Two capsules contain: Vitamin A (100% as Acetate) 5000 IU • Vitamin C (as Ascorbic Acid) 200 mg • Vitamin E (as d-alpha Tocopheryl Succinate) 100 IU • Selenium (as Selenium Yeast) 100 mcg • Soy Isoflavone Concentrate (34% Isoflavones = 8.5 mg) 25 mg. Other Ingredients: Cellulose, Calcium Carbonate, Gelatin.
Brand name products often contain multiple ingredients. To read detailed information about each ingredient, click on the link for the individual ingredient shown above.
This product has been discontinued by the manufacturer.
This product has been discontinued by the manufacturer.
Below is general information about the effectiveness of the known ingredients contained in the product Soy Preventive. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product Soy Preventive. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when used orally and appropriately. Selenium appears to be safe when taken short-term in amounts below the tolerable upper intake level (UL) of 400 mcg daily (4844,7830,7831,7836,7841,9724,9797,14447,17510,17511)(17512,17513,17515,17516,97087,97943,109085); however, there is concern that taking selenium long-term might not be safe. Some evidence shows that consuming a diet containing more than the recommended dietary allowance (RDA) of selenium, which is 55 mcg daily for most adults, is associated with an increased risk for developing type 2 diabetes (99661). Some evidence also shows that taking a selenium supplement 200 mcg daily for an average of 3-8 years increases the risk of developing type 2 diabetes (97091,99661). Higher serum levels of selenium are also associated with an increased risk of developing diabetes and increased mortality (16710,99661). ...when used intravenously. Selenium, as selenious acid, is an FDA-approved drug. Sodium selenite intravenous infusions up to 1000 mcg daily have been safely used for up to 28 days (90347,92910).
POSSIBLY UNSAFE ...when used orally in high doses or long-term. Doses above 400 mcg daily can increase the risk of developing selenium toxicity (4844,7825). Additionally, some evidence shows that consuming a diet containing more than the recommended dietary allowance (RDA) of selenium, which is 55 mcg daily for most adults, is associated with an increased risk for developing type 2 diabetes (99661). There is also concern that taking a selenium supplement 200 mcg daily long-term, for an average of 3-8 years, increases the risk of developing type 2 diabetes (99661). Higher serum levels of selenium are also associated with an increased risk of developing diabetes and increased mortality (16710,99661).
CHILDREN: POSSIBLY SAFE
when used orally and appropriately.
Selenium seems to be safe when used short-term in doses below the tolerable upper intake level (UL) of 45 mcg daily for infants up to age 6 months, 60 mcg daily for infants 7 to 12 months, 40-90 mcg daily for children 1 to 3 years, 100-150 mcg daily for children 4 to 8 years, 200-280 mcg daily for children 9 to 13 years, and 400 mcg daily for children age 14 years and older (4844,86095); however, there is some concern that long-term use might not be safe. ...when used via a nasogastric tube in premature infants (7835,9764).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately.
Selenium appears to be safe when used short-term in amounts that do not exceed the tolerable upper intake level (UL) of 400 mcg daily (4844,17507,74419,74481,74391); however, there is concern that long-term use might not be safe.
PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses.
Doses above 400 mcg daily may cause significant toxicity (4844).
LACTATION: POSSIBLY SAFE
when used orally and appropriately.
Selenium appears to be safe when used short-term in amounts that do not exceed the tolerable upper intake level (UL) of 400 mcg daily when taken short-term (4844,74467); however, there is concern that long-term use might not be safe.
LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses.
Doses above 400 mcg daily may cause significant toxicity (4844,7838). ...when used orally in HIV-positive women. Selenium supplementation in HIV-positive women not taking highly active antiretroviral therapy may increase HIV-1 levels in breast milk (90358).
LIKELY SAFE ...when soy protein is used orally and appropriately. Soy protein products in doses up to 60 grams, providing up to 185 mg isoflavones, daily have been safely used in studies lasting up to 16 weeks (842,2293,2294,2296,3025,3402,3977,4755,6412,8530)(10372,11805).
POSSIBLY SAFE ...when soy extracts are used orally and appropriately, short-term. Soy extracts containing concentrated isoflavones in doses of 35-120 mg daily have been used with apparent safety for up to 6 months (4751,6455,7802,12040,12048,13209,95994,95999).
CHILDREN: LIKELY SAFE
when consumed in amounts commonly found in foods or as a component of infant formula (3400,4912,7331).
Soy milk that's not designed for infants should not be used as a substitute for infant formula. Regular soy milk can lead to nutrient deficiencies (12045). Most evidence shows that exposure to soy formula or other soy products in infancy does not cause early onset of puberty or health or reproductive problems later in life (7331,11080,108245). However, some small cohort studies have suggested that higher soy intake during childhood may be associated with an increased risk of precocious puberty (108240) and may be weakly correlated with the development of breasts in children less than 2 years of age (75520). This is in contrast to an observational study in Chinese children ages 7-9 years which suggests that higher soy intake is associated with delayed puberty (108252). One small cohort study has also found that use of soy infant formula may be associated with an increased risk of endometriosis in adulthood, although endometriosis was also correlated with prematurity, which may have confounded the findings (101803).
CHILDREN: POSSIBLY UNSAFE
when used orally as an alternative to cow's milk in children with severe milk allergy (75359).
Although soy protein-based infant formulas are often promoted for children with milk allergy, children with a severe allergy to cow's milk are also frequently sensitive to soy protein (9883). There is insufficient reliable information available about the safety of soy products when used in amounts higher than typical food quantities for children.
PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (4912).
PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts.
Soy contains mildly estrogenic constituents (3373,3988,3989,3990,3994,6029,75303). Theoretically, therapeutic use of soy might adversely affect fetal development; avoid using.
LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912).
A single 20-gram dose of roasted soybeans, containing 37 mg isoflavones, produces four to six times less isoflavones in breast milk than provided in a soy-based infant formula (2290). There is insufficient reliable information available about the safety of long-term use of therapeutic amounts of soy during lactation.
LIKELY SAFE ...when used orally or intramuscularly and appropriately. Vitamin A, as pre-formed vitamin A (retinol or retinyl ester), is safe in adults when taken in doses below the tolerable upper intake level (UL) of 10,000 IU (3000 mcg) daily (7135). Higher doses increase the risk of side effects. In an analysis of studies, taking vitamin A supplements alone or in combination with other antioxidants is associated with an increased risk of mortality from all causes (15305,90775). Vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake refer to pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used as the reference amount to determine safety.
POSSIBLY SAFE ...when used topically and appropriately, short-term. Retinol up to 0.5% has been used on the skin daily for up to 12 weeks with apparent safety. No serious adverse effects have been reported in clinical trials (103671,103680,114500).
POSSIBLY UNSAFE ...when used orally in high doses. Doses higher than the UL of 10,000 IU (3000 mcg) per day of pre-formed vitamin A (retinol or retinyl ester) might increase the risk of side effects (7135). While vitamin A 25,000 IU (as retinyl palmitate) daily for 6 months followed by 10,000 IU daily for 6 months has been used with apparent safety in one clinical trial (95052), prolonged use of excessive doses of vitamin A can cause hypervitaminosis A (7135). The risk for developing hypervitaminosis A is related to total cumulative dose of vitamin A rather than a specific daily dose (1467,1469). In an analysis of studies, taking vitamin A supplements alone or in combination with other antioxidants is associated with an increased risk of mortality from all causes (15305,90775). There is insufficient reliable information available about the safety of using sublingual formulations of vitamin A.
