Safe practice recommendations
for using vitamin K1 to reverse excessive warfarin anticoagulation
From the November 3, 1999 issue
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
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
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
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