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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(fye toe na DYE one)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Prevention and treatment of hypoprothrombinemia caused by coumarin derivative-induced or other drug-induced vitamin K deficiency, hypoprothrombinemia caused by malabsorption or inability to synthesize vitamin K; hemorrhagic disease of the newborn
Use: Unlabeled/Investigational
Treatment of hypoprothrombinemia caused by anticoagulant rodenticides
Pregnancy Risk Factor
C
Pregnancy Considerations
Animal reproduction studies have not been conducted.
Lactation
Enters breast milk/use caution (AAP rates "compatible"; AAP 2001 update pending)
Contraindications
Hypersensitivity to phytonadione or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Anaphylaxis/hypersensitivity reactions: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Anaphylaxis/hypersensitivity reactions: [U.S. Boxed Warning]: Severe reactions resembling hypersensitivity (eg, anaphylaxis) reactions have occurred rarely during or immediately after I.V. administration (even with proper dilution and rate of administration). Allergic reactions have also occurred with I.M. and SubQ injections.
Disease-related concerns:
• Anticoagulant induced hypoprothrombinemia: Administer a dose 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.
• Renal impairment: Use with caution in patients with renal impairment (including premature infants).
Special populations:
• Newborns: Use with caution in newborns, especially premature infants; hemolysis, jaundice, and hyperbilirubinemia have been reported with larger than recommended doses.
Dosage form specific issues:
• Aluminum: Injectable products may contain aluminum; may result in toxic levels following prolonged administration.
• Benzyl alcohol: Some dosage forms contain benzyl alcohol which has been associated with "gasping syndrome" in neonates.
• Polysorbate 80: Product may contain polysorbate 80.
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 I.V. route in patients with serious or life-threatening bleeding secondary to use of vitamin K antagonists such as warfarin. The I.V. 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.
Adverse Reactions
Parenteral administration: Frequency not defined.
Cardiovascular: Cyanosis, flushing, hypotension
Central nervous system: Dizziness
Dermatologic: Scleroderma-like lesions
Endocrine & metabolic: Hyperbilirubinemia (newborn; greater than recommended doses)
Gastrointestinal: Abnormal taste
Local: Injection site reactions
Respiratory: Dyspnea
Miscellaneous: Anaphylactoid reactions, diaphoresis, hypersensitivity reactions
Drug 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
Vitamin K Antagonists (eg, warfarin): Phytonadione may diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification
Storage
Injection: Store at 15°C to 30°C (59°F to 86°F). Note: Store Hospira product at 20°C to 25°C (68°F to 77°F).
Oral: Store tablets at 15°C to 30°C (59°F to 86°F). Protect from light.
Reconstitution
Dilute injection solution in preservative-free NS, D5W, or D5NS.
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: 6-10 hours; I.V.: 1-2 hours
Peak effect: INR values return to normal: Oral: 24-48 hours; I.V.: 12-14 hours
Absorption: Oral: From intestines in presence of bile; SubQ: Variable
Metabolism: Rapidly hepatic
Excretion: Urine and feces
Dosage
Note: According to the manufacturer, SubQ is the preferred parenteral route; I.M. route should be avoided due to the risk of hematoma formation; I.V. route should be restricted for emergency use only. The American College of Chest Physicians recommends the I.V. route in patients with serious or life-threatening bleeding secondary to use of vitamin K antagonists.
Adequate intake:
Children:
1-3 years: 30 mcg/day
4-8 years: 55 mcg/day
9-13 years: 60 mcg/day
14-18 years: 75 mcg/day
Adults: Males: 120 mcg/day; Females: 90 mcg/day
Hemorrhagic disease of the newborn:
Prophylaxis: I.M.: 0.5-1 mg within 1 hour of birth
Treatment: I.M., SubQ: 1 mg/dose/day; higher doses may be necessary if mother has been receiving oral anticoagulants
Hypoprothrombinemia due to drugs (other than coumarin derivatives) or factors limiting absorption or synthesis: Adults: Oral, SubQ, I.M., I.V.: Initial: 2.5-25 mg (rarely up to 50 mg)
Vitamin K deficiency (supratherapeutic INR) secondary to coumarin derivative (Ansell, 2008): Adults:
If INR above therapeutic range to <5 (no significant bleeding and rapid reversal unnecessary):
Lower or hold next dose and monitor frequently; when INR approaches desired range, resume dosing with a lower dose.
If INR ≥5 and <9 (no significant bleeding):
If no risk factors for bleeding exist, omit next 1 or 2 doses, monitor INR more frequently, and resume with an appropriately adjusted dose when INR in desired range.
Alternatively, if other risk factors for bleeding exist, omit next dose and administer vitamin K orally 1-2.5 mg; resume with an appropriately adjusted dose when INR in desired range.
