| Ingredients | Amount Per Serving |
|---|---|
|
(Vitamin A Acetate)
|
16.6 IU |
|
(Cholecalciferol)
|
133.3 IU |
|
(Seaweed extract)
|
333.3 mg |
|
(Mg)
(Magnesium Citrate)
|
66.6 mg |
|
(Zn)
(Zinc Picolinate)
|
8 mg |
|
(Se)
(Selenium Picolinate)
|
33 mcg |
|
(Mo)
(Molybdenum Citrate)
|
3.3 mcg |
|
Ipriflavones
|
46.6 mg |
|
(Betaine HCl)
|
33.3 mg |
|
(Equisetum arvense )
(herb)
|
33.3 mg |
|
(1,000 IU/g)
|
20 mg |
|
(Gentiana lutea )
(root)
|
6.6 mg |
|
(Boron Citrate)
|
1.3 mg |
|
(Vanadium Citrate)
|
16.6 mg |
Cellulose, Rice Extract, Magnesium Citrate (Alt. Name: Mg Citrate), Rice Concentrate, Silicon Dioxide (Alt. Name: SiO2)
In 2004, Canada began regulating natural medicines as a category of products separate from foods or drugs. These products are officially recognized as "Natural Health Products." These products include vitamins, minerals, herbal preparations, homeopathic products, probiotics, fatty acids, amino acids, and other naturally derived supplements.
In order to be marketed in Canada, natural health products must be licensed. In order to be licensed in Canada, manufacturers must submit applications to Health Canada including information about uses, formulation, dosing, safety, and efficacy.
Products can be licensed based on several criteria. Some products are licensed based on historical or traditional uses. For example, if an herbal product has a history of traditional use, then that product may be acceptable for licensure. In this case, no reliable scientific evidence is required for approval.
For products with non-traditional uses, some level of scientific evidence may be required to support claimed uses. However, a high level of evidence is not necessarily required. Acceptable sources of evidence include at least one well-designed, randomized, controlled trial; well-designed, non-randomized trials; cohort and case control studies; or expert opinion reports.
Finished products licensed by Health Canada must be manufactured according to Good Manufacturing Practices (GMPs) as outlined by Health Canada.
Below is general information about the effectiveness of the known ingredients contained in the product Phytocal A. 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
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
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 Phytocal A. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
POSSIBLY SAFE ...when taken orally as a single dose of up to 1500 mg (93328,93329). There is insufficient reliable information available about the safety of betaine hydrochloride when used in multiple doses.
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally and appropriately. Boron is safe in amounts that do not exceed the tolerable upper intake level (UL) 20 mg daily (7135). ...when used vaginally. Boric acid, the most common form of boron, has been safely used for up to six months (15443,15444,15445,15446,15458,15449,15451,15453,15454). ...when used topically. Boron, in the form of sodium pentaborate pentahydrate 3% gel, has been applied to the skin with apparent safety up to four times daily for up to 5 weeks (95660,109557).
POSSIBLY UNSAFE ...when used orally in doses exceeding the UL of 20 mg daily. Higher doses might adversely affect the testes and male fertility (7135). Poisoning has occurred after ingestion of boron 2.12 grams daily for 3-4 weeks (17). Death has occurred after ingesting a single dose of 30 grams (36848,36863).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Boron is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL by age is 3 mg daily at 1-3 years, 6 mg daily at 4-8 years, 11 mg daily at 9-13 years, and 17 mg daily at 14 years or older (7135). The UL for infants has not been determined (7135).
CHILDREN: POSSIBLY UNSAFE
when used orally in doses exceeding the age-based UL (7135).
...when applied topically in large quantities. Infant deaths have occurred after the use of topical boric acid powder to prevent diaper rash (36873,36874).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately.
Boron is safe in amounts that do not exceed the UL during pregnancy or lactation, which is 20 mg daily in those 19-50 years of age or 17 mg daily for those 14-18 years of age (7135).
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL.
Higher doses might impair growth and cause adverse effects in the developing fetus (7135,102058). ...when used vaginally. Intravaginal boric acid has been associated with a 2.7- to 2.8-fold increased risk of birth defects when used during the first 4 months of pregnancy (15443,15645).
