VA Class:VT050
ATC Class:A11HA
Beta carotene, a precursor of vitamin A, protects patients with erythropoietic protoporphyria (EPP) against severe photosensitivity reactions (burning sensation, edema, erythema, pruritus, and/or cutaneous lesions) and is a weak antioxidant.
Beta carotene is used to reduce the severity of photosensitivity reactions in patients with erythropoietic protoporphyria (EPP). When patients with EPP were phototested with artificial light, beta carotene therapy increased the development time for minimal erythema in nearly all patients. Similarly, most patients with EPP have been able to tolerate exposure to sunlight without discomfort for much longer periods of time during beta carotene therapy. Some patients have been able to remain in the sun all day without experiencing photosensitivity reactions. The protective effect of beta carotene is not total, and each patient must determine his own time limit of exposure to the sun. Patients who respond to beta carotene usually develop enough protection so that they can remain in the sun without discomfort for about the same length of time as normal individuals. After beta carotene therapy is discontinued, patients exhibit decreased tolerance to artificial light and/or sunlight, usually returning to pretreatment hypersensitivity.
Some clinicians have recommended high-dose antioxidant supplements containing ascorbic acid, beta carotene, and vitamin E with zinc in high-risk patients with age-related macular degeneration†.128, 130 This recommendation is based on results of a randomized, placebo-controlled study in adults 55-80 years of age with age-related macular degeneration who received a high-dose antioxidant vitamin supplement (ascorbic acid 500 mg, vitamin E 400 units, beta carotene 15 mg) daily, zinc 80 mg (as zinc oxide) daily (with copper 2 mg [as cupric oxide] daily to prevent potential anemia), high-dose antioxidant vitamin supplement plus zinc, or placebo for about 6.3 years.128, 130 Although patients in all treatment groups continued to progress toward advanced age-related macular degeneration and lost vision over the study period, results indicated that administration of zinc or high-dose antioxidant vitamin supplement plus zinc lowered the risk of developing advanced age-related macular degeneration in high-risk patients (i.e., those with intermediate stage age-related macular degeneration or advanced stage macular degeneration in only one eye).128, 130 In addition, administration of high-dose antioxidant vitamin supplement plus zinc reduced the risk of vision loss caused by advanced age-related macular degeneration in high-risk patients.128 Administration of a high-dose antioxidant vitamin supplement, zinc, or high-dose antioxidant vitamin supplement plus zinc did not delay progression of age-related macular degeneration in adults with early disease.128, 130 However, patients in these groups had a lower incidence of developing advanced age-related macular degeneration during the study period, and it is not known whether longer-term (e.g., 10-20 years) supplementation with high-dose antioxidant vitamins and zinc would be effective in these patients.128, 130 Based on results of this study, some clinicians suggest that adults with extensive intermediate size drusen, at least one large drusen, noncentral geographic atrophy in one or both eyes, or advanced age-related macular degeneration or vision loss due to macular degeneration in one eye should consider taking a vitamin and zinc supplement similar to the one evaluated in this study.128, 130 Because beta carotene has been associated with an increased incidence of lung cancer in smokers, these individuals may choose a vitamin and zinc supplement with only some of the ingredients used in this study.128
Beta carotene also has been used with variable success in the management of polymorphous light eruption† and photosensitivity caused by diseases other than EPP†. Further studies are required to determine the value of the drug in these conditions. In some patients with polymorphous light eruption, concomitant use of beta carotene and a sunscreen (e.g., aminobenzoic acid, sulisobenzone) may protect against photosensitivity. Beta carotene is not effective as a sunscreen in normal individuals and should not be used for that purpose. A combination preparation containing beta carotene and canthaxanthin has been used orally for cosmetic “tanning” by coloring the skin (carotenodermia).
Current evidence from controlled clinical studies does not support a benefit of beta carotene supplementation on cardiovascular risk.100, 101, 102, 105, 106, 107 (See Pharmacology.)
Beta carotene is administered orally. The drug may be administered as a single daily dose or in divided doses, preferably with meals. The contents of beta carotene capsules may be mixed with orange or tomato juice to facilitate administration to children.
Dosage of beta carotene should be adjusted according to individual requirements and response. Several weeks of therapy are often required before enough beta carotene has accumulated in the skin to exert a protective effect. Patients should be cautioned not to increase time of exposure to the sun until carotenodermia is evident. Exposure to the sun then may be cautiously and gradually increased. The usual adult dosage of beta carotene is 30-300 mg daily. The usual dosage for children younger than 14 years of age is 30-150 mg daily. It has been recommended that the dosage of beta carotene be adjusted to maintain blood carotene concentrations of 4-6 mcg/mL.
