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Phytomenadione [Phytonadione] (Lexi-Drugs Multinational)

ALERT: US Boxed Warning
Hypersensitivity/anaphylactoid reactions (injection):

Severe reactions, including fatalities, have occurred during and immediately after intravenous (IV) injection of phytonadione, even
when precautions have been taken to dilute the phytonadione and to avoid rapid infusion. Severe reactions, including
fatalities, also have been reported following intramuscular (IM) administration. Typically, these severe reactions have
resembled hypersensitivity or anaphylaxis, including shock and cardiac or respiratory arrest. Some patients have exhibited
these severe reactions on receiving phytonadione for the first time. Therefore, restrict the IV and IM routes to those situations
where the subcutaneous route is not feasible and the serious risk involved is considered justified.

Brand Names: International Bonadiona (CR, DO, GT, HN, NI, PA, SV); Haemokion (AE, BH, CY, EG, IQ, IR, JO, KW, LB,
LY, OM, QA, SA, SY, YE); Hema-K (PH); Kanakion (PT); Kanavit (CZ); Katimin-1 (TW); Kenadion (IN); Konakion (10 mg) (AE, AU, BG,
BH, CY, DE, EC, EG, GB, GH, IE, IL, IQ, IR, IT, JO, KE, KW, LB, LY, NL, OM, QA, SA, SE, SY, TZ, UG, YE, ZM); Konakion (BE, DK, ES,
HU, IS, LU, NO, SI, TR, ZW); Konakion 10 mg (AT, FI, HN); Konakion MM (BH, CL, HR, KW, LB, LK, LV, MX); Konakion MM Paediatric
(BB, BM, BS, BZ, GY, JM, SR, TT); Konakion MM Pediatric (AR, AU, BR, CH, CO, NZ, PE, PK, PY, UY, VN); Neokay (GB); Phytomen
(PH); Prohem (ID); Univitan K1 (HK); Vitacon (PL); Vitak (JP); Vitamin K (HK); Vitamin K1 (KR); Vitamine K!1 Roche (FR); Vitka Infant
(ID)

Brand Names: US Mephyton

Brand Names: Canada AquaMEPHYTON; Konakion; Mephyton

International Nonproprietary Names (INN) Fitomenadiona [Spanish]; Phytomenadione [English]; Phytomenadionum

[Latin]; Phytomnadione [French]; [Russian]; [ Arabic]

Brazilian Nonproprietary Names (DCB) Fitomenadiona

Anatomic Therapeutic Chemical (ATC) Classification

B02BA01

Pharmacologic Category Vitamin, Fat Soluble

Dosing: Adult Note: Oral route is more effective than the SubQ route in the treatment of nonbleeding patients with warfarin-
associated coagulopathy; SubQ route has therefore fallen out of favor due to erratic and unpredictable absorption (Crowther 2002). If
administering parentally, SubQ is the preferred parenteral route; IM route should be avoided due to the risk of hematoma formation; IV
route should be restricted for emergency use only. The American College of Chest Physicians (ACCP) recommends the IV route in
patients with major bleeding secondary to use of vitamin K antagonists (VKAs).

Adequate intake (AI): Oral: Males: 120 mcg/day; Females: 90 mcg/day

Hypoprothrombinemia due to drugs (other than coumarin derivatives) or factors limiting absorption or synthesis: Oral, SubQ,
IV: Initial: 2.5 to 25 mg (rarely up to 50 mg)

Acute liver failure coagulopathy: SubQ, IV: 5 to 10 mg (at least one dose) (AASLD [Lee 2011]; Pereira 2005)

Vitamin K deficiency (supratherapeutic INR) secondary to VKAs (eg, warfarin) (off-label dose):

If INR above therapeutic range to <4.5 (no evidence of bleeding): Lower or hold next VKA dose and monitor frequently; when INR
approaches desired range, resume VKA dosing with a lower dose (Patriquin 2011).

If INR 4.5 to 10 (no evidence of bleeding): The 2012 ACCP guidelines recommend against routine phytonadione (aka, vitamin K)
administration in this setting (Guyatt 2012). Previously, the 2008 ACCP guidelines recommended if no risk factors for bleeding
exist, to omit next 1 or 2 VKA doses, monitor INR more frequently, and resume with an appropriately adjusted VKA dose when
INR in desired range; may consider administering vitamin K orally 1 to 2.5 mg if other risk factors for bleeding exist (Hirsh
2008). Others have recommended consideration of vitamin K 1 mg orally or 0.5 mg IV (Patriquin 2011).

