BPD and vitamin K deficiency

[Guest guest]

Does anyone know a safe dose to treat a vitamin K deficiency? We

recently saw a pt who is s/p BPD and has deficiencies in all the fat

soluble vitamins.

TIA.

[Guest guest]

Information regarding Vitamin K, repletion is different than maintenance doses -- which would likely require 2-3 tablets of ADEKs per day.

Jeanne Blankenship, MS RD

Sacramento, CA

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 (AquaMEPHYTONâ) may be given IM, subcutaneously, or, when these routes are not feasible, IV. 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 AquaMEPHYTONâ 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.34, 113, 135, 136 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.135, 136, 137 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).131, 132, 133 Neonates whose mothers received oral phytonadione during pregnancy should also receive phytonadione at birth.131, 132, 133 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.113 Larger doses may be required for neonates whose mothers have received oral anticoagulant therapy during pregnancy.113

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.121 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.121 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.121

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.121

Limited data suggest that the vitamin K status in pregnant women does not differ from that in nonpregnant women.121 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).121 Available evidence indicates that the vitamin K status of lactating women is comparable to that of nonlactating women.121 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.121

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 phyton

adione 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 AquaMEPHYTONâ contains 9 mg of benzyl alcohol as a preservative.113 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.113, 114, 115, 116, 117, 118, 119, 120 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.114, 115, 116, 117, 118, 119, 120 Although use of drugs preserv

ed with benzyl alcohol should be avoided in neonates whenever possible,114, 116 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 neonates114 and the manufacturer states that there is no evidence that the amount of benzyl alcohol contained in AquaMEPHYTONâ is associated with toxicity when the drug is used as recommended.113

· 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).122 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.122, 124, 128, 130 Although the manufacturer of orlistat recommends that a vitamin supplement containing fat-soluble vitamins (A, D, E, and K) be used during orlistat therapy,122, 128 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.123, 124, 125, 126, 127, 129

Pharmacology

Phytonadione has the same activity as naturally occurring vitamin K1, which is required for the synthesis of blood coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor or plasma thromboplastin component), and X (Stuart-Prower factor) in the liver. Studies indicate vitamin K is involved in carboxylation of the preformed, inactive precursors of these coagulation factors. The resulting g-carboxyglutamyl residues are required for the calcium-dependent phospholipid binding exhibited by active vitamin K-dependent clotting factors. In adequate doses, phytonadione reverses the inhibitory effect of coumarin and indandione derivatives on the synthesis of these factors. A rare genetic mutation of the vitamin K receptor site which is associated with resistance to coumarin and indandione derivative anticoagulants and increased sensitivity to small amounts of exogenous vitamin K has occurred in some patients.

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.100, 101, 102 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.103

· 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.34, 102, 107 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.107 Phytonadione is distributed into milk.34, 35, 108, 109, 110, 111 Although vitamin K1 is present in human breast milk in relatively low concentrations34, 35, 108, 109, 110, 111 (about 2 ng/m

L),108 oral administration of phytonadione to lactating women may increase the concentration of the vitamin in breast milk.102, 108 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.108 Phytonadione concentrations are higher in cow's milk than in human breast milk.34, 35, 108, 109, 110, 111

· Elimination

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

Chemistry and Stability

· Chemistry

Phytonadione is a fat-soluble naphthoquinone derivative which is identical to naturally occurring vitamin K1. Vitamin K1 is present in many foods including leafy green vegetables, meat, cow's milk, vegetable oils, egg yolks, and tomatoes; it differs from other naturally occurring types of vitamin K in the degree of saturation and length of its 20-carbon polyisoprenoid side chain. Commercially available phytonadione is prepared synthetically. Natural vitamin K1 occurs as the all-trans-isomer, whereas phytonadione occurs as a mixture of the cis- and trans-isomers, with the cis-isomer not exceeding 20%. Phytonadione occurs as a clear, yellow to amber, very viscous liquid and is insoluble in water and slightly soluble in alcohol.

Phytonadione injection is a sterile, aqueous dispersion of phytonadione and contains suitable solubilizing and/or dispersing agents. Phytonadione injections have a pH of 5-7.