CHILDREN: LIKELY SAFE
when used orally or intramuscularly and appropriately.
The amount of pre-formed vitamin A (retinol or retinyl ester) that is safe depends on age. For children up to 3 years of age, doses less than 2000 IU (600 mcg) per day seem to be safe. For children ages 4 to 8, doses less than 3000 IU (900 mcg) per day seem to be safe. For children ages 9 to 13, doses less than 5667 IU (1700 mcg) per day seem to be safe. For children 14 to 18, doses less than 9333 IU (2800 mcg) per day seem to be safe (7135). Vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used as the reference amount for determining safety.
CHILDREN: POSSIBLY UNSAFE
when pre-formed vitamin A (retinol or retinyl ester) is used orally in excessive doses.
For children up to 3 years of age, avoid doses greater than 2000 IU (600 mcg) per day. For children ages 4 to 8, avoid doses greater than 3000 IU (900 mcg) per day. For children ages 9 to 13, avoid doses greater than 5667 IU (1700 mcg) per day. For children ages 14 to 18, avoid doses greater than 9333 IU (2800 mcg) per day (7135). Higher doses of vitamin A supplementation have been associated with increased risk of side effects such as pneumonia, bone pain, and diarrhea (319,95051). Long-term supplementation with low to moderate doses on a regular basis can cause severe, but usually reversible, liver damage (11978).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally or intramuscularly and appropriately.
Vitamin A, as pre-formed vitamin A (retinol or retinyl ester), is safe during pregnancy and lactation when used in doses less than 10,000 IU (3000 mcg) per day in adults 19 years of age and older and 2800 mcg daily in those 14-18 years of age (7135,16823,107293). Vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used as the reference amount to determine safety.
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally or intramuscularly in excessive doses.
Daily intake of greater than 10,000 IU (3000 mcg) can cause fetal malformations (3066,7135). Excessive dietary intake of vitamin A has also been associated with teratogenicity (11978). The first trimester of pregnancy seems to be the critical period for susceptibility to vitamin A-associated birth defects such as craniofacial abnormalities and abnormalities of the central nervous system (7135). Pregnant patients should monitor their intake of pre-formed vitamin A (retinol or retinyl ester). This form of vitamin A is found in several foods including animal products, particularly fish and animal liver, some fortified breakfast cereals, and dietary supplements (3066).
LIKELY SAFE ...when used orally, topically, intramuscularly, or intravenously and appropriately. Vitamin C is safe when taken orally in doses below the tolerable upper intake level (UL). Tell patients not to exceed the UL of 2000 mg daily (1959,4713,4714,4844). ...when used intravenously or intramuscularly and appropriately. Injectable vitamin C is an FDA-approved prescription product (15) and has been used with apparent safety in clinical trials up to 150 mg/kg daily for up to 4 days (114489) and up to 200 mg/kg daily for up to 2 days (114492).
POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 2000 mg daily can significantly increase the risk of adverse effects such as osmotic diarrhea and gastrointestinal upset (4844).
CHILDREN: LIKELY SAFE
when used orally and appropriately (4844,10352,14443).
CHILDREN: POSSIBLY UNSAFE
when used orally in excessive amounts.
Tell patients not to use doses above the tolerable upper intake level (UL) of 400 mg daily for children ages 1 to 3 years, 650 mg daily for children 4 to 8 years, 1200 mg daily for children 9 to 13 years, and 1800 mg daily for adolescents 14 to 18 years. Higher doses can cause osmotic diarrhea and gastrointestinal upset (4844).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (4844).
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses.
Tell patients over age 19 not to use doses exceeding the UL of 2000 mg daily when pregnant or breast-feeding and for those 14-18 years of age not to use doses exceeding 1800 mg daily when pregnant or breast-feeding. Higher doses can cause osmotic diarrhea and gastrointestinal upset. Large doses of vitamin C during pregnancy can also cause newborn scurvy (4844); avoid using.
LIKELY SAFE ...when used orally or topically and appropriately. Vitamin E is generally considered safe, even at doses exceeding the recommended dietary allowance (RDA); however, adverse effects are more likely to occur with higher doses. The tolerable upper intake level (UL) in healthy people is 1000 mg daily, equivalent to 1100 IU of synthetic vitamin E (all-rac-alpha-tocopherol) or 1500 IU of natural vitamin E (RRR-alpha-tocopherol) (4668,4681,4713,4714,4844,89234,90067,90069,90072,19206)(63244,97075). Although there is some concern that taking vitamin E in doses of 400 IU (form unspecified) per day or higher might increase the risk of adverse outcomes and mortality from all causes (12212,13036,15305,16709,83339), most of this evidence comes from studies that included middle-aged or older patients with chronic diseases or patients from developing countries in which nutritional deficiencies are prevalent.
POSSIBLY UNSAFE ...when used orally in high doses. Repeated doses exceeding the tolerable upper intake level (UL) of 1000 mg daily are associated with significant side effects in otherwise healthy people (4844). ...when used intravenously in large doses. Large repeated intravenous doses of all-rac-alpha-tocopherol (synthetic vitamin E) were associated with decreased activity of clotting factors and bleeding in one report (3074). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults who use e-cigarette, or vaping, products, which often contain vitamin E acetate. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Vitamin E acetate has been detected in most bronchoalveolar lavage samples taken from patients with EVALI. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. While this association shows a correlation between vitamin E acetate inhalation and lung injury, a causal link has not yet been determined, and it is not clear if other toxic compounds are also involved (101061,101062,102970).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Vitamin E has been safely used in children in amounts below the tolerable upper intake level (UL). The UL for healthy children is: 200 mg in children aged 1-3 years, 300 mg in children aged 4-8 years, 600 mg in children aged 9-13 years, and 800 mg in children aged 14-18 years. A UL has not been established for infants up to 12 months of age (23388).
CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL due to increased risk of adverse effects (23388).
...when alpha-tocopherol is used intravenously in large doses in premature infants. Large intravenous doses of vitamin E are associated with an increased risk of necrotizing enterocolitis and sepsis in this population (85062,85083). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adolescents and teenagers who use e-cigarette, or vaping, products. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Constituents in E-cigarette or vaping products with the potential to cause lung injury or impaired lung function include lipids, such as vitamin E acetate. Vitamin E acetate has been detected in all bronchoalveolar lavage samples taken from patients with EVALI. No other ingredient, including THC or nicotine, was found in all samples, and other ingredients, including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable This shows that vitamin E acetate is at the primary site of lung injury. A causal link has not yet been described and it is not clear if other compounds are also involved (101061,101062).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately.
