Arginaid (arginine/ascorbate sodium/vitamin E acetate)

Vitamin E activity is generally expressed in USP or International Units which are equivalent; the International Unit of vitamin E is no longer officially recognized but continues to be used in the labeling of some preparations. It should be noted that vitamin E preparations are historically and incorrectly labeled as d- or dl-alpha-tocopherol and their respective esters. Vitamin E compounds include the all racemic (all rac)-alpha-tocopherol (dl-alpha-tocopherol (RRR-, RRS-, RSR-, RSS-, SSS-, SRS-, SSR-, and SRR-) or synthetic) form and its esters and the RRR-alpha-tocopherol (d-alpha-tocopherol or natural) form and its esters, and any of these compounds may be present in fortified foods and vitamin preparations.

One unit of vitamin E equals the biologic activity of 1 mg of all rac-alpha-tocopheryl acetate (dl-alpha-tocopheryl acetate), 1.12 mg of all rac-alpha-tocopheryl succinate (dl-alpha-tocopheryl acid succinate), 910 mcg of all rac-alpha-tocopherol (dl-alpha-tocopherol), 735 mcg of RRR-alpha-tocopheryl acetate (d-alpha-tocopheryl acetate), 830 mcg of RRR-alpha-tocopheryl succinate (d-alpha-tocopheryl acid succinate), and 670 mcg of RRR-alpha-tocopherol (d-alpha-tocopherol). However, because the USP potency unit for vitamin E was defined before studies showed a lack of human activity for the 2S-stereoisomers, the National Academy of Sciences (NAS) Food and Nutrition Board recommended in 2000 that the current equivalency defined in the USP standard be redefined based on the R-stereoisomeric forms of alpha-tocopherol, which are the forms that are active in humans. According to the NAS definition, each USP unit of vitamin E is equivalent to the biologic activity of 450 mcg of the synthetic all rac-alpha-forms of tocopherol and its esters or 670 mcg of the RRR-alpha-forms of tocopherol and its esters.

Arginine hydrochloride is administered by IV infusion via an indwelling needle or soft catheter into the antecubital or other suitable vein. Because of its hypertonicity, the injection should only be injected IV.

For use in acute hyperammonemia, 10% arginine hydrochloride should be administered through a central IV line. The drug may be mixed in the same infusion container with sodium phenylacetate and sodium benzoate; however, other infusion solutions and drug products should not be admixed with the drugs.

Arginine hydrochloride injection should be inverted and inspected visually prior to administration to ensure that the solution is clear. The manufacturer states that warming the injection prior to use is not necessary, but solutions that are not clear or containers lacking a vacuum should be discarded.

Ascorbic acid is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered IM, IV, or subcutaneously. When given parenterally, utilization of the vitamin reportedly is best after IM administration and that is the preferred parenteral route.

Vitamin E is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be given parenterally as a component of a multivitamin injection. Some clinicians use water-miscible oral vitamin E preparations in patients with malabsorption syndromes.

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Estrogens and estrogen-progestin combination oral contraceptives may elevate growth hormone response, and reduce glucagon and insulin response to arginine. Reduction of arginine-induced growth hormone response by medroxyprogesterone acetate and of insulin response by norethindrone has also been reported.

Plasma insulin concentrations following arginine stimulation may be further elevated by thiazide diuretics, xylitol, and aminophylline. The latter 2 drugs may also reduce glucagon response to arginine.

Long-term administration of sulfonylurea oral antidiabetic agents may suppress plasma glucagon response to arginine. In one study, phenytoin reduced the plasma insulin response to arginine when glucose intolerant patients were given a glucose load.

Severe, potentially fatal, hyperkalemia has occurred following arginine hydrochloride therapy for metabolic alkalosis in several patients with severe hepatic disease who had recently received spironolactone. Severe hyperkalemia, requiring treatment, developed within several hours after initiating arginine therapy; spironolactone had been discontinued 2-3 days prior to initiation of arginine. Death occurred in one patient subsequent to ventricular tachycardia and asystole despite attempts to decrease serum potassium concentrations and treat cardiac abnormalities. Severe hyperkalemia in these patients probably resulted from an arginine-induced extracellular shift of potassium from cells, impaired hepatic metabolism of arginine, and/or a spironolactone-induced decrease in renal excretion of the ion; spironolactone's effect on potassium persists for several days following discontinuance of the drug. Patients receiving a potassium-sparing diuretic are at increased risk of arginine-induced hyperkalemia, and therefore combined use of the drugs should be avoided.