LIKELY SAFE ...when used orally or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).
POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Calcium is safe when used in appropriate doses (17506).
CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses.
The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506).
The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses.
The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).
LIKELY SAFE ...when the root preparations are used in amounts commonly found in foods. Gentian root is categorized by the FDA as a safe food additive flavoring in the US (4912).
POSSIBLY SAFE ...when gentian root is used orally in a specific combination that contains gentian root, elderflower, verbena, cowslip flower, and sorrel (SinuComp, Sinupret) (374,379,95907). There is insufficient reliable information available about the safety of the topical use of gentian.
PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of gentian in medicinal amounts during pregnancy and lactation; avoid using.
POSSIBLY UNSAFE ...when horsetail products containing thiaminase are used orally, long-term. Thiaminase is an enzyme that destroys thiamine, which could theoretically lead to thiamine deficiency. In Canada, horsetail products are required to be thiaminase-free (105301).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
There is insufficient reliable information available about the safety of lipase.
CHILDREN: POSSIBLY UNSAFE
when recombinant human bile salt-stimulated lipase (rhBSSL) is used orally by premature infants.
Adding rhBSSL to infant formula or pasteurized breast milk increases the risk for serious gastrointestinal adverse effects in premature infants (101940).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally and appropriately. Oral magnesium is safe when used in doses below the tolerable upper intake level (UL) of 350 mg daily (7555). ...when used parenterally and appropriately. Parenteral magnesium sulfate is an FDA-approved prescription product (96484).
POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 350 mg daily frequently cause loose stools and diarrhea (7555).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Magnesium is safe when used in doses below the tolerable upper intake level (UL) of 65 mg daily for children 1 to 3 years, 110 mg daily for children 4 to 8 years, and 350 mg daily for children older than 8 years (7555,89396). ...when used parenterally and appropriately (96483).
CHILDREN: LIKELY UNSAFE
when used orally in excessive doses.
Tell patients not to use doses above the tolerable upper intake level (UL). Higher doses can cause diarrhea and symptomatic hypermagnesemia including hypotension, nausea, vomiting, and bradycardia (7555,8095).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately.
Magnesium is safe for those pregnant and breast-feeding when used in doses below the tolerable upper intake level (UL) of 350 mg daily (7555).
PREGNANCY AND LACTATION: POSSIBLY SAFE
when prescription magnesium sulfate is given intramuscularly and intravenously prior to delivery for up to 5 days (12592,89397,99354,99355).
However, due to potential adverse effects associated with intravenous and intramuscular magnesium, use during pregnancy is limited to patients with specific conditions such as severe pre-eclampsia or eclampsia. There is some evidence that intravenous magnesium can increase fetal mortality and adversely affect neurological and skeletal development (12590,12593,60818,99354,99355). However, a more recent analysis of clinical research shows that increased risk of fetal mortality seems to occur only in the studies where antenatal magnesium is used for tocolysis and not for fetal neuroprotection or pre-eclampsia/eclampsia (102457). Furthermore, antenatal magnesium does not seem to be associated with increased risk of necrotizing enterocolitis in preterm infants (104396). There is also concern that magnesium increases the risk of maternal adverse events. A meta-analysis of clinical research shows that magnesium sulfate might increase the risk of maternal adverse events, especially in Hispanic mothers compared to other racial and ethnic groups (60971,99319).
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses.
Tell patients to avoid exceeding the tolerable upper intake level (UL) of 350 mg daily. Taking magnesium orally in higher doses can cause diarrhea (7555). ...when prescription magnesium sulfate is given intramuscularly and intravenously prior to delivery for longer than 5 days (12592,89397,99354,99355). Maternal exposure to magnesium for longer than 5-7 days is associated with an increase in neonatal bone abnormalities such as osteopenia and fractures. The U.S. Food and Drug Administration (FDA) recommends that magnesium injection not be given for longer than 5-7 days (12590,12593,60818,99354,99355).
LIKELY SAFE ...when used orally and appropriately. Molybdenum is safe in amounts that do not exceed 2 mg/day, the Tolerable Upper Intake Level (UL) (7135).