The tolerable upper intake level (UL) during pregnancy is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older. However, maternal supplementation is not generally recommended unless dietary vitamin E falls below the RDA (4260). No serious adverse effects were reported with oral intake of 400 IU per day starting at weeks 9-22 of pregnancy in healthy patients or those at high risk for pre-eclampsia (3236,97075), or with 600-900 IU daily during the last two months of pregnancy (4260). However, some preliminary evidence suggests that taking vitamin E supplements might be harmful when taken in early pregnancy. A case-control study found that taking a vitamin E supplement during the first 8 weeks of pregnancy is associated with a 1.7-9-fold increase in odds of congenital heart defects (16823). However, the exact amount of vitamin E consumed during pregnancy in this study is unclear. Until more is known, advise patients to avoid taking a vitamin E supplement in early pregnancy unless needed for an appropriate medical indication.
LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL).
The UL during lactation is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older (4844).
LACTATION: POSSIBLY UNSAFE
when used orally in amounts that exceed the UL due to increased risk of adverse effects (4844).
Below is general information about the interactions of the known ingredients contained in the product Soy Preventive. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Selenium may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
 Details
Clinical research suggests that taking selenium 10 mcg/kg/day can increase bleeding times by increasing prostacyclin production, which inhibits platelet activity (14540). Other clinical research suggests that taking selenium 75 mcg daily, in combination with ascorbic acid 600 mg, alpha-tocopherol 300 mg, and beta-carotene 27 mg, reduces platelet aggregation (74406).
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Theoretically, selenium might prolong the sedating effects of barbiturates.
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Contraceptive drugs might increase levels of selenium, although the clinical significance of this effect is unclear.
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Some research suggests that oral contraceptives increase serum selenium levels in women taking oral contraceptives; however, other research shows no change in selenium levels (14544,14545,14546,101343). It is suggested that an increase could be due to increased carrier proteins, indicating a redistribution of selenium rather than a change in total body selenium (14545).
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Gold salts might interfere with selenium activity in tissues.
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Theoretically, selenium supplementation may reduce the effectiveness of immunosuppressant therapy.
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Selenium might reduce the beneficial effects of niacin on high-density lipoprotein (HDL) levels.
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A combination of niacin and simvastatin (Zocor) effectively raises HDL cholesterol levels in patients with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% in patients with coronary disease (7388,11537). It is not known whether this adverse effect is due to a single antioxidant such as selenium, or to the combination. It also is not known whether it will occur in other patient populations.
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Theoretically, selenium might interfere with warfarin activity.
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Animal research suggests that selenium can increase warfarin activity. Selenium might interact with warfarin by displacing it from albumin binding sites, reducing its metabolism in the liver, or by decreasing production of vitamin K-dependent clotting factors (14541). Selenium can also prolong bleeding times in humans by increasing prostacyclin production, which inhibits platelet activity (14540).
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Theoretically, antibiotics may decrease the activity of soy isoflavones.
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Intestinal bacteria are responsible in part for converting soy isoflavones into their active forms. Antibiotics may decrease the amount of intestinal bacteria and decrease its ability to convert isoflavones (7657).
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Soy can lower blood glucose and have additive effects with antidiabetes drugs.
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Clinical research shows that whole soy diets and soy-based meals reduce fasting glucose levels in diabetic and non-diabetic individuals (75268,75296,75378,75493,96001). Also, individuals following a soy-based meal replacement plan seem to require lower doses of sulfonylureas and metformin to manage blood glucose levels when compared with individuals following a diet plan recommended by the American Diabetes Association (75268).
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Theoretically soy protein may have additive effects with antihypertensive drugs and increase the risk of hypotension.
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Theoretically, soy might reduce the clearance of caffeine.
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Soy contains genistein. Taking genistein 1 gram daily for 14 days seems to inhibit caffeine clearance and metabolism in healthy females (23582). This effect has been attributed to inhibition of the cytochrome P450 1A2 (CYP1A2) enzyme, which is involved in caffeine metabolism. It is unclear if this effect occurs with the lower amounts of genistein found in soy.
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Soy might modestly induce CYP2C9 enzymes. However, this effect does not seem to be clinically significant.
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In vitro research suggests that an unhydrolyzed soy extract might induce CYP2C9. However, the significance of this interaction is likely minimal. In healthy females taking a specific extract of soy (Genistein Soy Complex, Source Naturals), blood levels of losartan, a CYP2C9 substrate, were not significantly affected (16825).
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Theoretically, soy might have additive effects when used with diuretic drugs.
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Animal research suggests that genistein, a soy isoflavone, increases diuresis within 6 hours of subcutaneous administration in rats. The effects seem to be similar to those of furosemide (75604). This effect has not been reported in humans.
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Theoretically, soy might competitively inhibit the effects of estrogen replacement therapy.
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Soy contains phytoestrogens and has been shown to have estrogenic activity in some patients (3860). Although this has not been demonstrated in humans, theoretically, concomitant use of soy with estrogen replacement therapy might reduce the effects of the estrogen replacement therapy.
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Soy products might reduce the absorption of levothyroxine in some patients.
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Preliminary clinical research and a case report suggest that soy-based formulas inhibit the absorption of levothyroxine in infants with congenital hypothyroidism (20636,20637,75548,90959). A levothyroxine dosage increase may be needed for infants with congenital hypothyroidism while using soy-based formulas, and the dose may need to be reduced when soy-based formulas are no longer administered. However, in postmenopausal adults, clinical research shows that taking a single dose of soy extract containing isoflavones 60 mg along with levothyroxine does not affect the oral bioavailability of levothyroxine (95996).
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Taking soy products containing high amounts of tyramine along with MAOIs can increase the risk of hypertensive crisis.
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Fermented soy products such as tofu and soy sauce contain tyramine, a naturally occurring chemical that affects blood pressure regulation. The metabolism of tyramine is decreased by MAOIs. Consuming more than 6 mg of tyramine while taking an MAOI can increase the risk of hypertensive crisis (15649). The amount of tyramine in fermented soy products is usually less than 0.6 mg per serving; however, there can be significant variation depending on the specific product used, storage conditions, and length of storage. Storing one brand of tofu for a week can increase tyramine content from 0.23 mg to 4.8 mg per serving (15649,15701,15702). Advise patients taking MAOIs to avoid fermented soy products that contain high amounts of tyramine.
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Theoretically, combining soy isoflavones with transdermal progesterone may worsen bone density.
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Clinical research suggests that significant bone loss may occur in females with osteoporosis who receive a combination of transdermal progesterone with soy milk containing isoflavones when compared with placebo, soy milk alone, or progesterone alone (69859).
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Theoretically, estrogenic soy isoflavones might alter the effects of tamoxifen.
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Laboratory research suggests that genistein and daidzen, isoflavones from soy, can antagonize the antitumor effects of tamoxifen under some circumstances (7072,14362,8966); however, soy isoflavones might have different effects when used at different doses. A relatively low in vitro concentration of soy isoflavones such as 1 microM/L seems to interfere with tamoxifen, whereas high in vitro concentrations such as those >10 microM/L might actually enhance tamoxifen effects. People on a high-soy diet have soy isoflavones levels ranging from 0.1-6 microM/L. Until more is known, advise patients taking tamoxifen to avoid therapeutic use of soy products.
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Theoretically, soy might interfere with the effects of warfarin.
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Soy milk has been reported to decrease the international normalized ratio (INR) in a patient taking warfarin. The mechanism of this interaction is not known (9672). However, animal and in vitro research suggests that soy may also inhibit platelet aggregation (3992). Dosing adjustments for warfarin may be necessary.
