Vitamin K

VITAMIN K

General Monograph,

Phytonadione

Hypoprothrombinemia Therapy

Action And Clinical Pharmacology: Vitamin K compounds are fat soluble naphthoquinones. Phytonadione (vitamin K1) and vitamin K2 occur in a variety of natural materials and are synthesized by certain bacteria in the gastrointestinal tract; however, commercially prepared phytonadione is synthetically produced. Phytonadione possesses essentially the same type and degree of activity as naturally occurring vitamin K1.

Vitamin K is necessary for synthesis in the liver of factor II (prothrombin), factor VII (proconvertin), factor IX (thromboplastin), and factor X. Deficiency of vitamin K or disturbances of liver function may lead to deficiencies of these factors. When the prothrombin level falls to about 10 to 15% of normal, even slight trauma may cause bleeding; when the level is below 10%, spontaneous hemorrhage may occur, in the form of hematoma, hematemesis, hematuria or melena. The mechanism by which vitamin K promotes formation in the liver of clotting factors II, VII, IX, and X is not known.

Vitamin K deficiency may occur in patients with biliary obstruction or other conditions limiting absorption of vitamin K such as celiac disease, ulcerative colitis, sprue, regional enteritis, cystic fibrosis, intestinal resection, and in patients receiving drugs that may affect liver function or intestinal flora.

Pharmacokinetics: Phytonadione is absorbed from the gastrointestinal tract only in the presence of bile salts and pancreatic lipase. Once absorbed, vitamin K accumulates in the liver, spleen, and lungs, but significant amounts are not stored in the body for long periods.

The action of phytonadione, when administered parenterally, is generally detectable within 1 or 2 hours and hemorrhage is usually controlled within 3 to 8 hours. A normal prothrombin level may often be obtained in 12 to 14 hours.

Indications And Clinical Uses: Phytonadione is used in the prevention and treatment of hypoprothrombinemia caused by vitamin K deficiency, oral anticoagulants, or other factors which impair the absorption or synthesis of vitamin K. Phytonadione is also used in the prevention and treatment of hemorrhagic disease of the newborn.

Phytonadione may have a role in restoring normal clotting time in patients with hypoprothrombinemia induced by salicylates, sulfonamides, quinidine, quinine or broad-spectrum antibiotics, when interference with vitamin K activity is clearly the cause.

Contra-Indications: Hypersensitivity to vitamin K.

Manufacturers’ Warnings In Clinical States: Severe reactions, including fatalities, have occurred during and immediately after i.v. phytonadione injection even when precautions have been taken to dilute the phytonadione solution and to avoid rapid infusion. These severe reactions, which may occur in patients receiving phytonadione for the first time, resemble hypersensitivity or anaphylaxis, including shock and cardiac or respiratory arrest. Therefore, use of the i.v. route should be restricted to those situations where other routes are not feasible and the serious risk involved is considered justified.

Benzyl alcohol contained in some products has been associated with toxicity in newborns. Toxicity appears to have resulted from administration of large amounts (100 to 400 mg/kg daily) of benzyl alcohol in these neonates. Products containing benzyl alcohol should be used cautiously in newborns who are also receiving other benzyl alcohol-containing medications. In each case, the attending physician must weigh the potential benefits against the possible risks.

Precautions: Because the liver is the site of prothrombin biosynthesis, hypoprothrombinemia resulting from hepatocellular damage is not corrected by administration of vitamin K. Repeated large doses of vitamin K are not warranted in liver disease if the response to initial use of the vitamin is unsatisfactory. Failure to respond to vitamin K may indicate that a coagulation defect exists or that the condition is unresponsive to vitamin K.

Vitamin K does not counteract the anticoagulant effect of heparin. Dietary supplements high in vitamin K (³0.7 mg/day) can block the effect of oral anticoagulants.

Vitamin K1 promotes the synthesis of prothrombin by the liver but does not directly reverse the effects of oral anticoagulants. Immediate coagulant effect should not be expected. It takes up to 2 hours for a measurable improvement in the prothrombin time. Whole blood or component therapy may also be necessary if bleeding is severe or if there is no response to phytonadione. Vitamin K1 is not a clotting agent, but overzealous therapy with phytonadione may restore conditions which originally permitted thromboembolic phenomena. Keep dosage as low as possible, and check prothrombin time regularly as clinical conditions indicate.

Newborns should be observed for vitamin K deficiency. The incidence of vitamin K deficiency is higher in breast-fed infants. This increase may be partly due to lower concentrations of vitamin K in human milk than in cow’s milk formula or it may be due to the smaller volume of milk infants may receive in their first few days of life, especially those exclusively breast-fed. Therefore, because an infant’s milk intake cannot be predicted at birth, it is recommended that vitamin K prophylaxis be given to all newborns.

Drug Interactions: Anticoagulants (coumarin): Anticoagulant effects are antagonized by vitamin K. Temporary resistance to prothrombin depressing anticoagulants may result from vitamin K administration, especially when relatively large doses have been given. Therefore, when reinstituting anticoagulant therapy, it may be necessary to use larger doses of the prothrombin depressing anticoagulant or to use one that acts on a different principle, such as heparin.