· Stability

Phytonadione is stable to heat and moisture and may be autoclaved. The drug is photosensitive and must be protected from light at all times. Infusion solutions should be protected from light by wrapping the container with aluminum foil or other opaque material. Phytonadione tablets should be stored at 25°C in well-closed, light-resistant containers, but may be exposed to temperatures ranging from 15-30°C.

Phytonadione injection has been reported to be incompatible with many drugs, but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

Preparations

* available generically

Phytonadione

Routes Dosage Strengths Brand Names Manufacturer Forms Oral Tablets 5 mg Mephytonâ (scored) Merck Parenteral Injection 2 mg/mL* AquaMEPHYTONâ (with polyoxyethylated fatty acid Merck derivative, dextrose, and benzyl alcohol 0.9%) Phytonadione Injection Hospira, IMS 10 mg/mL* AquaMEPHYTONâ (with polyoxyethylated fatty acid Merck derivative, dextrose, and benzyl alcohol 0.9%) Phytonadione Injection Hospira

AHFS Drug Information. ã Copyright, 1959-2008, Selected Revisions January 2004. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, land 20814.

# Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

34. American Academy of Pediatrics Committee on Nutrition. Vitamin K compounds and the water-soluble analogues: use in therapy and prophylaxis in pediatrics. Pediatrics. 1961; 28:501-7.

35. American Academy of Pediatrics Committee on Nutrition. Vitamin K supplementation for infants receiving milk substitute infant formulas and for those with fat malabsorption. Pediatrics. 1971; 48:483-7. [PubMed 5109893]

37. Vest M. Vitamin K in medical practice¾pediatrics. Vitam Horm. 1966; 24:649-63. [PubMed 5340884]

100. Shearer MJ, Barkhan P, Webster GR. Absorption and excretion of an oral dose of titrated vitamin K1 in man. Br J Haematol. 1970; 18:297-308. [PubMed 5491582]

101. Hollander D. Intestinal absorption of vitamins A, E, D, and K. J Lab Clin Med. 1981; 97:449-62. [PubMed 7205056]

102. Lane PA, Hathaway WE. Vitamin K in infancy. J Pediatr. 1985; 106:351-9. [PubMed 3973772]

103. Sann L, Leclercq M, Bourgeois J et al. Pharmacokinetics of vitamin K1 in newborn infants. Pediatr Res. 1983; 17:155A.

104. Dunn PM. Vitamin K1 for all newborn babies. Lancet. 1982; 2:770. [PubMed 6125839]

105. Shoskes M. "Solubilized" vitamin K1 (phytonadione) in neonatal hypoprothrombinemia. J Pediatr. 1961; 58:27-31.

106. Hemorrhage in the newborn infant. In: Behrman RE, Vaughn RC III, eds. textbook of pediatrics. 12th ed. Philadelphia: WB Saunders Company; 1983:389-90.

107. Shearer MJ, Rahim S, Barkhan P et al. Plasma vitamin K1 in mothers and their newborn babies. Lancet. 1982; 2:460-3. [PubMed 6125638]

108. Haroon Y, Shearer MJ, Rahim S et al. The content of phylloquinone (vitamin K1) in human milk, cow's milk and infant formula foods determined by high-performance liquid chromatography. J Nutr. 1982; 112:1105-17. [PubMed 7086539]

109. O'Connor ME, Livingstone DS, Hannah J et al. Vitamin K deficiency and breast feeding. Am J Dis Child. 1983; 137:601-2. [PubMed 6846298]

110. Sutherland JM, Glueck HI, Gleser G. Hemorrhagic disease of the newborn: breast feeding as a necessary factor in the pathogenesis. Am J Dis Child. 1967; 113:524-33. [PubMed 6071586]

111. Keenan WJ, Jewett T, Glueck HI. Role of feeding and vitamin K in hypoprothrombinemia of the newborn. Am J Dis Child. 1971; 121:271-7. [PubMed 5108035]

112. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998. (Prepublication copy uncorrected proofs.)

