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phytonadione 5 mg tablet generic mephyton

Out of Stock Manufacturer AMNEAL PHARMACE 69238105101
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Uses

Phytonadione is used in the prevention and treatment of hypoprothrombinemia caused by vitamin K deficiency. Phytonadione is more effective and is preferred to other vitamin K preparations in the presence of impending or actual hemorrhage. However, because phytonadione may require 3 hours or longer to stop active bleeding, administration of fresh whole blood or plasma may be necessary when bleeding is severe.

Anticoagulant-induced Hypoprothrombinemia

Phytonadione is the drug of choice for the treatment of moderate or severe hemorrhage caused by overdosage of coumarin or indandione derivatives, but it will not antagonize the anticoagulant action of heparin. Withdrawal of the oral anticoagulant usually corrects excessively prolonged prothrombin time or minor hemorrhage. If excessive phytonadione dosage is used, near-normal prothrombin times produced may restore the conditions that originally required administration of anticoagulant drugs, and large doses of coumarin or indandione anticoagulants may be required to reinstitute anticoagulant therapy. If anticoagulation is needed following overdosage of phytonadione, heparin may be used.

Hemorrhagic Disease of the Newborn

Phytonadione is used in the prevention and treatment of hemorrhagic disease of the newborn and is also effective in the prevention of neonatal hemorrhage resulting from anticonvulsant therapy during pregnancy. The American Academy of Pediatrics (AAP) recommends that phytonadione be routinely administered IM to infants at birth to prevent hemorrhagic disease of the newborn. Some clinicians recommend that phytonadione be administered during the last month of pregnancy (from the 36th week of gestation until delivery) to women receiving anticonvulsant therapy; however, the efficacy of such therapy has not been clearly established. Neonates whose mothers received phytonadione during pregnancy should also receive phytonadione at birth.

Hypoprothrombinemia from Other Causes

Phytonadione is used in the treatment of hypoprothrombinemia secondary to factors limiting absorption or synthesis of Vitamin K. Although dietary sources of vitamin K are usually adequate (except during the first 5-8 days of the neonatal period), deficiency can occur in infants who are breast-fed and in patients receiving prolonged hyperalimentation, as well as in the presence of malabsorption syndromes such as sprue, celiac disease, ulcerative colitis, regional enteritis, cystic fibrosis, prolonged diarrhea, obstructive jaundice, internal biliary fistula, dysentery, and after extensive bowel resection. Diagnosis of vitamin K deficiency may be based on tests for vitamin K-dependent clotting factors (e.g., prothrombin time, which is sensitive to the levels of factors II, VII, and X) or on a therapeutic trial of phytonadione.

Phytonadione may also be valuable in restoring normal clotting time in hypoprothrombinemia induced by salicylates, sulfonamides, quinine, quinidine, or broad-spectrum antibiotic therapy, when it is definitely caused by interference with vitamin K activity. If possible, discontinuance or reduction of the dosage of drugs interfering with the coagulation mechanism should be used as an alternative to phytonadione therapy.

Phytonadione is ineffective in the treatment of hereditary hypoprothrombinemia. The drug is also ineffective in reversing hypoprothrombinemia caused by severe liver disease, and high doses may prolong the prothrombin time and aggravate the disease. Failure to respond to a test dose of phytonadione indicates a disorder that is not vitamin K-dependent, and repeated large doses of the drug are contraindicated.

Dietary Requirements

The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941. In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs). DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).

Because of the lack of adequate data, the NAS was unable to establish accurate EARs and RDAs for vitamin K. The NAS has established an AI for vitamin K for adults, adolescents, and children 1 year of age or older based on reported vitamin K dietary intake in apparently healthy population groups (Third National Health and Nutrition Examination Survey [NHANES III]). Dietary intakes reportedly are slightly lower in women than men. An AI has been established for infants through 6 months of age based on the observed mean vitamin K intake of infants fed principally human milk. An AI for infants 7-12 months of age has been set based on the AI for younger infants. (For a definition of Estimated Average Intake, Recommended Dietary Allowance, Adequate Intake, and other reference values for dietary nutrient intakes, .)

The principal goal of maintaining an adequate intake of vitamin K in the US and Canada is to prevent Vitamin K deficiency, and thus prevent vitamin K-responsive hypothrombinemia. Adequate intake of vitamin K usually can be accomplished through consumption of foodstuffs. Spinach, collards, broccoli, iceberg lettuce, and plant oils are the major contributors of vitamin K in the diet of US adults and children.

For specific information on currently recommended AIs of vitamin K for various life-stage and gender groups, see Dosage: Dietary and Replacement Requirements, under Dosage and Administration.