POSSIBLY UNSAFE ...when used orally in high doses. Use of molybdenum in doses exceeding the Tolerable Upper Intake Level (UL) of 2 mg/day might not be safe (7135).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Molybdenum is safe in amounts that do not exceed the Tolerable Upper Intake Level (UL) of 0.3 mg/day for children 1 to 3 years, 0.6 mg/day for children 4 to 8 years, 1.1 mg/day for children 9 to 13 years, and 1.7 mg/day for adolescents (7135).
CHILDREN: POSSIBLY UNSAFE
when used orally in high doses.
Molybdenum might not be safe when used in doses exceeding the UL of 0.3 mg/day for children 1 to 3 years, 0.6 mg/day for children 4 to 8 years, 1.1 mg/day for children 9 to 13 years, and 1.7 mg/day for adolescents (7135).
PREGNANCY: LIKELY SAFE
when used orally and appropriately.
Molybdenum crosses the placenta by passive diffusion and is exchanged freely between the mother and fetus (16482). However, molybdenum is safe when used in amounts that do not exceed the Tolerable Upper Intake Level (UL) of 1.7 mg/day for women 14 to 18 years, or 2 mg/day for women 19 years of age and older (7135).
PREGNANCY: POSSIBLY UNSAFE
when used orally in high doses.
Molybdenum might not be safe during pregnancy when used in doses exceeding the UL of 1.7 mg/day for women 14 to 18 years, or 2 mg/day for women 19 and older (7135).
LACTATION: LIKELY SAFE
when used orally and appropriately.
Molybdenum is safe when used in amounts that do not exceed the Tolerable Upper Intake Level (UL) of 2 mg/day for breast-feeding women 19 years of age or older, or 1.7 mg/day for breast-feeding women ages 14 to 18 years (7135).
LACTATION: POSSIBLY UNSAFE
when used orally in high doses.
Molybdenum might not be safe when used in doses exceeding the UL of 2 mg/day for breast-feeding women 19 or older, or 1.7 mg/day for breast-feeding women ages 14 to 18 years (7135).
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 used orally and appropriately. Vanadium is safe when taken in amounts below the tolerable upper intake level (UL) of 1.8 mg daily (7135).
POSSIBLY UNSAFE ...when used orally in high doses. Taking more than the tolerable upper intake level (UL) of 1.8 mg daily can increase the risk of gastrointestinal side effects and theoretically, kidney toxicity (7135). In some cases, patients with diabetes have used very high doses (100 mg daily) safely for up to 4 weeks (3055,3056,3057). However, there is concern that prolonged use of high doses might cause serious side effects including kidney damage (7135). Doses of 22.5 mg daily for five months can cause cramps and diarrhea (3012).
CHILDREN: LIKELY SAFE
when used orally in amounts found in foods (7135).
There is insufficient reliable information available about the safety of vanadium when used in amounts greater than those typically found in foods.
PREGNANCY: LIKELY SAFE
when used orally in amounts found in foods (7135).
PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts.
Epidemiological research has found that increased urinary levels of vanadium are associated with an increased risk of both term and preterm premature rupture of membranes (PROM). When comparing tertiles of urinary vanadium levels, patients in the middle tertile had 1.66 times the risk of term PROM when compared with the lowest tertile, and those in the highest tertile had 3.75 times the risk. For preterm PROM (rupture prior to 37 weeks' gestation), those in the highest tertile had an 8.14 times increased risk when compared with those in the lowest tertile (99052). Epidemiological research has also found that higher prenatal serum levels of vanadium are associated with impaired fetal growth, particularly in male newborns. The risk appears greatest with vanadium exposure in the second trimester (102096).
LACTATION: LIKELY SAFE
when used orally in amounts found in foods (7135).
There is insufficient reliable information available about the safety of vanadium when used in amounts greater than those typically found in foods; avoid using.
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 or intramuscularly and appropriately. Vitamin D has been safely used in a wide range of doses (7555,16888,16891,17476,95913,98186,104619,105209,109040,109059)(115580,115590). When used orally long-term, doses should not exceed the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults (17506,99773); however, much higher doses such as 50,000 IU (1250 mcg) weekly orally for 6-12 weeks are often needed for the short-term treatment of vitamin D deficiency (16891,17476,115590). Monthly oral doses of up to 60,000 IU (1500 mcg) have also been safely used for up to 5 years (105726). Toxicity usually does not occur until plasma levels exceed 150 ng/mL (17476).