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Theoretically, taking high doses of vitamin A in combination with other potentially hepatotoxic drugs might increase the risk of liver disease.
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Concomitant use of retinoids with vitamin A supplements might produce supratherapeutic vitamin A levels.
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Retinoids, which are vitamin A derivatives, could have additive toxic effects when taken with vitamin A supplements (3046).
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Theoretically, taking tetracycline antibiotics with high doses of vitamin A can increase the risk of pseudotumor cerebri.
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Benign intracranial hypertension (pseudotumor cerebri) can occur with tetracyclines and with acute or chronic vitamin A toxicity. Case reports suggest that taking tetracyclines and vitamin A concurrently can increase the risk of this condition (10545,10546,10547). Avoid high doses of vitamin A in people taking tetracyclines chronically.
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Theoretically, high doses of vitamin A could increase the risk of bleeding with warfarin.
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Vitamin A toxicity is associated with hemorrhage and hypoprothrombinemia, possibly due to vitamin K antagonism (505). Advise patients taking warfarin to avoid doses of vitamin A above the tolerable upper intake level of 10,000 IU/day for adults.
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High-dose vitamin C might slightly prolong the clearance of acetaminophen.
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A small pharmacokinetic study in healthy volunteers shows that taking high-dose vitamin C (3 grams) 1.5 hours after taking acetaminophen 1 gram slightly increases the apparent half-life of acetaminophen from around 2.3 hours to 3.1 hours. Ascorbic acid competitively inhibits sulfate conjugation of acetaminophen. However, to compensate, elimination of acetaminophen glucuronide and unconjugated acetaminophen increases (6451). This effect is not likely to be clinically significant.
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Theoretically, antioxidant effects of vitamin C might reduce the effectiveness of alkylating agents.
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The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs that generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin C have on chemotherapy.
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Vitamin C can increase the amount of aluminum absorbed from aluminum compounds.
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Research in animals and humans shows that vitamin C increases aluminum absorption, theoretically by chelating aluminum and keeping it in solution where it is available for absorption (10549,10550,10551,21556). In people with normal renal function, urinary excretion of aluminum will likely increase, making aluminum retention and toxicity unlikely (10549). Patients with renal failure who take aluminum-containing compounds such as phosphate binders should avoid vitamin C supplements in doses above the recommended dietary allowances.
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Theoretically, the antioxidant effects of vitamin C might reduce the effectiveness of antitumor antibiotics.
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The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as doxorubicin (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effects, if any, antioxidants such as vitamin C have on chemotherapy.
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Acidification of the urine by vitamin C might increase aspirin levels.
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It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction is not clinically significant.
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Acidification of the urine by vitamin C might increase choline magnesium trisalicylate levels.
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It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046,4531). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.
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Vitamin C might increase blood levels of estrogens.
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Increases in plasma estrogen levels of up to 55% occur under some circumstances when vitamin C is taken concurrently with oral contraceptives or hormone replacement therapy, including topical products (129,130,11161). It is suggested that vitamin C prevents oxidation of estrogen in the tissues, regenerates oxidized estrogen, and reduces sulfate conjugation of estrogen in the gut wall (129,11161). When tissue levels of vitamin C are high, these processes are already maximized and supplemental vitamin C does not have any effect on estrogen levels. Increases in plasma estrogen levels may occur when patients who are deficient in vitamin C take supplements (11161). Monitor these patients for estrogen-related side effects.
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Theoretically, vitamin C might decrease levels of fluphenazine.
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In one patient there was a clinically significant decrease in fluphenazine levels when vitamin C (500 mg twice daily) was started (11017). The mechanism is not known, and there is no further data to confirm this interaction.
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Vitamin C can modestly reduce indinavir levels.
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One pharmacokinetic study shows that taking vitamin C 1 gram orally once daily along with indinavir 800 mg orally three times daily reduces the area under the concentration-time curve of indinavir by 14%. The mechanism of this interaction is unknown, but it is unlikely to be clinically significant in most patients. The effect of higher doses of vitamin C on indinavir levels is unknown (11300,93578).
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Vitamin C can increase levothyroxine absorption.
Details
Two clinical studies in adults with poorly controlled hypothyroidism show that swallowing levothyroxine with a glass of water containing vitamin C 500-1000 mg in solution reduces thyroid stimulating hormone (TSH) levels and increases thyroxine (T4) levels when compared with taking levothyroxine alone. This suggests that vitamin C increases the oral absorption of levothyroxine, possibly due to a reduction in pH (102978).
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Vitamin C might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.
Details
A combination of niacin and simvastatin (Zocor) effectively raises HDL cholesterol levels in patients with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% in patients with coronary disease (7388,11537). It is not known whether this adverse effect is due to a single antioxidant such as vitamin C, or to the combination. It also is not known whether it will occur in other patient populations.
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Acidification of the urine by vitamin C might increase salsalate levels.
Details
It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams/day vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.
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High-dose vitamin C might reduce the levels and effectiveness of warfarin.
Details
Vitamin C in high doses may cause diarrhea and possibly reduce warfarin absorption (11566). There are reports of two people who took up to 16 grams daily of vitamin C and had a reduction in prothrombin time (9804,9806). Lower doses of 5-10 grams daily can also reduce warfarin absorption. In many cases, this does not seem to be clinically significant (9805,9806,11566,11567). However, a case of warfarin resistance has been reported for a patient who took vitamin C 500 mg twice daily. Cessation of vitamin C supplementation resulted in a rapid increase in international normalized ratio (INR) (90942). Tell patients taking warfarin to avoid taking vitamin C in excessively high doses (greater than 10 grams daily). Lower doses may be safe, but the anticoagulation activity of warfarin should be monitored. Patients who are stabilized on warfarin while taking vitamin C should avoid adjusting vitamin C dosage to prevent the possibility of warfarin resistance.
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of alkylating agents.
Details
There's concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.
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Concomitant use of vitamin E and anticoagulant or antiplatelet agents might increase the risk of bleeding.
Details
Vitamin E seems to inhibit of platelet aggregation and antagonize the effects of vitamin K-dependent clotting factors (4733,4844,11580,11582,11583,11584,11586,112162). These effects appear to be dose-dependent, and are probably only likely to be clinically significant with doses of at least 800 units daily (11582,11585). Mixed tocopherols, such as those found in food, might have a greater antiplatelet effect than alpha-tocopherol (10364). RRR alpha-tocopherol (natural vitamin E) 1000 IU daily antagonizes vitamin K-dependent clotting factors (11999). Advise patients to avoid high doses of vitamin E, especially in people with low vitamin K intake or other risk factors for bleeding.
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of antitumor antibiotics.
Details
There's concern that antioxidants could reduce the activity of antitumor antibiotic drugs such as doxorubicin, which generate free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy involving antitumor antibiotics. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.
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A specific form of vitamin E might increase absorption and levels of cyclosporine.
Details
There is some evidence that one specific formulation of vitamin E (D-alpha-tocopheryl-polyethylene glycol-1000 succinate, TPGS, tocophersolan, Liqui-E) might increase absorption of cyclosporine. This vitamin E formulation forms micelles which seems to increase absorption of cyclosporine by 40% to 72% in some patients (624,625,10368). However, this interaction is unlikely to occur with the usual forms of vitamin E.
