Summary Of Exposure |
A) USES: Vitamin K1 is indicated for the following coagulation disorders due to factors II, VII, IX and X when caused by vitamin K deficiency. It is also used to treat anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives and hypoprothrombinemia secondary to antibacterial therapy, salicylates, obstructive jaundice or biliary fistulas. Vitamin K3 (menadione) is no longer available in the US.
B) PHARMACOLOGY: Phytonadione (vitamin K1), a 2-methyl-3-phytyl-1, 4-naphthoquinone, has the same activity as naturally occurring vitamin K1. Vitamin K is an essential cofactor for a microsomal enzyme that catalyzes the posttranslational carboxylation of multiple, specific peptide bound glutamine acid residues in inactive hepatic precursors of factors, II, VII, IX and X which converts the precursors into active coagulation factors that are subsequently secreted by liver cells into the blood. In healthy individuals, oral phytonadione is virtually devoid of pharmacodynamic activity, however, if an individual is deficient in vitamin K, the administration of vitamin K will promote the hepatic biosynthesis of vitamin K-dependent clotting factors.
C) TOXICOLOGY: Phytonadione is not a clotting agent, but excessive therapy with vitamin K may reproduce the underlying conditions that caused the thromboembolic event.
D) EPIDEMIOLOGY: Exposure is uncommon; premature neonates may be at greatest risk to develop hemolysis or hyperbilirubinemia following parenteral overdose.
E) WITH THERAPEUTIC USE
1) ADVERSE EVENTS: Most adverse events have been reported with parenteral administration. Transient flushing, alterations in taste, dizziness, diaphoresis, dyspnea, brief hypotension and cyanosis have occurred with parenteral administration.
2) NEONATES: The parenteral product contains aluminum and benzyl alcohol, which may produce toxicity following prolonged exposure in premature neonates. Hyperbilirubinemia (rare finding) has occurred following parenteral administration in premature infants, usually due to excessive dosing.
3) INJECTION SITE: Pain, swelling and tenderness can occur at the injection site.
4) SEVERE: INTRAVENOUS or INTRAMUSCULAR USE: Reactions typically resemble hypersensitivity or anaphylaxis, including shock and cardiac and/or respiratory arrest can develop. Fatalities have occurred. Therefore, IV or IM use should be restricted to those situations where SubQ administration is not feasible and the benefit outweighs the risk. Acute cardiovascular collapse, appears to be related to rapid rates of infusion (greater than 1 mg/min) in most cases.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Overdose events are anticipated to be similar to adverse events reported with therapy. Events that may require intervention are likely due to parenteral administration.
2) SEVERE TOXICITY: Severe hypersensitivity and/or anaphylaxis, including fatalities, can occur with parenteral exposure.
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Vital Signs |
3.3.1) SUMMARY
A) Hypotension and a weak rapid pulse may occur following IV injection of phytonadione (Prod Info VITAMIN K1 injection, 2004).
3.3.4) BLOOD PRESSURE
A) Hypotension may occur precipitously following intravenous injection of phytonadione (Prod Info VITAMIN K1 injection, 2004).
3.3.5) PULSE
A) A weak and rapid pulse may rarely occur with parenteral phytonadione therapy (Prod Info VITAMIN K1 injection, 2004)
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Cardiovascular |
3.5.1) SUMMARY
A) Phytonadione intravenous injections have resulted in acute cardiovascular collapse with precipitous hypotension, and asystole in some cases, within minutes of injection. Chest pain and dyspnea were reported in some patients.
3.5.2) CLINICAL EFFECTS
A) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Several cases of acute cardiovascular collapse, with precipitous hypotension, bradycardia, and asystole in some cases, within 5 minutes of bolus intravenous injection of phytonadione, have been reported (Songy & Layon, 1997; Barash et al, 1976; Rich & Drage, 1982; Lefrere & Girot, 1987). In one case report, the authors believed that an allergic reaction to vitamin K may have caused the cardiovascular collapse observed in this patient (Songy & Layon, 1997). Severe reactions, such as cardiac and respiratory arrest, have resembled hypersensitivity or anaphylaxis (Prod Info Aquamephyton(R), phytonadione, 2001).
b) CASE REPORT: In three cases, the rate of infusion was 1 mg/min, and in one case 5 mg/min. Reinstitution of a slow infusion over one hour was subsequently tolerated in one patient (Barash et al, 1976).
c) These reactions have been attributed to the Cremophor(R) solvent in the phytonadione preparation.
