Vitamins A & D (vitamin A palmitate/ergocalciferol (vitamin D2))

Each mg of ergocalciferol is equivalent to 40,000 USP units; each mcg of the drug is equivalent to 40 USP units.

Dosage is expressed by weight (mg, mcg) or in terms of units.

During therapy with ergocalciferol, dosage depends on the nature and severity of the patient's hypocalcemia and must be individualized to maintain serum calcium concentrations of 9-10 mg/dL. In patients with familial hypophosphatemia (vitamin D-resistant rickets) or hypoparathyroidism, determinations of serum calcium and phosphorus concentrations should be made every 2 weeks or more frequently as needed. In these patients, the manufacturers of ergocalciferol recommend that radiographic examination of the bones be performed every month until the condition stabilizes or is corrected; however, some clinicians believe that this is unnecessary.

The manufacturers state that patients with malabsorption syndrome should not receive oral ergocalciferol.

To avoid toxicity, dietary intake of vitamin A should be estimated and considered when determining the dosage of the vitamin. Vitamin A activity is expressed in terms of the equivalent amount of retinol (i.e., as retinol equivalents (RE) or retinol activity equivalents (RAE)) and is expressed also in USP units or International Units (IU, units). USP units and International Units are equivalent. One USP vitamin A unit is the specific biologic activity of 0.3 mcg of all-trans-retinol; one retinol equivalent (RE) is the specific biologic activity of 1 mcg of all-trans-retinol; one retinol activity equivalent (RAE) is equal to 1 mcg of all-trans-retinol, 12 mcg of all trans-beta-carotene, or 24 mcg of other provitamin A carotenoids. The use of RAE is preferred when calculating and reporting the amount of total vitamin A in mixed foods or assessing the amount of dietary and supplemental vitamin A consumed.

Ergocalciferol is usually administered orally once daily. Ergocalciferol has been administered IM+ in some patients (e.g., those with GI, liver, or biliary disease associated with malabsorption of vitamin D analogs); however, ergocalciferol injection is no longer commercially available in the US.

When ergocalciferol is administered as an oral solution, the oral syringe provided by the manufacturer should be used to measure the dose and administer the solution directly into the patient's mouth.

Vitamin A usually is administered orally. Oral vitamin A capsules containing high strengths (e.g., 50,000 units) no longer are commercially available in the US; however, high-strength oral capsules and solutions may be available from various organizations (e.g., United Nations Children's Fund (UNICEF), the International Dispensary Association (IDA)) for treatment of deficiencies in developing countries. When oral administration is not feasible or when malabsorption is present, the drug may be given IM.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Vitamin A/Selected Retinoids

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The retinoids are structurally related to vitamin A. (1-6)

CLINICAL EFFECTS: Concurrent use of retinoids with vitamin A supplements may result in signs of vitamin A toxicity.(1-6) Symptoms of vitamin A toxicity include nausea, vomiting, loss of appetite, weakness, dry or itchy skin or lips, irritability, and hair loss.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of acitretin states that concomitant use of vitamin A supplements should be avoided.(1) The manufacturer of bexarotene states that patients should be advised to limit vitamin A supplements. In clinical studies, patients were advised to limit their vitamin A intake to less than or equal to 15,000 International Units/day.(2) The manufacturer of isotretinoin states that patients should be advised against taking vitamin A supplements.(3) The manufacturer of palovarotene states that concomitant use of vitamin A must be avoided.(4) The manufacturer of tretinoin states that tretinoin must not be administered in combination with vitamin A.(5) The UK manufacturer of alitretinoin states that tretinoin must not be administered in combination with vitamin A.(6)

DISCUSSION: The retinoids are structurally related to vitamin A. The concurrent use of retinoids with vitamin A may result in signs and symptoms of vitamin A toxicity.(1-6)

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

Serum Phosphate Level-Altering Drugs/Erdafitinib

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

MECHANISM OF ACTION: Medications that alter serum phosphate may interfere with interpretation of phosphate levels that are needed to determine initial erdafitinib dose.(1)