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Theoretically, vitamin E might induce metabolism of CYP3A4, possibly reducing the levels CYP3A4 substrates.
Details
Vitamin E appears to bind with the nuclear receptor, pregnane X receptor (PXR), which results in increased expression of CYP3A4 (13499,13500). Although the clinical significance of this is not known, use caution when considering concomitant use of vitamin E and other drugs affected by these enzymes.
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Vitamin E might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.
Details
A combination of niacin and simvastatin (Zocor) effectively raises high-density lipoprotein (HDL) cholesterol levels in people with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% (7388,11537). Vitamin E alone combined with a statin does not seem to decrease HDL levels (11286,11287). It is not known whether the adverse effect on HDL is due to one of the other antioxidants or to the combination. It also is not known whether it will occur in other patient populations.
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Taking selumetinib with vitamin E can result in a total daily dose of vitamin E that exceeds safe limits and therefore might increase the risk of bleeding.
Details
Selumetinib contains 48-54 IU vitamin E per capsule (102971). The increased risk of bleeding with vitamin E appears to be dose-dependent (11582,11585,34577). Be cautious when using selumetinib in combination with supplemental vitamin E, especially in patients at higher risk of bleed, such as those with chronic conditions and those taking antiplatelet drugs (102971).
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Using vitamin E with warfarin might increase the risk of bleeding.
Details
Due to interference with production of vitamin K-dependent clotting factors, use of more than 400 IU of vitamin E daily with warfarin might increase prothrombin time (PT), INR, and the risk of bleeding, (91,92,93). At a dose of 1000 IU per day, vitamin E can antagonize vitamin K-dependent clotting factors even in people not taking warfarin (11999). Limited clinical evidence suggests that doses up to 1200 IU daily may be used safely by patients taking warfarin, but this may not be applicable in all patient populations (90).
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Below is general information about the adverse effects of the known ingredients contained in the product Soy Preventive. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Orally, selenium is generally well-tolerated when used in doses that do not exceed the tolerable upper intake level (UL) of 400 mcg daily.
Intravenously, selenium is generally well-tolerated.
Most Common Adverse Effects:
Orally: Gastric discomfort, headache, and rash. Excessive amounts can cause alopecia, dermatitis, fatigue, nail changes, nausea and vomiting, and weight loss.
Serious Adverse Effects (Rare):
Orally: Excessive ingestion has led to cases of multi-organ failure and death.
Dermatologic ...Excess selenium can produce selenosis in humans, affecting liver, skin, nails, and hair (74304,74326,74397,74495,90360,113660) as well as dermatitis (74304). Results from the Nutritional Prevention of Cancer Trial conducted among individuals at high risk of nonmelanoma skin cancer demonstrate that selenium supplementation is ineffective at preventing basal cell carcinoma and that it increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer (10687). Mild skin rash has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months (97943).
Endocrine
...Multiple clinical studies have found an association between increased intake of selenium, either in the diet or as a supplement, and the risk for type 2 diabetes (97091,99661).
One meta-analysis shows that a selenium plasma level of 90 mcg/L or 140 mcg/L is associated with a 50% or 260% increased risk for developing type 2 diabetes, respectively, when compared with plasma levels below 90 mcg/L. Additionally, consuming selenium in amounts exceeding the recommended dietary allowance (RDA) is associated with an increased risk of developing diabetes when compared with consuming less than the RDA daily. Also, taking selenium 200 mcg daily as a supplement is associated with an 11% increased risk for diabetes when compared with a placebo supplement (99661).
Hypothyroidism, secondary to iodine deficiency, has been reported as a result of selenium intravenous administration (14563,14565). One large human clinical trial suggested a possible increased risk of type 2 diabetes mellitus in the selenium group (16707).
Gastrointestinal ...In human research, nausea, vomiting, and liver dysfunction has been reported as a result of high selenium exposure (74439,74376,113660). Mild gastric discomfort has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months (97943).
Genitourinary ...The effect of selenium supplementation on semen parameters is unclear. In human research, selenium supplementation may reduce sperm motility (9729); however, follow-up research reported no effect on sperm motility or any other semen quality parameter (74441).
Musculoskeletal ...Chronic selenium exposure of 30 mg daily for up to 24 weeks may cause arthralgia, myalgia, and muscle spasms (113660).
Neurologic/CNS ...Chronic exposure to organic and inorganic selenium may cause neurotoxicity, particularly motor neuron degeneration, leading to an increased risk of amyotrophic lateral sclerosis (ALS) (74304). Headache has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months and in patients taking sodium selenate 30 mg daily for up to 24 weeks (97943,113660).
General
...Orally, soy is well tolerated.
Most Common Adverse Effects:
Orally: Bloating, constipation, diarrhea, and nausea.
All ROAs: Allergic reactions.
Endocrine
...In the 1950s and 1960s, cases of altered thyroid function, particularly goiter, were reported in children taking soy formula.
However, adding iodine to soy formula or replacing soy flour in formula with soy protein isolate has nearly eliminated the risk of altered thyroid function in most infants (75353,75651).
In adults, there is some evidence that soy intake can alter thyroid function. Results from one clinical trial suggests that consuming soybeans 30 grams daily for as little as one month can increase thyroid-stimulating hormone (TSH) and decrease thyroxine, causing diffuse goiters, constipation, fatigue, and lethargy in some Japanese men. Recovery was achieved by discontinuing soybean intake (75206,75353). There is also some evidence that soy inhibits thyroid hormone synthesis resulting in increased secretion of TSH in some postmenopausal patients (7806). However, this seems to only occur in people with iodine deficiency (6466,75311). In postmenopausal patients with normal levels of iodine, taking a soy extract for 6 months does not seem to significantly affect thyroid hormone levels (13010).
Evidence from a single case-control study suggests that consumption of soy-based formulas may be associated with an observed three-fold increase in the risk of breast development in Puerto Rican children less than 2 years-old (75520). The correlation has been attributed to the estrogenic activity of soy. However, other risk factors, including a maternal history of ovarian cysts and consumption of meat products were also associated with the increased risk of breast development prior to 2 years of age. Also, the investigators noted that in over half of the cases, the child had not been exposed to soy or any of the other risk factors. Therefore, factors other than soy consumption may be more strongly associated with the increased risk of breast development prior to 2 years of age.
Gastrointestinal ...Gastrointestinal upset, such as constipation, diarrhea, bloating, and nausea are the most common side effects of soy (2297,11033,11082,15851,75491,95999). Reports of "bad taste" and taste intolerance have also been documented in clinical research (15851,39007,75491). Firmer stools, diarrhea, colitis, and intestinal mucosal damage has been reported in infants fed soy protein formula (75161,75448,75516,75525).
Genitourinary
...Orally, soy might increase discomfort during menstrual periods.
Evidence from a small, retrospective cohort study has found that consuming soy formula as an infant may slightly increase the duration and discomfort of menstrual periods later in life. However, the investigators noted that these differences may not be clinically significant (7331).
Orally, frequent soy consumption might be a risk factor for uterine leiomyoma, an estrogen-dependent benign tumor located on the uterus. Observational research found that consumption of soy milk or soybean at least four times weekly is associated with a 7-fold increased odds of uterine leiomyoma (98869).