B) CHEST PAIN 1) WITH THERAPEUTIC USE a) Chest pain has been reported after rapid intravenous infusion of phytonadione (Prod Info MEPHYTON(R) oral tablets, 2008; Rich & Drage, 1982).
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Respiratory |
3.6.1) SUMMARY
A) Dyspnea has been reported after rapid intravenous infusion of phytonadione.
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) Dyspnea has been reported after rapid IV infusion of phytonadione (Prod Info VITAMIN K1 injection, 2004; Rich & Drage, 1982).
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Neurologic |
3.7.1) SUMMARY
A) Seizures have been rarely reported following intravenous phytonadione injection.
3.7.2) CLINICAL EFFECTS
A) CEREBRAL THROMBOSIS 1) WITH THERAPEUTIC USE a) CASE REPORT: Two patients with chronic intestinal inflammation and malabsorption syndromes developed cerebral thrombosis 12 days after receiving vitamin K 10 mg IM or IV for correction of severe deficiency of vitamin K-dependent clotting factors. It was suggested that patients with longstanding vitamin K deficiency due to coeliac disease or chronic inflammatory intestinal disease be treated only with small doses of vitamin K for bleeding (Florholmen et al, 1980).
B) SEIZURE 1) WITH THERAPEUTIC USE a) CASE REPORT: A single seizure was possibly associated with the administration of 50 mg IV of vitamin K1 oxide to a 65-year-old woman following warfarin overdose (BCDSP, 1972).
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Gastrointestinal |
3.8.1) SUMMARY
A) Transient nausea may occur following injection.
3.8.2) CLINICAL EFFECTS
A) NAUSEA 1) WITH THERAPEUTIC USE a) Transient low back pain and nausea were described after 100 mg IV menadiol sodium diphosphate (Turner, 1959).
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Hepatic |
3.9.1) SUMMARY
A) Hyperbilirubinemia has been associated with administration of large parenteral doses of menadione to neonates, and with IV menadiol in adults with infectious hepatitis.
3.9.2) CLINICAL EFFECTS
A) HYPERBILIRUBINEMIA 1) WITH THERAPEUTIC USE a) Increased serum bilirubin and hemolysis were observed in both premature and full term infants given 10 to 50 mg of menadione IM compared to infants who did not receive vitamin K. These adverse effects are suspected to be due to excessive dosage (Meyer & Angus, 1956).
b) CASE SERIES: A dose-related increase in the incidence of kernicterus of prematurity was described, with an incidence of 0.5% to 2.1% at total doses of 1 to 2 mg, 1.2% to 1.6% at 10 mg, 0.4% to 1.1% at 30 mg, and 3.6% to 4.1% at greater than 30 mg of menadione (Crosse et al, 1955).
c) CASE SERIES: In another study, 40% of premature infants receiving 30 mg of menadione had bilirubin levels of 18 mg/dL or greater compared to 3.9% of those receiving 1 mg (Bound & Telfer, 1956).
d) Hyperbilirubinemia has been transiently observed in adults with infectious hepatitis following large IV doses of menadiol sodium diphosphate (Gottsegen, 1956).
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Genitourinary |
3.10.1) SUMMARY
A) Acute renal failure was reported in animals receiving parenteral menadione.
3.10.2) CLINICAL EFFECTS
A) ACUTE RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) CASE REPORT: A 24-year-old renal allograft recipient developed prolonged nonoliguric acute renal failure after inadvertently receiving an excessive dose of IV vitamin K2 (menaquinone) (100 mg) immediately following the transplant. Renal biopsy performed 130 days posttransplant revealed normal glomeruli, tubules, and vessels (Chung et al, 1994).
3.10.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) RENAL FAILURE ACUTE a) Acute renal failure has been reported in animals (horses and cattle) given parenteral doses of 2 to 8 mg/kg of menadione (Rebhun et al, 1984).
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Hematologic |
3.13.1) SUMMARY
A) Heinz body hemolytic anemia has been associated with excessive parenteral doses of menadiol in neonates.
B) Paradoxical worsening of hypoprothrombinemia has been reported following administration of menadiol to patients with severe liver disease.