Dosage and Administration

Administration

Phytonadione may be administered orally or parenterally. In patients with decreased bile secretion, bile salts (e.g., ox bile extract 300 mg or dehydrocholic acid 500 mg) should be given with each oral dose of phytonadione to ensure absorption. Phytonadione (AquaMEPHYTON) may be given IM, subcutaneously, or, when these routes are not feasible, IV. (See Cautions: Adverse Effects.) The parenteral preparation has also been administered orally to neonates.

The route of administration of phytonadione depends on the severity of the prothrombin deficiency and the risks associated with administration by each route. Parenteral administration is indicated in patients who are unable to retain or absorb the drug from the GI tract. Subcutaneous or IM administration may be contraindicated in hypoprothrombinemia because of the possibility of inducing hemorrhage or hematoma at the site of injection. Because of the possibility of severe adverse reactions (see Cautions: Adverse Effects), IV administration is indicated only when other routes of administration are not feasible.

When AquaMEPHYTON is administered IV, it should be injected at a rate not exceeding 1 mg/minute. The drug may be diluted for infusion with preservative-free 5% dextrose, 0.9% sodium chloride, or 5% dextrose in 0.9% sodium chloride injection; other diluents should not be used. The drug should be administered immediately after dilution, and any unused portion of the dilution and the unused contents of the ampul should be discarded. The infusion bottle must be protected from light at all times. (See Chemistry and Stability: Stability.)

Dosage

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

Anticoagulant-induced Hypoprothrombinemia

For the treatment of oral anticoagulant-induced hypoprothrombinemia, the usual initial dose of phytonadione is 2.5-10 mg administered orally or by IV, IM or subcutaneous injection, although initial doses of up to 25 mg have been used in some patients. In rare instances, larger doses (e.g., 50 mg) may be required; however, phytonadione should be administered in the lowest effective dosage so that refractoriness to further anticoagulant therapy is minimized and prothrombin time is not decreased below the effective anticoagulant level. The dose may be repeated 12-48 hours after the first oral dose or 6-8 hours after the first parenteral dose if the initial response is not satisfactory.

Hemorrhagic Disease of the Newborn

For the prevention of hemorrhagic disease of the newborn, phytonadione in doses of 0.5-1 mg IM should be administered to the neonate within 1 hour of delivery. Alternatively, some authorities state that neonates may receive 1-2 mg of phytonadione orally immediately after delivery. Several oral doses, administered over a period of up to 3 months, may be required. These doses are usually adequate for prevention of hemorrhagic disease of the newborn. For the prevention of neonatal hemorrhage resulting from anticonvulsant therapy during pregnancy, some clinicians recommend that the woman receive phytonadione 10 mg orally daily during the last month of pregnancy (from the 36th week of gestation until delivery). Neonates whose mothers received oral phytonadione during pregnancy should also receive phytonadione at birth. Phytonadione administration to women before delivery to prevent hemorrhagic disease of the newborn is not recommended by most authorities.

For the treatment of hemorrhagic disease of the newborn, the usual dose of phytonadione is 1 mg administered IM or subcutaneously. Larger doses may be required for neonates whose mothers have received oral anticoagulant therapy during pregnancy.

Hypoprothrombinemia from Other Causes

For the treatment of hypoprothrombinemia resulting from malabsorption syndromes or therapy with broad-spectrum antibiotics, salicylates, sulfonamides, quinine, or quinidine, oral or parenteral doses of 2-25 mg may be administered to adults; the dose and route of administration depend on the severity of the deficiency and the response to the drug. Up to 50 mg may be given, but doses over 25 mg are rarely required. For the treatment of prothrombin deficiency in pediatric patients, infants may receive 2 mg and older children may be given 5-10 mg orally or parenterally.

Dietary and Replacement Requirements

The Adequate Intake (AI) (see Uses: Dietary Requirements) of vitamin K currently recommended by the National Academy of Sciences (NAS) for healthy infants through 6 months of age is 2 mcg daily and for those 7-12 months of age is 2.5 mcg daily. The substantial increase in the AI from infancy to early childhood presumably is due to the method used to set the AI for older infants and the increased proportion of the diet containing vitamin K-rich vegetables as the diet becomes more diversified. The AI of vitamin K currently recommended by NAS for healthy children 1-3, 4-8, 9-13, or 14-18 years of age is 30, 55, 60, or 75 mcg daily, respectively. The AI for healthy men of all ages (19-70 years of age and those older than 70 years of age) is 120 mcg of vitamin K daily, and the AI for healthy women of all ages (19-70 years of age and those older than 70 years of age) is 90 mcg daily.

Limited data suggest that the vitamin K status in pregnant women does not differ from that in nonpregnant women. Therefore, the NAS states that the AI of vitamin K does not need to be increased during pregnancy (i.e., pregnant women can receive the usual AI appropriate for their age). Available evidence indicates that the vitamin K status of lactating women is comparable to that of nonlactating women. Vitamin K is not distributed in clinically important amounts into milk, and the AI for lactating women does not differ from that for nonlactating women.

