Pharmacology
Vitamin A is a fat-soluble vitamin and is readily absorbed from the normal gastrointestinal tract. Absorption is impaired in the presence of hepatic or pancreatic disease or in patients with low protein intake. Plasma concentrations peak within 3 to 5 hours. Beta-carotene is converted to retinal, which is mostly reduced to retinol. Some retinol is esterified, mainly to retinyl palmitate which is stored in the liver along with small amounts of retinol and retinal. Normal plasma concentration is approximately 1.4 µmol/L (130 units/100 mL). Retinyl esters are released from the liver bound to retinol-binding protein. Body stores of vitamin A are normally sufficient to meet the body's needs for up to 2 years. Retinol in the circulation is conjugated with glucuronic acid, further oxidized and excreted in the urine and feces.
Indications
Prophylaxis and treatment of vitamin A deficiency.
Vitamin A has been used to measure fat absorption. Fasting serum vitamin A levels are measured before and 4 hours after an oral dose of 2100 RAE/kg of oil-soluble vitamin A. Patients with normal fat absorption will have an increase of 1 µg/mL or more in their fasting vitamin A level.
Vitamin A has been used to treat rare forms of retinitis pigmentosa associated with abetalipoproteinemia (Bassen-Kornzweig syndrome).
A review of vitamin A treatment in children with measles found that two high doses of vitamin A reduced overall and pneumonia-specific mortality in children less than 2 years of age. Some experts recommend vitamin A be given to children aged 6 months to 2 years who are hospitalized with measles and its complications, and in children with measles who show ophthalmic signs of vitamin A deficiency.
There is no conclusive evidence to support use of vitamin A in the prevention of cancer. High doses of beta-carotene supplements have been associated with increased incidence of lung cancer in men (see Warnings).
Synthetic retinoid analogues are used orally (isotretinoin, acitretin) or topically (tretinoin, adapalene, tazarotene) to treat acne and certain other skin disorders. Oral tretinoin is also used for induction of remission in acute promyelocytic leukemia.
Precautions
Vitamin A should not be used concurrently with oral retinoids (e.g., tretinoin, isotretinoin, acitretin) because of possible additive toxicity.
Significant increases in plasma vitamin A concentrations have been demonstrated in women taking oral contraceptives.
Excessive use of mineral oil as a laxative may reduce the utilization of the provitamin by carrying away large amounts in the feces.
Cholestyramine can bind to and impair absorption of fat-soluble vitamins including vitamin A.
Orlistat decreases the absorption of fat-soluble vitamins including vitamin A. Supplementation with a standard multiple vitamin preparation is sometimes recommended during orlistat therapy. To avoid interference with vitamin absorption, doses of orlistat and fat-soluble vitamins should be separated by at least 2 hours.
Large doses of vitamin A may increase the hypoprothrombinemic effect of warfarin.
Vitamin A is distributed into milk. Hypervitaminosis is a theoretical possibility, but this normally does not occur with normal maternal daily doses.
Vitamin A is teratogenic in animals. Although pregnant women require adequate vitamin A, they should not exceed a daily supplement of 3300 units. Excessive intake of vitamin A during pregnancy may be a potential hazard to the mother and fetus. Effective measures to avoid pregnancy are necessary with high dose vitamin A therapy.
Oral retinoids (isotretinoin, tretinoin, acitretin) are contraindicated during pregnancy. There is an extremely high risk that major fetal abnormalities will result if pregnancy occurs during treatment with these drugs.
Contraindications
Hypervitaminosis A; hypersensitivity to vitamin A or any component of a vitamin A-containing pharmaceutical preparation. Doses exceeding the recommended daily allowance (RDA) are contraindicated in pregnancy.
Warnings
See Precautions.
Some studies have shown an increased incidence of lung cancer in men taking high-dose beta-carotene supplements, with or without vitamin A.
Adverse Effects
See Overdose.
Overdose
The amount required to cause toxicity will vary among individuals. The manifestations of toxicity will depend on the patient's age and hepatic function, and on the dose and duration of administration.
Acute toxicity, i.e., single ingestion of 7500 µg RAE/kg (25 000 units/kg) or more: Signs and symptoms may be delayed for 8 to 24 hours and include: increased intracranial pressure, headache, irritability, drowsiness, dizziness, lethargy, vomiting, diarrhea, bulging fontanels in infants, diplopia, papilledema. Peeling of skin around mouth may be observed from 1 to several days after ingestion and may spread to the rest of the body. Hepatotoxicity has been reported with acute ingestion of > 600 000 units.