3.13.2) CLINICAL EFFECTS
A) HEMOLYTIC ANEMIA 1) WITH THERAPEUTIC USE a) Hemolytic anemia has been associated with the use of excessive doses of menadiol (10 mg or greater) in premature infants (Finkel, 1961; Allison, 1955).
b) HEINZ BODIES were found in up to 67% of circulating red cells in premature infants who received menadiol sodium diphosphate 30 mg/day (Allison, 1955).
B) PROTHROMBIN TIME LOW 1) WITH THERAPEUTIC USE a) HYPOPROTHROMBINEMIA: Paradoxical worsening of hypoprothrombinemia has been reported following the use of menadiol in patients with severe liver disease (Gupta & Banerji, 1967; Richards & Shapiro, 1945).
3.13.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) METHEMOGLOBINEMIA a) DOGS given massive doses of menadione sodium bisulfite developed methemoglobinemia and cyanosis, with evidence of hepatic damage on postmortem examination (Richards & Shapiro, 1945).
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Dermatologic |
3.14.1) SUMMARY
A) Dermatologic reactions have included a delayed (generally 1 to 2 weeks) pruritic, erythematous eruption at sites of injection, occasionally with persistence of pruritus. A chronic progressive scleroderma-like reaction has also been described.
B) Occupational contact dermatitis to menadione and menadiol has been reported.
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) PHYTONADIONE 1) Phytonadione administration has resulted in generalized skin eruptions (Prod Info MEPHYTON(R) oral tablets, 2008; Balato et al, 1998; Pigatto et al, 1990; Joyce et al, 1988; Finkelstein et al, 1987; Texier et al, 1972; Honda et al, 1970; Anekoji, 1970).
2) A delayed cutaneous reaction was reported in 2 patients beginning 1 to 2 weeks after intramuscular injection of phytonadione 10 to 20 mg. Pruritic, erythematous, confluent macular lesions were described at the intramuscular injection site of 2 patients. The reaction persisted 3 and 6 months later, despite therapy with corticosteroids and antihistamines (Joyce et al, 1988).
3) Generalized skin eruptions have been associated with the intravenous administration of phytonadione (Honda et al, 1970; Anekoji, 1970).
4) CASE SERIES: An acute onset (2 to 14 days) of a local cutaneous reaction was described in 6 patients. Pruritic, erythematous, eczematoid, indurated plaques appeared, resolving within 2 to 4 weeks. Continued pruritus persisted at the affected sites (Finkelstein et al, 1987).
5) CASE REPORT: A 9-year-old child developed pruritic bilateral erythematous vesicular lesions of the buttocks after injection of Konakion(R) (3 vials/day for 10 days). Patch tests revealed response to phytomenadione only. The dermatopathy disappeared when vitamin K injections were discontinued; subsequent oral therapy did not produce reaction (Pigatto et al, 1990).
b) SCLERODERMA 1) This condition has been called "Texier's disease" after an early report of this reaction. It typically involves progressive sclerotic plaques extending from the upper buttock to lateral aspects of both thighs and around the waist, resembling a cowboy gunbelt and holster (Texier et al, 1972). a) CASE REPORT: A 66-year-old woman developed erythematous, indurated, large plaques on the lateral thighs 18 weeks after receiving 13 10-mg injections of phytomenadione. Twelve months later, the hardened plaques were still present, and histopathology revealed diffuse, mild infiltration with lymphocytes, eosinophils, and mast cells (Brunskill et al, 1988).
b) CASE REPORT: Two men separately treated with phytonadione developed symmetrical, indurated plaques at the site of injection 8 and 15 months later. Histopathology revealed sclerosis of the reticular dermis indistinguishable from deep morphea or scleroderma (Pujol et al, 1989).
c) CASE REPORT: Subcutaneous sclerosis and eosinophilia were reported after injection of 100 mg IM phytonadione in a 62-year-old man. Lesions evolved over 5 weeks to 18 months postinjection, and slowly resolved over 3 years with local corticosteroid therapy (Janin-Mercier et al, 1985).
c) MENATRETRENONE 1) MENATRETRENONE (Vitamin K2) administration has resulted in delayed cutaneous reactions: a) CASE SERIES: Delayed cutaneous reactions were reported after local injection in four cases; all had positive intradermal skin tests to the drug and negative tests to the vehicle (Tsuboi & Ogawa, 1988).