POSSIBLY UNSAFE ...when used orally in excessive doses, long-term. Taking doses greater than the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults for long periods can increase the risk of hypercalcemia (17506); however, much higher doses are often needed for short-term treatment of vitamin D deficiency. Toxicity typically occurs when levels exceed 150 ng/mL (17476).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
When used long-term, doses should not exceed the tolerable upper intake level (UL) of 1000 IU (25 mcg) daily for those 0-6 months of age, 1500 IU (37.5 mcg) daily for those 6-12 months of age, 2500 IU (62.5 mcg) daily for those 1-3 years of age, 3000 IU (75 mcg) daily for those 4-8 years of age, and 4000 IU (100 mcg) daily for those 9 years and older (17506); however, much higher doses are often needed for the short-term treatment of vitamin D deficiency. Some research shows that giving vitamin D 14,000 IU (350 mcg) weekly for a year in children aged 10-17 years is safe (16875). A meta-analysis of clinical studies shows that 1000 IU (25 mcg) daily in those up to a year of age and greater than 2000 IU (50 mcg) daily in those aged 1-6 years does not increase the risk of serious adverse events (108424).
CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses for longer than one year.
Taking doses greater than the tolerable upper intake level (UL) long-term can increase the risk of hypercalcemia (17506).
PREGNANCY: LIKELY SAFE
when used orally and appropriately.
Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506,95910).
PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive amounts.
Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily. Hypercalcemia during pregnancy due to excessive vitamin D intake can lead to several fetal adverse effects, including suppression of parathyroid hormone, hypocalcemia, tetany, seizures, aortic valve stenosis, retinopathy, and mental and/or physical developmental delay (17506).
LACTATION: LIKELY SAFE
when used orally and appropriately.
Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).
LACTATION: POSSIBLY UNSAFE
when used orally in excessive amounts.
Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).
LIKELY SAFE ...when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 40 mg daily (7135). ...when used topically and appropriately (2688,6538,6539,7135,8623,11051,111291).
POSSIBLY SAFE ...when used orally and appropriately in doses higher than the tolerable upper intake level (UL). Because the UL of zinc is based on regular daily intake, short-term excursions above 40 mg daily are not likely to be harmful. In fact, there is some evidence that doses of elemental zinc as high as 80 mg daily in combination with copper 2 mg can be used safely for approximately 6 years without significant adverse effects (7303,8622,92212). However, there is some concern that doses higher than the UL of 40 mg daily might decrease copper absorption and result in anemia (7135).
POSSIBLY UNSAFE ...when used intranasally. Case reports and animal research suggest that intranasal zinc might cause permanent anosmia or loss of sense of smell (11155,11156,11703,11704,11705,11706,11707,16800,16801,17083). Several hundred reports of anosmia have been submitted to the US Food and Drug Administration (FDA) and the manufacturer of some intranasal zinc products (Zicam) (16800,16801). Advise patients not to use intranasal zinc products.
LIKELY UNSAFE ...when taken orally in excessive amounts. Ingestion of 10-30 grams of zinc sulfate can be lethal in adults (7135). Chronic intake of 450-1600 mg daily can cause multiple forms of anemia, copper deficiency, and myeloneuropathies (7135,17092,17093,112473). This has been reported with use of zinc-containing denture adhesives in amounts exceeding the labeled directions, such as several times a day for several years (17092,17093). Advise patients to follow the label directions on denture adhesives that contain zinc.
CHILDREN: LIKELY SAFE
when used orally and appropriately (7135).
Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL for children is based on age: 4 mg daily for 0-6 months, 5 mg daily for 7-12 months, 7 mg daily for 1-3 years, 12 mg daily for 4-8 years, 23 mg daily for 9-13 years, and 34 mg daily for 14-18 years (7135,97140).
CHILDREN: POSSIBLY UNSAFE
when used orally in high doses.