If INR >10 (no evidence of bleeding): The 2012 ACCP guidelines recommend administration of oral vitamin K (dose not specified) in
this setting (Guyatt 2012). Previously, the 2008 ACCP guidelines recommended to hold warfarin, administer vitamin K orally 2.5
to 5 mg, expect INR to be reduced within 24 to 48 hours, monitor INR more frequently and give additional vitamin K at an
appropriate dose if necessary; resume warfarin at an appropriately adjusted dose when INR is in desired range (Hirsh 2008).
Others have recommended consideration of vitamin K 2 to 2.5 mg orally or 0.5 to 1 mg IV (Patriquin 2011).

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If minor bleeding at any INR elevation: Hold warfarin, may administer vitamin K orally 2.5 to 5 mg, monitor INR more frequently, may
repeat dose after 24 hours if INR correction incomplete; resume warfarin at an appropriately adjusted dose when INR is in
desired range (Patriquin 2011).

If major bleeding at any INR elevation: The 2012 ACCP guidelines recommend administration of four-factor prothrombin complex
concentrate (PCC) and IV vitamin K 5 to 10 mg in this setting (Guyatt 2012). The only available four-factor PCC in the US is
Kcentra. Other four-factor PCCs not available in the US include Beriplex P/N, Cofact, and Octaplex. Bebulin VH and Profilnine
SD do not contain adequate levels of factor VII and are considered three-factor PCCs. Previously, the 2008 ACCP guidelines
recommended to hold warfarin, administer vitamin K 10 mg by slow IV infusion and supplement with PCC depending on the
urgency of the situation; IV vitamin K may be repeated every 12 hours (Hirsh 2008).

Note: Use of high doses of vitamin K (eg, 10 to 15 mg) may cause warfarin resistance for 1 week. During this period of resistance,
heparin or low-molecular-weight heparin (LMWH) may be given until INR responds (Ansell 2008).

Preprocedural/surgical INR normalization in patients receiving warfarin (routine use): Oral: 1 to 2.5 mg once administered on the
day before surgery; recheck INR on day of procedure/surgery (Douketis 2012). Others have recommended the use of vitamin K 1
mg orally for mild INR elevations (ie, INR 3.0 to 4.5) (Patriquin 2011).

Intracranial hemorrhage associated with vitamin K antagonist anticoagulants (eg, warfarin) (off-label use): IV: Initial: 10 mg once
given as soon as possible and concomitantly with 4-factor prothrombin complex concentrate (PCC) for INR 1.4 (3-factor PCC may
be given concomitantly with phytonadione but 4-factor PCC is preferred). Subsequent phytonadione administration is guided by
follow-up INR; if subsequent INR 1.4 within the first 24 to 48 hours after the initial dose, give a repeat dose of phytonadione 10 mg
IV (NCS/SCCM [Frontera 2016]).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric Refer to adult dosing.

Dosing: Pediatric Note: According to the manufacturer, SubQ is the preferred parenteral route; IM route should be avoided due
to the risk of hematoma formation; IV route should be restricted for emergency use only. The American College of Chest Physicians
(ACCP) recommends the IV route in patients with major bleeding secondary to use of vitamin K antagonists (VKAs).

Adequate intake (AI): Oral:

Infants:

0 to 6 months: 2 mcg/day

7 to 12 months: 2.5 mcg/day

Children:

1 to 3 years: 30 mcg/day

4 to 8 years: 55 mcg/day

9 to 13 years: 60 mcg/day

14 to 18 years: 75 mcg/day

Hemorrhagic disease of the newborn:

Prophylaxis: IM: 0.5 to 1 mg within 1 hour of birth

Treatment: IM, SubQ: 1 mg/dose/day; higher doses may be necessary if mother has been receiving oral anticoagulants

Vitamin K deficiency (supratherapeutic INR) secondary to vitamin K antagonists (VKAs) (eg, warfarin) (off-label use): Infants
and Children: Excessively prolonged INR (usually INR >8; no significant bleeding): Note: Limited data available: IV: 0.03
mg/kg/dose; maximum dose: 1 mg (Bolton-Maggs, 2002); if significant bleeding, consider use of fresh frozen plasma, prothrombin
complex concentrates, or recombinant factor VIIa (Monagle, 2012).