If INR ≥5 and <9 (no significant bleeding and rapid reversal required for surgery):
Administer vitamin K orally ≤5 mg and hold warfarin. Expect INR to be reduced within 24 hours; if INR still elevated, another 1-2 mg of vitamin K orally may be given.
If INR ≥9 (no significant bleeding):
Hold warfarin, administer vitamin K orally 2.5-5 mg, expect INR to be reduced within 24-48 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.
If serious bleeding at any INR elevation:
Hold warfarin, administer vitamin K 10 mg by slow I.V. infusion and supplement with FFP, PCC, or rFVIIa depending on the urgency of the situation; I.V. Vitamin K may be repeated every 12 hours.
If life-threatening bleeding:
Hold warfarin, give FFP, PCC, or rFVIIa supplemented with vitamin K 10 mg slow I.V. infusion; repeat if necessary, depending on INR.
Notes:
If mild-moderate INR elevation without major bleeding occurs, administer vitamin K orally instead of subcutaneously.
Use of high doses of vitamin K (eg, 10-15 mg) may cause warfarin resistance for ≥1 week. During this period of resistance, heparin or low molecular weight heparin may be given until INR responds.
FFP=fresh frozen plasma; PCC=prothrombin complex concentrate; rFVIIa=recombinant factor VIIa
Administration: Oral
The parenteral preparation has been administered orally to neonates.
Administration: I.V.
Infuse slowly; rate of infusion should not exceed 1 mg/minute (3 mg/m2/minute in children and infants). The injectable route should be used only if the oral route is not feasible or there is a greater urgency to reverse anticoagulation.
Administration: I.V. Detail
pH: 3.5-7.0
Monitoring Parameters
PT, INR
Patient Education
Oral: Consult prescriber for recommended diet. Report bleeding gums; blood in urine, stool, or vomitus; unusual bruising or bleeding; or abdominal cramping.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Abnormal taste.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May rarely cause dizziness
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Note dosing specifics according to use. Assess degree of bleeding.
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) [contains benzyl alcohol]; 10 mg/mL (1 mL) [contains benzyl alcohol]
Injection, aqueous colloidal [preservative free]: 1 mg/0.5 mL (0.5 mL) [contains polysorbate 80, propylene glycol 10.4 mg/0.5 mL]
Tablet, oral: 100 mcg
Mephyton®: 5 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Mephyton)
5 mg (30): $244.00
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.
References
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
Andersen P and Godal HC, “Predictable Reduction in Anticoagulant Activity of Warfarin by Small Amounts of Vitamin K,” Acta Med Scand, 1975, 198:269-70.
Ansell J, Hirsh J, Hylek E, et al, “Pharmacology and Management of the Vitamin K Antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):160-98.
Barash P, Kitahata LM, and Mandel S, “Acute Cardiovascular Collapse After Intravenous Phytonadione,” Anesth Analg, 1976, 55(2):304-6.
Broderick J, Connolly S, Feldmann E, et al, "Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group," Stroke, 2007, 38(6):2001-23.
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. A Randomized, Controlled Trial," Ann Intern Med, 2002, 137(4):251-4.
"Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc," Food and Nutrition Board, Institute of Medicine. National Academy of Sciences, Washington, DC: National Academy Press, 2001, 162-84.
Fiore LD, Scola MA, Cantillon CE, et al, "Anaphylactoid Reactions to Vitamin K," J Thromb Thrombolysis, 2001, 11(2): 175-83.
Harrell CC and Kline SS, “Oral Vitamin K1: An Option to Reduce Warfarin's Activity,” Ann Pharmacother, 1995, 29(12):1228-32.
Hirsh J, Guyatt G, Albers GW, et al, “Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):71-109.
Hopkins CS, “Adverse Reaction to a Cremophor-Containing Preparation of Intravenous Vitamin K,” Intensive Therapy Clin Monit, 1988, 9:254-5.
Martinez-Abad M, Delgado F, Palop V, et al, “Vitamin K1 and Anaphylactic Shock,” DICP, 1991, 25(7-8):871-2.
Monagle P, Michelson AD, Bovill E, et al, “Antithrombotic Therapy in Children,” Chest, 2001, 119(1 Suppl):344-70.
Shearer MJ, “Vitamin K,” Lancet, 1995, 345(8944):229-34.
Watt BE, Proudfoot AT, Bradberry SM, et al, "Anticoagulant Rodenticides," Toxicol Rev, 2005, 24(4):259-69.
Weibert RT, Le DT, Kayser SR, et al, "Correction of Excessive Anticoagulation With Low-Dose Oral Vitamin K1," Ann Intern Med, 1997, 126(12):959-62.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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