CLINICAL EFFECTS: Serum phosphate levels that are elevated by concomitant medications may result in an inappropriately low dose and decreased effectiveness of erdafitinib. Serum phosphate levels that are decreased by concomitant medications may result in an inappropriately high dose and increased toxicity from erdafitinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of erdafitinib states that agents that alter serum phosphate levels should be avoided before the initial dose increase period for erdafitinib based on serum phosphate levels (days 14 to 21).(1)

DISCUSSION: Concomitant administration of serum phosphate level-altering agents during the initial dose increase period of erdafitinib based on serum phosphate levels (days 14 to 21) may interfere with serum phospate levels and lead to incorrect dosing of erdafitinib.(1) Agents that may alter serum phosphate levels linked to this monograph include: aluminum carbonate, aluminum hydroxide, calcium acetate, calcium carbonate, calcium citrate, cod liver oil, ferric citrate, lanthanum, magnesium carbonate, magnesium hydroxide, potassium phosphate, sevelamer, sodium phosphate, sucroferric oxyhydroxide, tenapanor, and vitamin D.(1)

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

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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• Hypervitaminosis A
• Hypervitaminosis D

• Hypercalcemia
• Hyperphosphatemia
• Kidney stone
• Pregnancy

• Disease of liver
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Malabsorption states
• Sarcoidosis

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Rare or Very Rare

• Abnormal hepatic function tests
• Anemia
• Hepatic cirrhosis
• Hypercalcemia
• Jaundice
• Leukocytosis
• Leukopenia
• Splenomegaly
• Thrombocytopenic disorder

Rare or Very Rare

• Abnormal desquamation
• Acute abdominal pain
• Alopecia
• Anorexia
• Arthralgia
• Cheilosis
• Diarrhea
• Dry skin
• Erythema
• Fatigue
• Fever
• Headache disorder
• Hypercalcinuria
• Hyperhidrosis
• Irritability
• Lethargy
• Malaise
• Menstrual disorder
• Nausea and vomiting
• Onychia sicca
• Papilledema
• Pruritus of skin
• Psychiatric disorder
• Skin pigmentation enhancement
• Skin scaling
• Vertigo
• Visual changes

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Vitamin A is teratogenic in animals; malformations of the CNS, eye, palate, and urogenital tract have been described in several species. Adequate and well-controlled studies in humans are not available. A limited number of reports of human fetal malformations (e.g., cranial neural crest defects) following maternal ingestion of large dosages of vitamin A (10,000 units or more daily) during or both before and during pregnancy suggest potential teratogenicity, at least at high dosages. The use of vitamin A in excess of the US RDA generally is contraindicated in women who are or may become pregnant. (See Dietary and Replacement Requirements in Dosage and Administration: Dosage.)If vitamin A is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard. It also has been suggested that women of reproductive age should limit their intake of dietary sources (e.g., liver) containing high concentrations of vitamin A; beta-carotene, a precursor of vitamin A, has not been shown to be teratogenic and may be considered as a source of vitamin A supplementation in such women. Dosages exceeding the RDA may be necessary in women of childbearing age with vitamin A deficiency. There is some evidence suggesting that dosages up to 10,000 units daily or up to 25,000 units weekly may be used safely in women of childbearing age (13-49 years of age), and such dosages are recommended in those with active xerophthalmia. Even higher dosages may be necessary if active corneal lesions are present. (See Vitamin A Deficiency under Dosage and Administration: Dosage.)

Vitamin A is distributed into milk. Unless the maternal diet is inadequate, infants can usually obtain sufficient vitamin A from nursing, at least for the first 6 months of life. The effect of large maternal dosages of vitamin A on nursing infants is not known.

For information on the currently recommended RDAs of vitamin A for pregnant and lactating women, see Dietary and Replacement Requirements, under Dosage and Administration: Dosage.

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