To reduce the risk of advanced age-related macular degeneration† in patients at high risk, some clinicians recommend beta carotene dosages of 15 mg daily in combination with ascorbic acid 500 mg daily, vitamin E 400 units daily, and zinc (as zinc oxide) 80 mg daily, with copper (as cupric oxide) 2 mg daily (to prevent anemia).128, 130 This recommendation is based on results of a clinical study in adults with age-related macular degeneration which demonstrated beneficial results in high-risk individuals receiving a high-dose antioxidant vitamin supplement and zinc in these dosages.128, 130
Beta carotene is well tolerated. Carotenodermia is usually the only adverse effect. Patients should be forewarned that carotenodermia will develop after 2-6 weeks of therapy, usually first noticed as yellowness of the palms of the hands or soles of the feet and to a lesser extent of the face. Some patients may experience loose stools during beta carotene therapy, but this is sporadic and may not require discontinuance of therapy. Ecchymoses and arthralgia have been reported rarely.
Beta carotene supplementation was associated with an increased incidence of lung cancer in adult smokers in 2 large randomized placebo-controlled studies.113, 129
Precautions and Contraindications
Beta carotene should be used with caution in patients with impaired renal or hepatic function because safe use of the drug in the presence of these conditions has not been established. Although abnormally high blood concentrations of vitamin A do not occur during beta carotene therapy, patients receiving beta carotene should be advised against taking supplementary vitamin A because beta carotene will fulfill normal vitamin A requirements. Patients should be cautioned that large quantities of green or yellow vegetables or their juices or extracts are not suitable substitutes for crystalline beta carotene because consumption of excessive quantities of these vegetables may cause adverse effects such as leukopenia or menstrual disorders. Patients should be warned that the protective effect of beta carotene is not total and that they may still develop considerable burning and edema after sufficient exposure to sunlight. Each patient must establish his own time limit of exposure.
Beta carotene is contraindicated in patients with known hypersensitivity to the drug.
Mutagenicity and Carcinogenicity
In vitro and in vivo studies have not shown beta carotene to be mutagenic. The carcinogenic potential of the drug has not been determined to date.
Pregnancy, Fertility, and Lactation
Reproduction studies in rats using beta carotene dosages 300-400 times the maximum usual human dosage have shown the drug to be fetotoxic (an increase in resorption rate) but not teratogenic; at 75 times the maximum usual human dosage or less, no such fetotoxicity was observed. A 3-generation reproduction study in rats receiving beta carotene at a dietary concentration of 0.1% has revealed no evidence of harm to the fetus. There are no adequate and controlled studies to date in humans. Beta carotene should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
The effect of beta carotene on fertility in humans is not known. No evidence of impaired fertility has been observed in a 3-generation reproduction study in rats receiving the drug at a dietary concentration of 0.1%, nor in male rats receiving 100 times the recommended human dosage.
Since it is not known whether beta carotene is distributed into milk, the drug should be used with caution in nursing women.
Orlistat may result in decreased GI absorption of fat-soluble vitamins such as beta carotene.119 At least 2 hours should elapse between (before or after) any orlistat dose and beta carotene administration; administering fat-soluble vitamins at bedtime may be a convenient time.119, 121, 125, 127 In clinical studies, fat-soluble vitamin (A, beta carotene, D, E, and K) concentrations remained within the normal range for most patients despite decreases, and supplemental vitamin administration was only occasionally needed.120, 121, 122, 123, 124, 126
Beta carotene protects patients with erythropoietic protoporphyria (EPP) against severe photosensitivity reactions (burning sensation, edema, erythema, pruritus, and/or cutaneous lesions). The drug has no effect on the basic biochemical abnormality of EPP (i.e., erythrocyte, plasma, and stool concentrations of protoporphyrins are not altered by the drug). The precise mechanism by which the drug exerts photoprotection has not been established. There is some evidence that photosensitizers may act through the formation of singlet excited oxygen and/or free radicals. Since in vitro studies indicate that beta carotene can quench free radicals and singlet excited oxygen, this may be the mechanism by which the drug acts. It is unlikely that beta carotene acts simply as a filter for the wavelengths of light that induce phototoxic effects.