There is some concern that use of soy-based formulas in infants might result in long-term health complications. However, results from a retrospective cohort study has found that intake of soy-based formula as an infant does not affect height, weight, body mass index, pubertal maturation, menstrual history, or pregnancy history, nor does it increase the risk of reproductive organ disorders, hormonal disorders, libido dysfunction, or birth defects in the offspring of adults who received soy formula as infants (7331,11080). Additionally, research in adults shows that urinary phytoestrogens are not associated with endometriosis risk (101804). However, some population research has found that regular exposure to soy-based formulas during infancy is associated with an increased risk for endometriosis (101803).
Immunologic
...Orally, soy can cause allergic reactions such as skin rash and itching in some people (6412).
In an 11-year-old female, allergy to soy protein resulting in a delayed itching papular rash was thought to be responsible for the reaction to injected benzathine benzylpenicillin containing possible soy protein-contaminated soy lecithin (96422).
Topically, soy-based ingredients were responsible for the development of hand atopic dermatitis in a young female using cosmetic lotions in the workplace. Percutaneous sensitization resulted in the development of anaphylaxis to oral soy (96000).
Neurologic/CNS ...Orally, one clinical study showed that insomnia was more common in postmenopausal adults taking soy isoflavone supplements when compared with those receiving placebo (9917). Some research suggests that dietary consumption of tofu during midlife might decrease cognitive function in later years. Evidence from one retrospective cohort study suggests that males who consume at least two servings of tofu weekly during midlife have increased risk of cognitive impairment in late life (19% vs. 4%) compared to those who consume tofu less frequently. Although the effect of tofu was considered to be marginal compared to other factors such as age, education, or history of stroke, results from the study suggest that the effect of significant midlife consumption of tofu is comparable to the effect of an age difference of 4 years or an education difference of 3 years. However, numerous other factors, such as lifestyle and health, could be involved (6415,6416). Therefore, these findings are too preliminary to be used as a basis for clinical recommendations.
Oncologic
...There is controversy about the role of soy in breast cancer.
Population studies suggest that soy is protective against breast cancer. Asian females who eat a traditional diet high in soy seem to have a lower risk of developing breast cancer (4590,5939,9674). Early exploratory studies have suggested that soy stimulates proliferation of normal human breast tissue (3980,3981). However, taking a soy tablet containing 50 mg soy isoflavones daily for 12 months does not alter mammographic or breast MRI tissue density in adults at high risk of breast cancer, with non-endocrine treated breast cancer, or previously treated for breast cancer and without evidence of recurrence (95999).
There is some concern that soy supplements, but not soy foods, might increase the risk of endometrial hyperplasia due to its estrogenic effects. Population and clinical research suggests that soy foods do not have a proliferative effect on endometrial cells (7358,2429,7654,9676,9917), and increased dietary soy and phytoestrogens are associated with reduced endometrial cancer risk (7338,10372). However, the effects seem to be different with concentrated soy isoflavone extract. While taking products providing isoflavones 120 mg daily for 6 months does not increase endometrial thickening (13209), taking higher doses such as isoflavones 150 mg daily for 5 years might increase the risk of simple endometrial hyperplasia (12105). However, there is no evidence that soy isoflavones increase the risk of atypical hyperplasia which has a much higher risk of developing into endometrial cancer than simple endometrial hyperplasia (12105,90973).
There is also concern that increased soy intake increases the risk for other types of cancer. Some observational research has found that higher dietary intake of soy is associated with a higher risk for bladder cancer and pancreatic cancer (9677,105609).
A meta-analysis of results from cohort and case-control studies evaluating the risk of stomach cancer related to consumption of fermented soy products is unclear and inconclusive. The highest quality data from cohort studies suggests that these products have no significant effect on stomach cancer (7340,7341). More research is required to determine if soy products have any correlation with stomach cancer.
Pulmonary/Respiratory ...Inhaled soy dust and soy hull aeroallergen can trigger symptoms of asthma and allergic rhinitis (5084,5085,5086).
General
...Orally, vitamin A is generally well-tolerated at doses below the tolerable upper intake level (UL).
Serious Adverse Effects (Rare):
Orally: In very high doses, vitamin A can cause pseudotumor cerebri, pain, liver toxicity, coma, and even death.
Dermatologic ...Chronic oral use of large amounts of vitamin A causes symptoms of vitamin A toxicity including dry skin and lips; cracking, scaling, and itchy skin; skin redness and rash; hyperpigmentation; shiny skin, and massive skin peeling (7135,95051). Hypervitaminosis A can cause brittle nails, cheilitis, gingivitis, and hair loss (15,95051). Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause skin redness and generalized peeling of the skin a few days later and may last for several weeks (15).
Gastrointestinal ...There is some evidence that oral vitamin A supplementation might increase the risk of diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with diarrhea in well-nourished children (319). Diarrhea (82326,82389), nausea (7135,100329), abdominal pain (95051), abdominal fullness (100329), and vomiting (7135,82559,95051,109755) have been reported following use of large doses of oral vitamin A. Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause vomiting and diarrhea (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including anorexia, abdominal discomfort, and nausea and vomiting (7135).
Genitourinary ...Hypervitaminosis A can cause reduced menstrual flow (15). Intravaginally, all-trans retinoic acid can cause vaginal discharge, itching, irritation, and burning (9199).
Hematologic ...Hypervitaminosis A can cause spider angiomas, anemia, leukopenia, leukocytosis, and thrombocytopenia (15,95051).
Hepatic ...Since the liver is the main storage site for vitamin A, hypervitaminosis A can cause hepatotoxicity, with elevated liver enzymes such as alanine aminotransferase (ALT, formerly SGPT) and aspartate aminotransferase (AST, formerly SGOT), as well as fibrosis, cirrhosis, hepatomegaly, portal hypertension, and death (6377,7135,95051).
Musculoskeletal
...Vitamin A can increase the risk for osteoporosis and fractures.
Observational research has found that chronic, high intake of vitamin A 10,000 IU or more per day is associated with an increased risk of osteoporosis and hip fracture in postmenopausal adults, as well as overall risk of fracture in middle-aged males (7712,7713,9190). A meta-analysis of these and other large observational studies shows that high dietary intake of vitamin A or retinol is associated with a 23% to 29% greater risk of hip fracture when compared with low dietary intake (107294). High serum levels of vitamin A as retinol also increase the risk of fracture in males. Males with high serum retinol levels are seven times more likely to fracture a hip than those with lower serum retinol levels (9190). Vitamin A damage to bone can occur subclinically, without signs or symptoms of hypervitaminosis A. Some researchers are concerned that consumption of vitamin A fortified foods such as margarine and low-fat dairy products in addition to vitamin A or multivitamin supplements might cause excessive serum retinol levels. Older people have higher levels of vitamin A and might be at increased risk for vitamin A-induced osteoporosis.
Vitamin A's effects on bone resorption could lead to hypercalcemia (95051).
Hypervitaminosis can cause slow growth, premature epiphyseal closure, painful hyperostosis of the long bones, general joint pain, osteosclerosis, muscle pain, and calcium loss from the bones (15,95051). One child experienced severe bone pain after taking vitamin A 600,000 IU daily for more than 3 months (95051). Vitamin A was discontinued and symptoms lessened over a period of 2 weeks. The patient made a full recovery 2 months later.