113. Merck. AquaMEPHYTONâ (phytonadione) injection aqueous colloidal solution of vitamin K1 prescribing information (dated 1997 Sep). In: Physicians' desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:2042-3

114. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [PubMed 6889041]

115. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10-1. [PubMed 7188569]

116. Anon. Neonatal deaths associated with use of benzyl alcohol¾United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [PubMed 6810084]

117. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [PubMed 7133084]

118. Menon PA, Thach BT, CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

119. CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [PubMed 6695984]

120. Food and Drug Administration. Parenteral drug products containing benzyl alcohol or other antimicrobial preservatives; intent and request for information. [Docket No. 85N-0043] Fed Regist. 1985; 50:20233-5.

121. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2001. (Prepublication copy uncorrected proofs.)

122. Roche Laboratories Inc. Xenicalâ (orlistat) capsules prescribing information. Nutley, NJ; 1999 April.

123. Sjostrom L, Rissanen A, Andersen T et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet. 1998; 352:167-72. [PubMed 9683204]

124. son MH, Hauptman J, DiGirolamo M et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat. JAMA. 1999; 281:235-42. [PubMed 9918478]

125. Hollander PA, Elbein SC, Hirsch IB et al. Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care. 1998; 21:1288-94. [PubMed 9702435]

126. Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol. 1996; 36:647-53. [PubMed 8844448]

127. Zhi J, Melia AT, Koss-Twardy SG et al. The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of b-carotene in healthy volunteers. J Clin Pharmacol. 1996; 36:152-9. [PubMed 8852391]

128. Roche Laboratories Inc. Xenicalâ (orlistat) capsules patient information. Nutley, NJ; 1999 April.

129. WP, Avenell A, Broom J et al. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Relat Metab Disord. 1997; 21(Suppl 3):S24-30. [PubMed 9225173]

130. Roche Laboratories Inc, Nutley, NJ: Personal communication on Orlistat 56:40.

131. Anon. Practice parameter: management issues for women with epilepsy (summary statement). Neurology. 1998; 51:944-8. [PubMed 9781510]

132. American College of Obstetricians and Gynecologists. ACOG educational bulletin No. 231: seizure disorders in pregnancy. Dec 1996.

133. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs. 1999; 57:535-44. [PubMed 10235691]

134. Merck. Mephytonâ (phytonadione) tablets vitamin K1 prescribing information (dated 1998 Aug). In: Physicians' desk reference. 56th ed. Montevale, NJ: Medical Economics Company Inc; 2002:2129-30.

135. American Academy of Pediatrics Vitamin K ad hoc task force. Controversies concerning vitamin K and the newborn. Pediatrics. 1993; 91:1001-3. [PubMed 8474790]

136. Buck ML. Vitamin K for the prevention of bleeding in newborns. Pediatric Pharmacotherapy. 2001. From the web site (http://www.hsc.virginia.edu/cmc/pedpharm/v7n10.pdf).

137. American Academy of Pediatrics Committee on Nutrition. Pediatric nutrition handbook. 4th ed. Elk Groove Village, IL: American Academy of Pediatrics; 1998:14,277-8.0

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-------------- Original message from "jenny_dickson" <.D.Letendre@...>: --------------

Does anyone know a safe dose to treat a vitamin K deficiency? We recently saw a pt who is s/p BPD and has deficiencies in all the fat soluble vitamins.TIA.

[Guest guest]

,

What panel do you use to test for all the fat-soluble vitamins? Are you

using what is available through Labcorp or Quest? Are people happy with

their reference ranges? I'd love to have your input, as this is an area

our DAN! doctors are exploring anew for autism, and we need as much wisdom

(especially practical wisdom) as we can muster!

There are some parents of autistic children using very high dose vitamin K

for reasons I think are questionable, but I haven't heard of any problems

from this...

The following article may be helpful, but I don't have access:

Vitamins and Trace Elements: The Distances between Deficiency and Repletion

and between Care and Prevention

Author(s): Jean-Louis Guéant | Layachi Chabraoui

Clinical Chemistry and Laboratory Medicine

Print ISSN: 1434-6621

Volume: 41 | Issue: 8

Cover date: August 2003

Page(s): 977-978

At 05:38 PM 4/9/2008, you wrote:

>Does anyone know a safe dose to treat a vitamin K deficiency? We

>recently saw a pt who is s/p BPD and has deficiencies in all the fat

>soluble vitamins.

>

>TIA.

>

>

>

>

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