg/mL solution for injection with 100 mL of simple syrup stored in an amber plastic bottle and a beyond use date of 90 days. The median patient age was 67 to 68.5 years, the percentage of female patients was 45.2 to 53.4%, median baseline INR was 4.3 in patients who received the IV solution orally and 3.4 in patients who received the oral tablets. The median phytonadione dose in 24 hours was 5 mg in both groups. Most patients were receiving vitamin K for supratherapeutic INR without bleeding (46.6% for those who received the IV solution orally and 34.5% for  those who received oral tablets) or for emergent procedures (36.2% for the IV solution given orally group and 44% for  oral tablet group). After adjustment for baseline INR, the primary outcome of INR < 1.5 at 24 hours was similar between the group that received the IV solution orally compared to the group that received oral tablets (odds ratio, 1.46; 95% CI, 0.7 to 3.11) and at 48 hours (odds ratio, 1.69; 95% CI, 0.92 to 3.17). Adverse events were not discussed.

In addition to the study, injectable vitamin K administered orally has been used for rodenticide exposure. A 2018 outbreak of patients exposed to synthetic cannabinoids tainted with anticoagulant rodenticide resulted in a shortage of oral vitamin K in Chicago.⁷ In order to administer the oral vitamin K doses required for treatment, IV vitamin K was administered orally after withdrawal from the ampule using a filter needle and administered with orange juice to help improve the taste. The authors stated that the vitamin K was tolerated with no adverse events after a follow up for up to 3 months. In addition, the injectable formulation of vitamin K has been administered orally for Brodifacoum intoxication in 3 patients without observed adverse events.¹⁷ The method of oral vitamin K preparation and administration was not clearly described.

Compounding of oral solution from injectable vitamin K
The injectable formulation of vitamin K can be given undiluted or diluted in a liquid such as orange juice.⁸ When protected from light at room temperature or refrigerated, the undiluted formulation is stable for 30 days.¹⁸ However, potential concerns with the use of undiluted vitamin K include the potential for incorrect route of administration and inaccuracy in measuring the dose.⁶ When diluted with sterile water for injection (SWFI), the formulation has an unpleasant taste. Therefore, recipes for compounded vitamin K have been published. The 2015 FAQ and 2017 review article summarized recipes involving preparation of injectable vitamin K with Cremophor EL, simple syrup, and SWFI.^1,8,19,20 However, Cremophor is associated with adverse reactions and the technique with the recipe involving Cremphor EL required the use of nitrogen sparging. A second recipe used simple syrup or SWFI with beyond-use dates of 104 days and 111 days, respectively, although the study could not be fully evaluated due to limitations with accessing the full article text.²⁰ However, the manufacturer Sandoz had later verified the beyond-use dating in amber glass bottles.^1,21

Two additional compounding studies were identified. Huffman et al evaluated the stability of phytonadione 10 mg/mL injectable emulsion (manufacturer, Hospira) in SWFI in the refrigerator and in amber glass bottles and amber plastic oral syringes.²² The solution was passed through a 5-micron filter when drawing the emulsion from the ampules to compound the recipe; a 0.2-micron filter was used when obtaining the samples prior to the analysis. In the stability study, the vitamin K 1 mg/mL in amber glass bottles percent recovery remained above 90% up to day 105. However, the 1 mg/mL aliquots in the plastic oral syringes had percent recovery that dropped below 90% starting at day 21. The authors concluded that vitamin K in refrigerated amber glass bottles had a beyond use date of 105 days, but a beyond-use date of 14 days when stored in amber plastic syringes.

Lawson et al evaluated the stability of vitamin K 10 mg/mL injectable emulsion (manufacturer, Hospira) when compounded with various vehicles into a 1 mg/mL oral liquid in amber plastic oral syringes for 90 days.⁶ The compounding vehicles had the following preservatives: cherry syrup (sodium benzoate), Ora-Sweet (methyl paraben and potassium sorbate), simple syrup (methyl paraben), and SyrPalta (sodium benzoate, benzalkonium chloride, and alcohol). The solution was passed through a 5-micron filter when drawing the emulsion from the ampules to compound the recipe; a 0.2-micron filter was used when obtaining the samples prior to the analysis. The following were the beyond use time points: SWFI (21 days), SyrPalta (7 days), and cherry syrup (24 hours). Simple syrup and Ora-Sweet did not have acceptable limits even on the date of compounding. The authors noted that there was variability in the samples which demonstrated that the drug was not homogenously distributed throughout the vehicle. The authors concluded that SWFI is most suitable for long-term storage with a beyond-use-time point of 21 days, SyrPalta has a storage of 7 days, cherry syrup has a beyond use of 24 hours so can be used right after preparation, while simple syrup or Ora-Sweet are not acceptable vehicles.

A summary of the stability studies with IV vitamin K are listed in the Table.