Concurrent administration of more than 200 mg of ascorbic acid per 30 mg of elemental iron increases absorption of iron from the GI tract; however, most individuals are able to absorb orally ingested iron adequately without concurrent administration of ascorbic acid.

Increased urinary excretion of ascorbic acid and decreased excretion of aspirin occur when the drugs are administered concurrently.

Salicylates inhibit uptake of ascorbic acid by leukocytes and platelets. As a result, leukocyte and plasma concentrations of ascorbic acid are decreased to concentrations slightly higher than those associated with tissue depletion of the vitamin; however, there is no evidence to date that salicylate therapy precipitates ascorbic acid deficiency. Although concomitant administration of ascorbic acid supplements in patients receiving salicylates increases plasma ascorbic acid concentrations, leukocyte ascorbic acid concentrations are not increased and tissue stores of the vitamin may not be increased. Therefore, routine administration of ascorbic acid supplements to patients receiving salicylates is not warranted; however, patients receiving high dosages of salicylates who exhibit any signs or symptoms of ascorbic acid deficiency should be evaluated for such a deficiency.

Ascorbic acid has reportedly decreased the anticoagulant effect of warfarin; however, other investigators have failed to show this effect. Concurrent administration of ascorbic acid and fluphenazine reportedly resulted in decreased fluphenazine plasma concentration. Acidification of the urine following administration of ascorbic acid may result in altered excretion of other drugs.

Vitamin E may increase the absorption, utilization, and storage of vitamin A and may protect against hypervitaminosis A; however, these effects are controversial.

Vitamin E in dosages of greater than 10 units/kg daily may delay the response to iron therapy in children with iron-deficiency anemia, and low-birthweight infants treated with iron supplements may develop vitamin E-deficiency hemolytic anemia.

Vitamin E or one of its metabolites reportedly may have anti-vitamin K effects; patients receiving oral anticoagulants may be at risk of hemorrhage after large doses of vitamin E. In normal healthy individuals, vitamin E caused no change in blood clotting.

Excessive use of mineral oil may decrease the absorption of vitamin E.

Orlistat may result in decreased GI absorption of fat-soluble vitamins such as vitamin E. At least 2 hours should elapse between (before or after) any orlistat dose and vitamin E administration; administering fat-soluble vitamins at bedtime may be a convenient 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.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Ascorbic Acid (Vitamin C)/Bortezomib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Vitamin C can form a complex with the boronic acid moiety of the bortezomib molecule, preventing its absorption into cells.(1-4) This may protect normal tissue in the body, which may have higher levels of Vitamin C.(5)

CLINICAL EFFECTS: Concurrent administration of Vitamin C may result in decreased bortezomib activity.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients receiving bortezomib therapy not to begin taking vitamin C supplements without consulting their oncologist first. Patients who are instructed to take vitamin C should follow their oncologist's instructions on how to separate dosages and should be carefully monitored for bortezomib efficacy.

DISCUSSION: An in vitro study with human plasma and multiple myeloma cells found that high levels of vitamin C (following 1 gram/day of ascorbic acid for 4 days) decreased bortezomib effectiveness by 26%. An in vivo study in mice found that vitamin C administration with bortezomib completely blocked the response of bortezomib.(6) An in vitro study in rat Schwann cells and myeloma cells(4) and an in vivo study in mice(7) found that delayed administration of vitamin C had no effect on bortezomib effects. In an in vivo study in multiple myeloma patients, concurrent ascorbic acid, arsenic trioxide, bortezomib, and high-dose melphalan in which ascorbic acid was administered close to bortezomib, the combination was safe and well tolerated, but produced no changes in response rates.(8) In another in vivo study in multiple myeloma patients, a regimen of ascorbic acid, bortezomib, and melphalan in which bortezomib was administered in the morning and ascorbic acid in the evening was found to be safe and efficacious, with 74% of patients responding to therapy.(9)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Ascorbic Acid (Vitamin C)/Deferoxamine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: It is believed that ascorbic acid increases the iron available for chelation from an labile intracellular iron pool. Ascorbic acid may then facilitate iron-induced oxidative tissue damage.(1)