Neurologic/CNS
...Orally, adverse effects from a single large dose of vitamin A are more common in young children than adults (15).
Headache, increased cerebrospinal fluid pressure, vertigo, and blurred vision have been reported following an acute oral dose of vitamin A 500,000 IU (7135). In children, approximately 25,000 IU/kg can cause headache, irritability, drowsiness, dizziness, delirium, and coma (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including fatigue, malaise, lethargy, and irritability (7135).
There are reports of bulging of the anterior fontanelle associated with an acute high oral dose of vitamin A in infants (7135,90784,95053,95054). In children, approximately 25,000 IU/kg can cause increased intracranial pressure with bulging fontanelles in infants (15). Also, muscular incoordination has been reported following short-term high doses of vitamin A (7135).
A case of intracranial hypertension involving diffuse headaches and brief loss of vision has been reported secondary to topical use of vitamin A. The patient was using over-the-counter vitamin A preparations twice daily including Avotin 0.05% cream, Retin-A gel 0.01%, and Isotrexin gel containing isotretinoin 0.05% and erythromycin 2%, for treatment of facial acne. Upon exam, the patient was noted to have bilateral optic disc edema. The patient discontinued use of topical vitamin A products. Two months later, the patient reported decreased headaches and an improvement in bilateral optic disc edema was seen (95056).
Ocular/Otic ...In children, oral vitamin A approximately 25,000 IU/kg can cause swelling of the optic disk, bulging eyeballs, and visual disturbances (15). Adverse effects from a single ingestion of a large dose of vitamin A are more common in young children than adults (15).
Oncologic ...There is concern that high intake of vitamin A might increase some forms of cancer. Population research suggests high vitamin A intake might increase the risk of gastric carcinoma (9194).
Psychiatric ...Chronic oral use of large amounts of vitamin A causes symptoms of vitamin A toxicity, which can include symptoms that mimic severe depression or schizophrenic disorder (7135).
Pulmonary/Respiratory ...There is some evidence that oral vitamin A supplementation might increase the risk of pneumonia and diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with pneumonia and diarrhea in well-nourished children (319). In preschool children, high-dose vitamin A also increases the risk of respiratory infection (82288).
Other ...Chronic use of large amounts of vitamin A (>25,000 IU daily for more than 6 years or 100,000 IU daily for more than 6 months) can cause symptoms of vitamin A toxicity including mild fever and excessive sweating (7135). High intakes of vitamin A may result in a failure to gain weight normally in children and weight loss in adults (15).
General
...Orally, intravenously, and topically, vitamin C is well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, esophagitis, heartburn, headache, osmotic diarrhea, nausea, vomiting. Kidney stones have been reported in those prone to kidney stones. Adverse effects are more likely to occur at doses above the tolerable upper intake level of 2 grams daily.
Topically: Irritation and tingling.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of carotid inner wall thickening after large doses of vitamin C.
Intravenously: There have been case reports of hyperoxalosis and oxalate nephropathy following high-dose infusions of vitamin C.
Cardiovascular
...Evidence from population research has found that high doses of supplemental vitamin C might not be safe for some people.
In postmenopausal adults with diabetes, supplemental vitamin C intake in doses greater than 300 mg per day is associated with increased risk of cardiovascular mortality. However, dietary intake of vitamin C is not associated with this risk. Also, vitamin C intake is not associated with an increased risk of cardiovascular mortality in patients without diabetes (12498).
Oral supplementation with vitamin C has also been associated with an increased rate of carotid inner wall thickening in men. There is preliminary evidence that supplemental intake of vitamin C 500 mg daily for 18 months can cause a 2.5-fold increased rate of carotid inner wall thickening in non-smoking men and a 5-fold increased rate in men who smoked. The men in this study were 40-60 years old (1355). This effect was not associated with vitamin C from dietary sources (1355).
There is also some concern that vitamin C may increase the risk of hypertension in some patients. A meta-analysis of clinical research suggests that, in pregnant patients at risk of pre-eclampsia, oral intake of vitamin C along with vitamin E increases the risk of gestational hypertension (83450). Other clinical research shows that oral intake of vitamin C along with grape seed polyphenols can increase both systolic and diastolic blood pressure in hypertensive patients (13162). Three cases of transient hypotension and tachycardia during intravenous administration of vitamin C have also been reported (114490).
Dental ...Orally, vitamin C, particularly chewable tablets, has been associated with dental erosion (83484).
Dermatologic ...Topically, vitamin C might cause tingling or irritation at the site of application (6166). A liquid containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) has been reported to cause mild tingling and skin tightness (102355). It is unclear if these effects are due to vitamin C, the other ingredients, or the combination.
Gastrointestinal ...Orally, the adverse effects of vitamin C are dose-related and include nausea, vomiting, esophagitis, heartburn, abdominal cramps, gastrointestinal obstruction, and diarrhea. Doses greater than the tolerable upper intake level (UL) of 2000 mg per day can increase the risk of adverse effects such as osmotic diarrhea and severe gastrointestinal upset (3042,4844,96707,104450,114493,114490). Mineral forms of vitamin C, such as calcium ascorbate (Ester-C), seem to cause fewer gastrointestinal adverse effects than regular vitamin C (83358). In a case report, high dose intravenous vitamin C was associated with increased thirst (96709).
Genitourinary ...Orally, vitamin C may cause precipitation of urate, oxalate, or cysteine stones or drugs in the urinary tract (10356). Hyperoxaluria, hyperuricosuria, hematuria, and crystalluria have occurred in people taking 1 gram or more per day (3042,90943). Supplemental vitamin C over 250 mg daily has been associated with higher risk for kidney stones in males. There was no clear association found in females, but the analysis might not have been adequately powered to evaluate this outcome (104029). In people with a history of oxalate kidney stones, supplemental vitamin C 1 gram per day appears to increase kidney stone risk by 40% (12653). A case of hematuria, high urine oxalate excretion, and the presence of a ureteral stone has been reported for a 9-year-old male who had taken about 3 grams of vitamin C daily since 3 years of age. The condition resolved with cessation of vitamin C intake (90936).
Hematologic ...Prolonged use of large amounts of vitamin C can result in increased metabolism of vitamin C; subsequent reduction in vitamin C intake may precipitate the development of scurvy (15). In one case, a patient with septic shock and a large intraperitoneal hematoma developed moderate hemolysis and increased methemoglobin 12 hours after a high-dose vitamin C infusion. The patient received a blood transfusion and the hemolysis resolved spontaneously over 48 hours (112479).
Neurologic/CNS ...Orally, the adverse effects of vitamin C are dose-related and include fatigue, headache, insomnia, and sleepiness (3042,4844,83475,83476).