Cautions

Adverse Effects

Phytonadione is relatively nontoxic; however, severe reactions have occurred rarely during or immediately following IV administration. These severe reactions, which may occur in patients receiving phytonadione for the first time, resemble hypersensitivity or anaphylaxis. Symptoms include cramp-like pains, convulsive movements, cardiac irregularities, chest pains, cyanosis, dulled consciousness, flushing of the face, a sense of chest constriction, circulatory collapse, bronchospasm, hyperhidrosis, dyspnea, alteration of taste, dizziness, rapid and weak pulse, brief hypotension, shock, cardiac and/or respiratory arrest, and death. It is not known whether these adverse reactions are caused by the drug or the injection vehicle. Dilution and slow infusion may not prevent severe reactions; therefore, IV administration of the drug should be restricted to emergency use. The possibility of allergic reactions, including anaphylaxis, should also be considered when phytonadione injection is given IM or subcutaneously. Erythematous, indurated, pruritic plaques have occurred infrequently, usually after repeated injection; rarely, these have progressed to scleroderma-like lesions that have persisted for long periods of time. In other cases, these lesions have resembled erythema perstans.

Pain, swelling, and tenderness at the injection site occur rarely after parenteral administration of phytonadione.

Precautions and Contraindications

Phytonadione is contraindicated in persons who are hypersensitive to the drug or any ingredients in the formulations.

Pediatric Precautions

Hyperbilirubinemia and severe hemolytic anemia have been reported rarely in neonates, particularly premature neonates, following large doses (10-20 mg) of phytonadione. However, the incidence of these adverse effects is much less with phytonadione than with other vitamin K preparations.

Each mL of AquaMEPHYTON contains 9 mg of benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates. Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates and the manufacturer states that there is no evidence that the amount of benzyl alcohol contained in AquaMEPHYTON is associated with toxicity when the drug is used as recommended.

Pregnancy and Fertility

Pregnancy

Reproduction studies have not been conducted in animals, and it is not known if phytonadione has teratogenic effects.

Fertility

Reproduction studies have not been conducted in animals, and it is not known if phytonadione affects fertility in humans.

Drug Interactions

Because vitamin K1 is a pharmacologic antagonist to coumarin and indandione derivatives, patients being treated with these anticoagulants should not receive phytonadione except for the treatment of excessive hypoprothrombinemia.

Orlistat may result in decreased GI absorption of fat-soluble vitamins such as phytonadione (vitamin K1). At least 2 hours should elapse between (before or after) any orlistat dose and phytonadione administration; administering fat-soluble vitamins at bedtime may be a conveninent time. Although the manufacturer of orlistat recommends that a vitamin supplement containing fat-soluble vitamins (A, D, E, and K) be used during orlistat therapy, such vitamin concentrations in clinical studies with the drug remained within the normal range for most patients despite decreases, and vitamin supplementation was only occasionally needed.

Pharmacokinetics

Absorption

Phytonadione is absorbed from the GI tract only in the presence of bile salts. Radioisotope studies show that absorption occurs via intestinal lymph. There is some evidence that absorption of phytonadione across the GI mucosa is a saturable, energy-dependent process that occurs in the proximal small intestine. Following oral administration of phytonadione, blood coagulation factors increase in 6-10 hours. The increase generally occurs within 1-2 hours following parenteral administration. Bleeding is usually controlled within 3-6 hours, and a normal prothrombin time may often be obtained 12-14 hours after parenteral administration. Following oral administration of a single 2-mg dose of the drug in neonates with a gestational age of 31-38 weeks, serum phytonadione concentrations increased from a baseline of 17 ng/mL to 213 and 275 ng/mL at 6 and 12 hours, respectively, after administration and were 65 ng/mL at 5 days.

Distribution

Although the drug may be concentrated in the liver for a short time after absorption, only small amounts of phytonadione are stored in body tissues.

Phytonadione appears to cross the placenta to a limited extent. Following IV administration of a 1-mg dose of phytonadione to pregnant women 11-47 minutes prior to delivery, cord plasma concentrations of the drug were undetectable to 0.14 ng/mL while concurrent maternal plasma concentrations were 45-93 ng/mL. Phytonadione is distributed into milk. Although vitamin K1 is present in human breast milk in relatively low concentrations (about 2 ng/mL), oral administration of phytonadione to lactating women may increase the concentration of the vitamin in breast milk. Oral administration of a single 20-mg dose of phytonadione in one lactating woman increased milk concentrations of the vitamin from undetectable to about 140, 50, and 5 ng/mL 12, 36, and 48 hours, respectively, after administration. Phytonadione concentrations are higher in cow's milk than in human breast milk.

Elimination

Little is known about the excretion of vitamin K. High fecal concentrations of vitamin K probably result from bacterial synthesis in the intestine.

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