Dosing: Renal Impairment No dosage adjustment provided in manufacturers labeling.

Dosing: Hepatic Impairment No dosage adjustment provided in manufacturers labeling.

Use: Labeled Indications Prevention and treatment of hypoprothrombinemia caused by vitamin K antagonist (VKA)-induced
(eg, warfarin-induced) or other drug-induced vitamin K deficiency, altered activity, or altered metabolism; hypoprothrombinemia caused
by malabsorption or inability to synthesize vitamin K; prophylaxis and treatment of hemorrhagic disease of the newborn

* See Uses in AHFS Essentials for additional information.

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Use: Off-Label
Hypoprothrombinemia due to long-acting anticoagulant rodenticides (LAARs) Level of Evidence [C]

Data from a few case reports suggest that phytonadione may be beneficial in the treatment of hypoprothrombinemia caused
by long-acting anticoagulant rodenticides (brodifacoum) Ref. Data from a limited number of patients (case series) also
suggest that phytonadione may be beneficial in this setting Ref. Additional data may be necessary to further define the role of
phytonadione in the treatment of this condition.

Intracranial hemorrhage associated with vitamin K antagonist anticoagulants (eg, warfarin) Level of Evidence [G]

Based on the Neurocritical Care Society and the Society of Critical Care Medicine guideline for reversal of antithrombotics in
intracranial hemorrhage, phytonadione, with 4-factor prothrombin complex concentrate (PCC), is recommended as soon as
possible for vitamin K antagonist-associated intracranial hemorrhage and INR 1.4. Three-factor PCC may be given with
phytonadione but 4-factor PCC is preferred Ref.

Level of Evidence Definitions

Level of Evidence Scale

A - Consistent evidence from well-performed randomized, controlled trials or overwhelming evidence of some other form (eg,
results of the introduction of penicillin treatment) to support the off-label use. Further research is unlikely to change
confidence in the estimate of benefit.

B - Evidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect
or imprecise), or very strong evidence of some other research design. Further research (if performed) is likely to have an
impact on confidence in the estimate of benefit and risk and may change the estimate.

C - Evidence from observational studies (eg, retrospective case series/reports providing significant impact on patient care),
unsystematic clinical experience, or from potentially flawed randomized, controlled trials (eg, when limited options exist
for condition). Any estimate of effect is uncertain.

G - Use has been substantiated by inclusion in at least one evidence-based or consensus-based clinical practice guideline.

Clinical Practice Guidelines

Life-Threatening Hemorrhage:

NCS/SCCM, Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage, 2016

Stroke:

AHA/ASA, Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, July 2015

Valvular Heart Disease:

AHA/ACC, 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease, March 2014

Other:

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition), February 2012

Administration: IV Infuse slowly; rate of infusion should not exceed 1 mg/minute. Alternatively, dilute dose in a minimum of 50
mL of compatible solution and administer using an infusion pump over at least 20 minutes (Ageno, 2012). The injectable route should be
used only if the oral route is not feasible or there is a greater urgency to reverse anticoagulation.

Administration: Injectable Detail pH: 3.5 to 7

Administration: Oral The parenteral formulation may also be used for small oral doses (eg, 1 mg) or situations in which
tablets cannot be swallowed (Crowther 2000; Crowther 2002; OConnor 1986); may administer undiluted or diluted in a beverage (eg,
orange juice) (Vanier 2006).

Storage/Stability
Injection: Store at 15C to 30C (59F to 86F). Protect from light. Note: Store Hospira product at 20C to 25C (68F to 77F).

Oral: Store tablets at 15C to 30C (59F to 86F). Protect from light.

Preparation for Administration Dilute injection solution in preservative-free NS, D5W, or D5NS. To reduce the incidence
of anaphylactoid reaction upon IV administration, dilute dose in a minimum of 50 mL of compatible solution and administer using an

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infusion pump over at least 20 minutes (Ageno, 2012).