Broad Spectrum Antibiotics, Quinidine, Quinine and High Dose Salicylates: Requirements for vitamin K may be increased. (see Indications).

Children: In newborns, particularly premature infants, hyperbilirubinemia and hemolytic anemia have been reported. The risk is much less with phytonadione than other vitamin K preparations unless high doses (10 to 20 mg) are given.

Pregnancy: Inadequate information exists as to whether vitamin K may affect fertility in human males or females or have a teratogenic potential or other adverse effect on the fetus. Large amounts of vitamin K in pregnancy, however, can cause jaundice in the newborn.

Lactation: Vitamin K may appear in human breast milk. Problems in humans have not been reported with the intake of normal daily requirements.

Adverse Reactions: Deaths have occurred following i.v. administration of phytonadione (see Warnings).

Transient flushing sensations and peculiar sensations of taste have been observed following phytonadione injection as well as rare instances of dizziness, rapid and weak pulse, profuse sweating, brief hypotension, dyspnea, and cyanosis. Bronchospasm, shock, cardiac and/or respiratory arrest may also occur.

Pain, swelling, and tenderness at the injection site may occur. The possibility of allergic sensitivity (i.e., rash, urticaria), including an anaphylactoid reaction, should be kept in mind.

Large doses of vitamin K or its analogues may further depress liver function in patients with severe hepatic disease and thereby further decrease the concentration of prothrombin.

Neonates: In infants (particularly premature babies), excessive doses of vitamin K analogs during the first few days of life may cause hyperbilirubinemia; this in turn may result in severe hemolytic anemia, hemoglobinuria, kernicterus, leading to brain damage or even death. Immaturity is apparently an important factor in toxic reactions to vitamin K analogs, as full term and larger premature infants show greater tolerance than smaller premature infants.

Dosage And Administration: Minimum daily requirements of vitamin K have not been fully established. They have been estimated at 1 to 5 g/kg for infants and 0.03 g/kg for adults. Dietary abundance of vitamin K normally satisfies these requirements, except for a neonatal period of 5 to 8 days during which the intestinal flora is not yet fully established.

Dose, frequency of administration, and duration of treatment with vitamin K depend on the severity of the prothrombin deficiency and the response of the patient.

At present only an injectable form of vitamin K1 (phytonadione) is available commercially. Phytonadione is intended for i.m., s.c. or i.v. injection, but has been administered orally. The i.v. route is indicated only when other routes of administration are not feasible (see Warnings).

In older children and adults, i.m. injection should be made in the upper outer quadrant of the buttocks. In infants and young children, the anterolateral aspect of the thigh or the deltoid region is preferred.

When i.v. administration is considered unavoidable, phytonadione should be injected very slowly, at a rate not exceeding 1 mg/minute.

Anticoagulant-Induced Hypoprothrombinemia: In less urgent situations, withdrawal or reduction of the dose of anticoagularnt may be sufficient. When phytonadione is used, it is important to use the lowest effective dose.

Adults: 2.5 to 10 mg i.m. or s.c. Rarely, higher doses of up to 25 to 50 mg have been required. The dose may be repeated if necessary after 6 to 8 hours. In cases of severe bleeding, higher doses may be required in conjunction with other measures such as replacement of clotting factors.

Children: 2.5 to 10 mg i.m. or s.c.; may be repeated in 6 to 8 hours.

Infants: 1 to 2 mg i.m. or s.c.; may be repeated in 4 to 8 hours.

Hemorrhagic Disease of the Newborn: Prophylaxis: In its 1997 clinical practice guidelines on vitamin K administration, the Canadian Paediatric Society recommends that vitamin K1 be given as a single i.m. injection to all newborns within 6 hours of birth, at a dose of 1 mg for infants with a birthweight of >1 500 g and 0.5 mg if birthweight is £1 500 g. The guidelines recommend the oral route only when the parents refuse an i.m. injection for the newborn. The recommended oral dose is 2 mg, given at the time of first feeding, and again at 2 to 4 weeks and 6 to 8 weeks of age, for a total of 3 doses. The importance of the follow-up doses should be stressed with the parents.

At present, there is no commerically available oral formulation of vitamin K1; however, the injectable formulation has been used orally.

Treatment: Vitamin K1 1 mg i.m. or s.c.

Hypoprothrombinemia from Other Causes: When other drug therapy is the cause, discontinuation or reduction of the dosage of drug is suggested as an alternative to administering phytonadione. The severity of the coagulation disorder should determine whether the immediate administration of vitamin K is required in addition to discontinuation or reduction of dose of interfering drug(s).

Adults: A dosage of 2.5 to 25 mg or more (rarely up to 50 mg) is recommended; the dose and route of administration should be based on the severity of the condition and patient response.

Children: For the treatment of hypoprothrombinemia, the dose for infants is 2 mg and for older children, 5 to 10 mg.

Total Parenteral Nutrition: For prevention of hypoprothrombinemia, the adult dosage is 5 to 10 mg i.m. weekly, and the dosage for children is 2 to 5 mg i.m. weekly.

VITAMIN K General Monograph, Phytonadione Hypoprothrombinemia Therapy

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