CLINICAL EFFECTS: Dietary ascorbic acid may increase the absorption of dietary iron. Supplemental ascorbic acid therapy given during chelation therapy may improve iron output;(1-9) however, excessive dosages may result in cardiac toxicity from iron-induced oxidative tissue damage.(1,2,11-13)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Ascorbic acid intake is often restricted in patients with iron overload; however, it has been used in conjunction with deferoxamine to increase iron excretion.(2) Supplemental ascorbic acid therapy should only be initiated after one month of deferoxamine therapy. Ascorbic acid therapy should only be given in patients receiving deferoxamine regularly and the dose should be given after the infusion has started. The dosage of ascorbic acid should be limited to 50 mg daily in children under 10 years of age; 100 mg daily in older children; and 200 mg daily, in divided doses, in adults.(2) Cardiac function should be monitored in patients receiving concurrent therapy. Discontinue ascorbic acid therapy in patients who develop cardiac dysfunction.(2)

DISCUSSION: Supplemental ascorbic acid therapy given during chelation therapy has been shown to improve iron output,(1-9) possibly by increasing iron available for chelation from an labile intracellular iron pool.(1) However, dosages in excess of 500 mg daily have been associated with cardiac dysfunction.(1,2,11-13)

Fat Soluble Vitamins/Colesevelam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Colesevelam may decrease the absorption of fat-soluble vitamins A, D, E, and K.(1)

CLINICAL EFFECTS: Colesevelam may reduce absorption of fat soluble vitamins, leading to a deficiency state.

PREDISPOSING FACTORS: A pre-existing deficiency of fat soluble vitamins (A,D,E and K) or chronic malabsorption syndrome.

PATIENT MANAGEMENT: The inhibition of fat soluble vitamin absorption by colesevelam should be borne in mind during implementation of a vitamin supplementation strategy. Oral multivitamin supplements should be taken at least four hours before the dose of colesevelam.(1)

DISCUSSION: Colesevelam may decrease the absorption of fat-soluble vitamins A, D, E, and K.(1)

Fat Soluble Vitamins/Orlistat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The acetate ester forms of vitamin A and vitamin E must undergo hydrolysis for absorption from the gastrointestinal tract.(1) The enzyme responsible for this hydrolysis is inhibited by orlistat.(2)

CLINICAL EFFECTS: Orlistat may reduce absorption of fat soluble vitamins, leading to a deficiency state.

PREDISPOSING FACTORS: A pre-existing deficiency of fat soluble vitamins (A,D,E and K) or chronic malabsorption syndrome.

PATIENT MANAGEMENT: The inhibition of fat soluble vitamin absorption by orlistat should be borne in mind during implementation of a vitamin supplementation strategy. Patients should be strongly encouraged to take a multivitamin supplement which contains fat soluble vitamins, particularly Vitamin D as it appears most susceptible to this interaction.(4,5) Multivitamin supplements should be taken at least two hours before or after the dose of orlistat, or at bedtime.(4) Patients with chronic malabsorption syndromes should not receive orlistat.(4)

DISCUSSION: Adult patients taking orlistat without supplementation showed a greater reduction in vitamin A,D,E and beta-carotene levels compared to placebo during two or more consecutive visits in studies of 1-2 years duration; these patients had normal baseline values prior to orlistat therapy. Low vitamin values in orlistat patients were as follows: low Vitamin D 12%, low beta-carotene 6.1%, low Vitamin E 5.8%, low Vitamin A 2.2%.(4) A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption and a 60% decreased in vitamin E acetate absorption with concomitant orlistat.(4) In a study, orlistat produced the vitamin net concentration by approximately 43%.(1) In a study, no statistically significant decrease in vitamin A absorption was observed with concurrent orlistat.(2) In a study, mean vitamin D levels were significantly reduced compared with baseline after one month of orlistat therapy despite multivitamin supplementation.(5)

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There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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Vitamin E has not been shown to be teratogenic. There is no evidence that vitamin E requirements in pregnant women differ from women who are not pregnant. (See Dosage: Dietary and Replacement Requirements, under Dosage and Administration.)

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