Extemporaneously Prepared A 1 mg/mL oral suspension may be made with tablets. Crush six 5 mg tablets in a mortar
and reduce to a fine powder. Add 5 mL each of water and methylcellulose 1% and mix to a uniform paste. Mix while adding sorbitol in
incremental proportions to almost 30 mL; transfer to a calibrated bottle, rinse mortar with sorbitol, and add quantity of sorbitol sufficient
to make 30 mL. Label "shake well" and "refrigerate". Stable for 3 days.

Nahata MC and Hipple TF, Pediatric Drug Formulations, 3rd ed, Cincinnati, OH: Harvey Whitney Books Co, 1997.

Note: The parenteral formulation may also be used for small oral doses (eg, 1 mg) or situations in which tablets cannot be swallowed
(Crowther, 2000; OConnor, 1986); may administer undiluted or diluted in a beverage (eg, orange juice) (Vanier 2006).

Medication Safety Issues

Sound-alike/look-alike issues:

Mephyton may be confused with melphalan, methadone

Contraindications Hypersensitivity to phytonadione or any component of the formulation

Warnings/Precautions
Concerns related to adverse effects:

Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]: Severe reactions resembling hypersensitivity reactions
(eg, anaphylaxis) have occurred rarely during or immediately after IV administration (even with proper dilution and
rate of administration); some patients had no previous exposure to phytonadione. Anaphylactoid reactions typically
occurred when patients received large IV doses administered rapidly with formulations containing polyethoxylated castor oil
(also called polyoxyethylated castor oil); proper dosing, dilution, and administration will minimize risk (Ageno 2012; Riegert-
Johnson 2002). Limit IV administration to situations where an alternative route of administration is not feasible and the benefit
of therapy outweighs the risk of hypersensitivity reactions. Allergic reactions have also occurred with IM and SubQ injections,
albeit less frequently.

Disease-related concerns:

Anticoagulant-induced hypoprothrombinemia: In patients receiving a therapeutic vitamin K antagonist (VKA) (eg, warfarin),
administer a dose of phytonadione that will quickly lower the INR into a safe range without causing resistance to warfarin.
High phytonadione doses may lead to warfarin resistance for at least one week.

Liver disease induced hypoprothrombinemia: If initial doses do not reverse coagulopathy, then higher doses are unlikely to have
any effect. Note: Ineffective in hereditary hypoprothrombinemia.

Long-acting anticoagulant rodenticide (LAAR) ingestion: Patients with LAAR-induced coagulopathy require much larger doses
and longer treatment durations (up to months) after exposure compared to that needed to reverse VKA-induced
coagulopathy.

Special populations:

Neonates: Use with caution in neonates, especially premature infants; severe hemolytic anemia, jaundice, and
hyperbilirubinemia have been reported with larger than recommended doses (10 to 20 mg).

Dosage form specific issues:

Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses,
prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum
intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone
toxicity; tissue loading may occur at lower doses (Federal Register, 2002). See manufacturers labeling.

Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (99
mg/kg/day) have been associated with a potentially fatal toxicity (gasping syndrome) in neonates; the gasping syndrome
consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial
hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that
benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol
with caution in neonates. See manufacturers labeling.

Polyoxyethylated castor oil: Some injectable dosage forms contain polyoxyethylated castor oil (Cremophor EL) which is
associated with hypersensitivity reactions.

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Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a
delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain
individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal
and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80
(Alade, 1986; CDC, 1984). See manufacturers labeling.

Other warnings/precautions:

Appropriate route: Oral administration is the safest and requires the presence of bile salts for absorption. In obstructive jaundice
or with biliary fistulas, concurrent administration of bile salts would be necessary for proper absorption. Manufacturers
recommend the SubQ route over other parenteral routes, however, SubQ is less predictable when compared to the oral
route, and efficacy may be delayed. The American College of Chest Physicians recommends the IV route in patients with
major bleeding secondary to use of VKAs such as warfarin. The IV route should be restricted to emergency situations only
where oral phytonadione cannot be used. Efficacy (eg, control of bleeding, decrease in INR) is delayed regardless of route of
administration; patient management may require other treatments in the interim.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations No special recommendation for use or dosing in elderly.

Pregnancy Risk Factor: US C

Pregnancy Considerations Animal reproduction studies have not been conducted. Phytonadione crosses the placenta in
limited concentrations (Kazzi, 1990). The dietary requirements of vitamin K are the same in pregnant and nonpregnant women (IOM
2000). In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should
be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity
(Bailey 2003).