Patients receiving chronic beta carotene therapy experience hypercarotenemia and carotenodermia (yellow or orange skin pigmentation because of accumulation of the drug in the skin). However, unlike patients with jaundice, the sclera does not become yellow. As blood beta carotene concentrations increases, patients with EPP react less intensely to artificial (xenon arc) light and sunlight. The response of the patient to artificial light shows a qualitative but not a quantitative relationship to the response to sunlight. Patients who reported increased tolerance to sunlight also demonstrated increased tolerance to exposure to artificial light, although the ability of a patient to tolerate a given amount of exposure to xenon arc light could not be correlated to the ability to tolerate a given amount of sunlight. Although dietary beta carotene is normally converted to vitamin A, blood concentrations of vitamin A do not rise above normal following chronic administration of beta carotene to patients with EPP.
There is epidemiologic evidence of an association between increased intake of antioxidants (e.g., vitamin E) and a reduction in cardiovascular morbidity and mortality.100, 108 The exact mechanism(s) of action of antioxidants in providing cardiovascular benefits currently is not known; however, it has been postulated (the oxidative-modification hypothesis of atherosclerosis) that atherogenesis is initiated by oxidation of lipids in low-density lipoproteins (i.e., by lipid peroxidation), and that antioxidants that inhibit lipid peroxidation in LDL should limit atherosclerosis and its clinical manifestations.100, 101, 108 Beta carotene is a weak antioxidant that is incorporated into LDL cholesterol, but most100, 101, 108, 109 (although not all)108, 110 evidence indicates that beta carotene, unlike vitamin E, does not increase the resistance of LDL to oxidation in the vascular endothelium. In addition, randomized, controlled clinical studies have failed to show a beneficial effect of beta carotene on coronary artery disease,100, 101, 102, 105, 106, 107 although one prospective cohort study reported an inverse relationship between beta carotene intake and coronary artery disease events (but only in current smokers not in nonsmokers)100, 104, 108 and another prospective cohort study reported an inverse relationship between pretreatment plasma carotene concentrations (but not subsequent supplementation) and death from cardiovascular disease.103 In fact, in a few studies, beta carotene actually was associated with an increase in cardiovascular risk.101, 105, 106
Although there is epidemiologic evidence that dietary intake (i.e., relatively high fruit and vegetable intake) may positively influence the risk of certain cancers,111, 112, 113 several placebo-controlled clinical studies114, 115 assessing the effect of supplementation rather than diet failed to demonstrate a beneficial effect of antioxidants (e.g., vitamin E, beta carotene) in reducing the risk of certain cancers (e.g., lung, colorectal).111, 113, 116, 117 In 2 studies, supplementation with beta carotene was associated with an increased incidence of lung cancer in adult smokers.113, 129 Additional study is needed to clarify the possible value of antioxidant vitamin supplements in reducing the risk of certain cancers.111, 113, 115
Absorption of dietary beta carotene depends on the presence of bile and absorbable fat in the intestinal tract and is greatly decreased by steatorrhea and chronic diarrhea. These factors may have a similar effect on absorption of therapeutic doses of beta carotene. During absorption, dietary beta carotene is metabolized to vitamin A in the wall of the small intestine. Studies utilizing 50-mcg doses of radiolabeled beta carotene indicated that only 20-30% of the drug was absorbed unchanged.
Blood carotene concentrations reach a maximum and carotenodermia usually develops about 4-6 weeks after beginning beta carotene therapy. The onset of the photosensitivity protecting action of beta carotene is a minimum of 2-4 weeks and usually coincides with the development of carotenodermia. Decreased tolerance to light is usually evident within 1-2 weeks after discontinuing beta carotene therapy. Therapeutic blood concentrations of the drug appear to be 4-6 mcg/mL for most patients and are usually achieved following daily doses of 60-180 mg. However, a few patients have not benefited from blood concentrations as high as 10-12 mcg/mL.
Beta carotene is widely distributed in the body and accumulates in the skin. An appreciable amount is stored in various tissues, particularly depot fat.
It is not known whether beta carotene is distributed into milk.
Beta carotene may be converted to 2 molecules of retinal by cleavage of the 15-15' double bond in the center of the molecule. Most of the retinal is reduced to retinol which is then conjugated with glucuronic acid and excreted in urine and feces. Some retinal may be further oxidized to retinoic acid which can be decarboxylated and further metabolized, secreted into bile, and excreted in feces as the glucuronide.
Beta carotene is a precursor of vitamin A that is present in green and yellow vegetables. Although beta carotene has 20 cis-trans isomers, it occurs in nature mainly as the all- trans isomer, and the commercially available synthetic drug consists of the all- trans isomer. trans -β-Carotene occurs as red or reddish brown to violet-brown crystals or crystalline powder and is insoluble in water, practically insoluble in alcohol, and sparingly soluble in vegetable oils.
Beta carotene capsules should be stored in tight, light-resistant containers.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Only references cited for selected revisions after 1984 are available electronically.
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