Chronic, excessive ingestion (1200 µg RAE/kg or 4000 units/kg daily in adults for 6 to 15 months) may produce symptoms of pseudotumor cerebri, anorexia, weakness, arthralgias, bone pain, bone demineralization, dry skin, cracked lips, brittle nails, hair loss, splenomegaly, hepatomegaly, hypoplastic anemia, leukopenia, optic neuropathy, and blindness. Increased plasma concentrations of vitamin A occur but do not necessarily correlate with toxicity.
For an acute overdose, activated charcoal should be used to achieve gastrointestinal decontamination. Treat symptomatically.
Intracranial pressure may be reduced with iv dexamethasone or iv mannitol. In untreated patients, increased intracranial pressure may persist for 4 weeks after discontinuation of vitamin A.
For chronic toxicity, discontinue vitamin A. Toxicity is slowly reversible but may persist for several weeks. Monitor blood pressure, fluids, electrolytes, CNS status, complete blood count and hepatic function.
Dosage
In preventing vitamin deficiency, adequate dietary intake is preferred over supplementation, whenever possible. Preformed vitamin A is found in animal products (e.g., liver, oily fish, whole eggs, dairy products) as well as in fortified foods such as cereals and margarine. Beta-carotene and other carotenoids are plant-derived and found in deep yellow and orange fruits and vegetables (e.g., apricots, cantaloupe, papaya, mangoes, carrots, sweet potatoes, pumpkin) and dark green leafy vegetables (e.g., kale, spinach).
Table 1 presents daily recommendations for vitamin A intake [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]. There is no distinct RDA for beta-carotene and other carotenoids. Evaluate and consider vitamin A intake from dietary sources when determining appropriate supplement doses. Patients taking >25 000 units daily should be closely monitored for evidence of toxicity.
Table 1: Vitamin ARecommended Dietary Allowance (RDA)a for Vitamin A | Life-Stage Group | RDA (µg Retinol Activity Equivalents per Day) |
| Birth to 6 months | 400 µg (AI)b |
| 7 to 12 months | 500 µg (AI)b |
| 1 to 3 years | 300 µg |
| 4 to 8 years | 400 µg |
| 9 to 13 years | 600 µg |
| ≥14 years | |
| Men | 900 µg |
| Women | 700 µg |
| Pregnancy | |
| ≤18 years | 750 µg |
| 19 to 50 years | 770 µg |
| Lactation | |
| ≤18 years | 1200 µg |
| 19 to 50 years | 1300 µg |
a. The RDA is the average daily dietary nutrient intake sufficient to meet the nutrient needs of nearly all healthy individuals (97 to 98%) in a particular life-stage and gender group.
b. For all healthy infants, the Adequate Intake (AI) is used and is based on estimated mean intakes of human milk.
Treatment of Xerophthalmia: The World Health Organization suggests the following for individuals with all stages of active xerophthalmia: Children less than 6 months of age: 50 000 units immediately on diagnosis; repeat dose of 50 000 units the next day and again at least 2 weeks later. Children 6-12 months of age: 100 000 units immediately on diagnosis; repeat dose of 100 000 units the next day and again at least 2 weeks later. Patients older than 1 year: 200 000 units immediately on diagnosis; repeat dose of 200 000 units the next day and again at least 2 weeks later.
Deficiency without Corneal Changes: Infants <1 year: 10 000 units/kg/day for 5 days, then 7500 to 15 000 units/day for 10 days.
Children 1 to 8 years: 5000 to 10 000 units/kg/day for 5 days, then 17 000 to 35 000 units per day for 10 days.
Children >8 years and Adults: 100 000 units/day for 3 days, then 25 000 to 50 000 units per day for 14 days.
As a Supplement in Children Hospitalized with Measles and Complications: 6 months to 1 year of age, 100 000 units as a single dose; 1 to 2 years of age, 200 000 units as a single dose. If there is ophthalmologic evidence of vitamin A deficiency the dose should be repeated the next day and again after 4 weeks.
It has been suggested that persons with chronic intestinal malabsorption be given vitamin A in a water-miscible preparation as follows: Infants and children <8 years 2000 units daily; Children >8 years and Adults 10 000 to 50 000 units daily. Monitor patients for signs of toxicity.