Renal ...Hyperoxalosis and oxalate nephropathy have been reported following high-dose infusions of vitamin C. Hyperoxalosis and acute kidney failure contributed to the death of a 76-year-old patient with metastatic adenocarcinoma of the lung who received 10 courses of intravenous infusions containing vitamins, including vitamin C and other supplements over a period of 1 month. Dosages of vitamin C were not specified but were presumed to be high-dose (106618). In another case, a 34-year-old patient with a history of kidney transplant and cerebral palsy was found unresponsive during outpatient treatment for a respiratory tract infection. The patient was intubated for acute hypoxemic respiratory failure, initiated on vasopressors, hydrocortisone, and antibacterial therapy, and received 16 doses of vitamin C 1.5 grams. Serum creatinine level peaked at greater than 3 times baseline and the patient required hemodialysis for oliguria and uncontrolled acidosis. Kidney biopsy revealed oxalate nephropathy with concomitant drug-induced interstitial nephritis (106625). In another case, a 41-year-old patient with a history of kidney transplant presented with fever, nausea, and decreased urine output 4 days after receiving intravenous vitamin C 7 grams for urothelial carcinoma. Serum creatinine levels increased from 1.7 mg/dL to 7.3 mg/dL over those 4 days, and hemodialysis was initiated 3 days after admission due to anuria. Renal biopsy confirmed the diagnosis of acute oxalate nephropathy (109962).
Other ...Intravenously, hypernatremia and falsely elevated ketone levels is reported in a patient with septic shock and chronic kidney disease after a high-dose vitamin C infusion. The hypernatremia resolved over 24 hours after cessation of the infusion (112479).
General
...Orally and topically, vitamin E is generally well-tolerated.
Serious Adverse Effects (Rare):
Orally: Bleeding, hemorrhagic stroke, cardiovascular complications.
Inhaled: Vitamin E acetate is thought to be responsible for e-cigarette, or vaping, product-use associated lung injury (EVALI).
Cardiovascular
...Some evidence suggests that taking vitamin E supplements, especially greater than or equal to 400 IU taken by mouth daily for over one year, might also increase the risk of mortality in non-healthy patients (12212,13036,15305,16709,83339).
A population study shows that vitamin E use is associated with a significantly increased risk of mortality in people with a history of severe cardiovascular disease such as stroke or myocardial infarction (16709). In an analysis of clinical trials, patients who took either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) in doses of 400 IU/day or higher had an increased risk of mortality from all causes. The risk of mortality seems to increase when higher doses are used (12212). A large-scale study also suggests that patients with diabetes or cardiovascular disease who take RRR-alpha-tocopherol (natural vitamin E) 400 IU daily have an increased risk of heart failure and heart failure-related hospitalization (13036). However, in another large scale study, taking 600 IU vitamin E every other day for 10 years did not increase the risk of heart failure in healthy females over 45 years of age (90068). There is speculation that high-dose vitamin E might disrupt the normal antioxidant balance and result in pro-oxidant rather than antioxidant effects.
There is some evidence that vitamin E in combination with simvastatin (Zocor), niacin, selenium, vitamin C, and beta-carotene might lower high density lipoprotein-2 (HDL-2) by 15%. HDL-2 is considered to be the most cardioprotective component of HDL (7388). However, vitamin E and a statin alone don't seem to negatively affect HDL (11286,11287). In addition, vitamin E has been associated with increased triglycerides (85215). Although only certain isomers of vitamin E are included for determination of dietary requirements, all isomers are considered for determining safe intake levels. All the isomers are thought to potentially contribute to toxicity.
Dermatologic
...Topically, vitamin E has been associated with contact dermatitis, inflammatory reactions, and eczematous lesions (11998,85066,85285).
Dermatitis, often associated with moisturizers containing vitamin E, has a scattered generalized distribution, is more common on the face than the hands, and is more common in females with a history of atopic dermatitis. In a retrospective analysis of results of patch tests for DL-alpha-tocopherol sensitivity, 0.9% of patients had a definite positive reaction, while over 50% had a weakly positive, non-vesicular erythematous reaction (107869).
Orally, vitamin E has been associated with pruritus in one clinical trial (34596).
Subcutaneously, vitamin E has been associated with reports of lipogranuloma (85188,112331). In one case, subcutaneous injection of a specific supplement (1Super Extenze), containing mineral oil and tocopherol acetate, into the penile tissue resulted in penile disfigurement due to sclerosing lipogranuloma (85188). In another case, a 50-year-old Iranian female presented with lipogranuloma of the face, characterized by severe facial erythema, edema, and tenderness, 3 months after receiving subcutaneous injections of vitamin E to the cheeks for "facial rejuvenation." The patient had noticed initial symptoms within 3 days, and her symptoms progressively worsened over time (112331).
Gastrointestinal ...Orally, vitamin E supplementation has been associated with abdominal pain, nausea, diarrhea, or flu-like symptoms (85040,85323). Intravenously, large doses of vitamin E in premature infants are associated with an increased risk of necrotizing enterocolitis and sepsis (85083,85231).
Genitourinary ...There is contradictory evidence about the effect of vitamin E on prostate cancer risk. One large-scale population study shows that males who take a multivitamin more than 7 times per week and who also take a separate vitamin E supplement have a significantly increased risk of developing prostate cancer (15607). In a large-scale clinical trial (The SELECT trial) in males over the age of 50 years, taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily increased the risk of developing prostate cancer by 17% when compared with placebo. However, the difference in prostate cancer risk between vitamin E and placebo became significant only 3 years after patients stopped taking supplementation and were followed in an unblinded fashion. Interestingly, patients taking vitamin E plus selenium did not have a significantly increased risk of prostate cancer (17688).
Hematologic ...High doses of vitamin E might increase the risk of bleeding due to antagonism of vitamin K-dependent clotting factors and platelet aggregation. Patients with vitamin K deficiencies or taking anticoagulant or antiplatelet drugs are at a greater risk for bleeding (4098,4844,11999,34596,34538,34626,34594,112162).
Neurologic/CNS ...There is concern that vitamin E might increase the risk of hemorrhagic stroke (16708,34594,34596,108641). In one clinical study, there was a higher incidence of hemorrhagic stroke in male smokers taking all-rac-alpha-tocopherol (synthetic vitamin E) for 5-8 years compared to those not taking vitamin E (3949). Other studies lasting from 1.4-4.5 years and using either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) showed no significantly increased risk for stroke (2307,3896,3936). A meta-analysis of studies shows that vitamin E in doses of 300-800 IU daily, including both natural and synthetic forms, does not significantly affect total stroke risk. However, it significantly increases the risk of hemorrhagic stroke by 22%. This means that there will be one additional hemorrhagic stroke for every 1250 patients taking vitamin E. In contrast to this finding, the analysis also found that vitamin E significantly reduces the risk of ischemic stroke by 10%. This means that one ischemic stroke will be prevented for every 476 patients taking vitamin E (14621). In patients with moderately severe Alzheimer disease, taking vitamin E 2000 IU for 2 years has been associated with a modest, but significant, increase in falls and episodes of syncope when compared to placebo (4635).
Pulmonary/Respiratory ...When inhaled, vitamin E acetate is thought to play a role in the development of e-cigarette, or vaping, product-use associated lung injury (EVALI). Although a causal link has not yet been determined, in two case series, vitamin E acetate has been found in most bronchoalveolar lavage samples taken from the primary site of lung injury in patients with EVALI, whereas no vitamin E was found in healthy control samples. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. EVALI has resulted in death in some patients (101062,102970).
Other ...In an analysis of 3 trials, taking vitamin E 400 IU with vitamin C 1000 mg daily for 14-22 weeks during gestation appears to increase the risk of gestational hypertension by 30% compared to placebo in patients at risk of pre-eclampsia. However, the risk of pre-eclampsia itself was not increased (83450).