Breast-Feeding Considerations Small amounts of dietary vitamin K can be detected in breast milk and the dietary
requirements of vitamin K are the same in nursing and non-nursing women (IOM, 2000). Information following the use of phytonadione
has not been located. The manufacturer recommends caution be used if phytonadione is administered to a nursing woman.

Briggs' Drugs in Pregnancy & Lactation

Phytonadione

Adverse Reactions
Frequency not defined.

Cardiovascular: Flushing, hypertension, hypotension

Central nervous system: Dizziness

Dermatologic: Diaphoresis, erythematous rash, pruritus

Gastrointestinal: Dysgeusia, nausea

Hypersensitivity: Anaphylactoid reaction (non-immunologic anaphylaxis), hypersensitivity reaction

Local: Fibrosis at injection site, injection site reaction

Respiratory: Cyanosis, dyspnea

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects None known.

Drug Interactions Open Interactions

Mineral Oil: May decrease the serum concentration of Phytonadione. Specifically, mineral oil may decrease the absorption of
phytonadione. Risk C: Monitor therapy

Orlistat: May decrease the serum concentration of Vitamins (Fat Soluble). Management: Administer oral fat soluble vitamins at least 2
hours before or after the administration of orlistat. Similar precautions do not apply to parenterally administered fat soluble
vitamins. Risk D: Consider therapy modification

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Vitamin K Antagonists (eg, warfarin): Phytonadione may diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider
therapy modification

Genes of Interest
Vitamin K Epoxide Reductase Complex, Subunit 1

Monitoring Parameters PT, INR; monitor for hypersensitivity reactions if administering IV.

Advanced Practitioners Physical Assessment/Monitoring Note dosing specifics according to use. Assess
degree of bleeding.

Nursing Physical Assessment/Monitoring Note dosing specifics according to use. Monitor degree of bleeding.

Dosage Forms Considerations

Injectable products may contain alcohol, benzyl alcohol, polysorbate 80, propylene glycol, or polyoxyethylated/polyethoxylated castor
oil (Cremophor EL).

Dosage Forms Excipient information presented when available (limited, particularly for generics); consult specific product
labeling.

Injection, aqueous colloidal: 1 mg/0.5 mL (0.5 mL); 10 mg/mL (1 mL)

Injection, aqueous colloidal [preservative free]: 1 mg/0.5 mL (0.5 mL)

Tablet, oral: 100 mcg

Mephyton: 5 mg [scored]

Generic Available (US) Yes

Pricing: US
Solution (Phytonadione Injection)

1 mg/0.5 mL (0.5 mL): $21.60

Tablets (Mephyton Oral)

5 mg (100): $7051.21

Disclaimer: The pricing data provide a representative AWP and/or AAWP price from a single manufacturer of the brand and/or
generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set
or adjudicate any prices for reimbursement or purchasing functions. Pricing data is updated monthly.

Mechanism of Action Promotes liver synthesis of clotting factors (II, VII, IX, X); however, the exact mechanism as to this
stimulation is unknown. Menadiol is a water soluble form of vitamin K; phytonadione has a more rapid and prolonged effect than
menadione; menadiol sodium diphosphate (K4) is half as potent as menadione (K3).

Pharmacodynamics/Kinetics
Onset of action: Increased coagulation factors: Oral: 6 to 10 hours; IV: 1 to 2 hours

Peak effect: INR values return to normal: Oral: 24 to 48 hours; IV: 12 to 14 hours

Absorption: Oral: From intestines in presence of bile; SubQ: Variable; IM: Readily

Metabolism: Rapidly hepatic

Excretion: Urine and feces

Local Anesthetic/Vasoconstrictor Precautions No information available to require special precautions

Effects on Dental Treatment Key adverse event(s) related to dental treatment: Abnormal taste.

Effects on Bleeding Phytonadione is a synthetic form of vitamin K and has been used as an antidote to reverse warfarin-
induced bleeding complications or endogenous vitamin K deficiencies.

Related Information
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Reversal of Oral Anticoagulants

Index Terms Methylphytyl Napthoquinone; Phylloquinone; Phytomenadione; Vitamin K; Vitamin K1

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