d) MENADIONE SODIUM BISULFITE 1) MENADIONE SODIUM BISULFITE exposure has resulted in contact dermatitis: a) CASE SERIES: Occupational contact dermatitis has been reported in employees of pharmaceutical or veterinary laboratories, or in the preparation of animal feeds. Cross-reactions to vitamin K4 (menadiol sodium diphosphate) have occurred in some cases (Dinis et al, 1988; Romaguera et al, 1980; Camarasa & Barnadas, 1982).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ANAPHYLACTOID REACTION 1) WITH THERAPEUTIC USE a) SUMMARY: Severe reactions including fatalities have occurred immediately after IV or IM administration. Symptoms, including fatalities, resemble anaphylaxis or severe hypersensitivity reactions (ie, shock, cardiac and/or respiratory arrest). Therefore, the manufacturer recommends that the IV or IM routes be limited to settings where the SubQ route is not feasible and the serious risk has been considered (Prod Info VITAMIN K1 injection, 2004).
b) CASE REPORT: A 74-year-old woman developed facial flush, dyspnea, hypotension, cyanosis, and loss of consciousness immediately after receiving 10 mg phytomenadione IV (rate of infusion unknown) as the 14th of 16 treatments. She recovered from anaphylaxis in a few minutes without treatment, and vitamin K therapy was discontinued (Martinez-Abad & Delgado, 1991).
c) In one case report, an allergic reaction to vitamin K was associated with cardiovascular collapse (Songy & Layon, 1997).
B) ACUTE ALLERGIC REACTION 1) WITH THERAPEUTIC USE a) SUMMARY: Severe reactions including fatalities have occurred immediately after IV or IM administration. Symptoms, including fatalities, resemble anaphylaxis or severe hypersensitivity reactions (ie, shock, cardiac and/or respiratory arrest). Therefore, the manufacturer recommends that the IV or IM routes be limited to settings where the SubQ route is not feasible and the serious risk has been considered (Prod Info VITAMIN K1 injection, 2004). b) CASE SERIES: Two patients experienced cutaneous hypersensitivity reactions after receiving fat-soluble vitamin K (K1) parenterally. One woman developed red, raised, pruritic lesions at the injection sites. Another woman developed round, red, slightly indurated, warm plaques on the right thigh and both hips (Chung et al, 1999). 1) Cutaneous side-effects (an erythematous plaque or pseudo-scleroderma at the injection site) of IM or SubQ administered fat-soluble vitamin K1 have been reported in patients with liver function disturbances, as well as, in patients without liver disease. The mechanism of action is probably a delayed-type hypersensitivity reaction (Balato et al, 1998; Bruynzeel et al, 1995).
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Reproductive |
3.20.1) SUMMARY
A) Menadione and phytonadione are classified as risk factor C. Menadione is no longer available in the US. It had been classified as risk factor X if used in the third trimester or close to delivery.
3.20.2) TERATOGENICITY
A) ANIMAL STUDIES 1) Animal reproduction studies have not been conducted with vitamin K1 (Prod Info MEPHYTON(R) oral tablets, 2008; Prod Info VITAMIN K1 injection, 2004)
3.20.3) EFFECTS IN PREGNANCY
A) LACK OF INFORMATION 1) It is not known if vitamin K1 causes fetal harm when administered to a pregnant woman. Vitamin K1 administration is only recommended if clearly needed in a pregnant woman (Prod Info MEPHYTON(R) oral tablets, 2008; Prod Info VITAMIN K1 injection, 2004).
B) PREGNANCY CATEGORY 1) Phytonadione is classified as FDA pregnancy category C (Prod Info MEPHYTON(R) oral tablets, 2008; Prod Info VITAMIN K1 injection, 2004).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) It is not known if phytonadione is excreted in human milk (Prod Info MEPHYTON(R) oral tablets, 2008; Prod Info VITAMIN K1 injection, 2004).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) CARCINOMA 1) Various reports have suggested that the prophylactic use of vitamin K intramuscularly in neonates may be associated with an increased risk of the development of childhood cancers. Although some positive results were found, most studies did not show a significant association between childhood cancer and vitamin K (Tripp & Mcninch, 1998; Passmore et al, 1998; Parker et al, 1998; Brousson & Klein, 1996; Henderson-Smart, 1996).
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