Taking amounts greater than the UL can cause sideroblastic anemia and copper deficiency (7135). ...when used topically on damaged skin. An infant treated with 10% zinc oxide ointment for severe diaper rash with perianal erosions developed hyperzincemia. Absorption seemed to occur mainly via the erosions; plasma levels dropped after the erosions healed despite continued use of the ointment (106905).
PREGNANCY: LIKELY SAFE
when used orally and appropriately.
Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during pregnancy in those 14-18 years of age and 40 mg daily in those 19-50 years of age (7135).
PREGNANCY: LIKELY UNSAFE
when used orally in doses exceeding the UL (7135).
LACTATION: LIKELY SAFE
when used orally and appropriately.
Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during lactation in those 14-18 years of age, and 40 mg daily for those 19-50 years of age (7135).
LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL.
Higher doses can cause zinc-induced copper deficiency in nursing infants (7135).
Below is general information about the interactions of the known ingredients contained in the product Phytocal A. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Betaine hydrochloride increases stomach acidity and could decrease the effects of antacids.
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Betaine hydrochloride increases stomach acidity and could decrease the effects of H2-blockers.
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Betaine hydrochloride increases stomach acidity and could decrease the effects of PPIs.
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Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.
Details
Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).
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Calcium reduces the absorption of bisphosphonates.
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Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).
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Taking calcipotriene with calcium might increase the risk for hypercalcemia.
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Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.
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Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.
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Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).
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Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.
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Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.
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Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.
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Theoretically, calcium may reduce the therapeutic effects of diltiazem.
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Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.
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Calcium seems to reduce levels of dolutegravir.
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Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).
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Calcium seems to reduce levels of elvitegravir.
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Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).
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Calcium seems to reduce the absorption and effectiveness of levothyroxine.
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Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.
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Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.
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Calcium seems to reduce the absorption of quinolone antibiotics.
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Calcium may reduce levels of raltegravir.
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Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).
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Calcium seems to reduce the absorption of sotalol.
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Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).
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Calcium seems to reduce the absorption of tetracycline antibiotics.
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Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).
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Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.
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Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.
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Theoretically, calcium may reduce the therapeutic effects of verapamil.
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Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.
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Theoretically, taking gentian with antihypertensive drugs might increase the risk of hypotension.
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Theoretically, taking horsetail with antidiabetes drugs might increase the risk of hypoglycemia.
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Theoretically, taking horsetail with diuretic drugs might increase potassium loss and the risk of hypokalemia.
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Laboratory research shows that various species of horsetail have diuretic properties (13574,13575). Due to its diuretic effects, there has been concern that taking horsetail along with potassium-depleting diuretics might increase the risk for hypokalemia. However, pharmacokinetic research in humans shows that taking horsetail 900 mg daily for 4 days does not affect urinary excretion of electrolytes, including potassium and sodium, despite having a diuretic effect similar to taking hydrochlorothiazide 25 mg daily (92288). It is unclear if taking horsetail for a longer duration would affect electrolyte levels. Until more is known, use with caution.
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Theoretically, horsetail might decrease the levels and clinical effects of efavirenz.
Details
In two case reports, patients were found to have detectable viral loads when taking horsetail-containing supplements along with an antiretroviral regimen that included efavirenz. In one case, the antiretroviral regimen included zidovudine, lamivudine, and efavirenz; in the other case, the regimen consisted of emtricitabine, tenofovir disoproxil fumarate, and efavirenz. One month after discontinuing horsetail, the viral loads became undetectable in both cases. The exact mechanism of this interaction is unknown (97573). It is also unclear if this interaction is specific to efavirenz or if it is related to various components of antiretroviral therapy.
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Theoretically, horsetail might increase the levels and adverse effects of lithium.
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Animal research suggests that horsetail has diuretic properties (13574). Theoretically, due to these potential diuretic effects, horsetail might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.
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Theoretically, horsetail might decrease the levels and clinical effects of NRTIs.
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In two case reports, patients were found to have detectable viral loads when taking horsetail-containing supplements along with an antiretroviral therapy. In one case, the antiretroviral regimen included zidovudine, lamivudine, and efavirenz; in the other case, the regimen consisted of emtricitabine, tenofovir disoproxil fumarate, and efavirenz. One month after discontinuing the supplement, the viral loads became undetectable in both cases. The exact mechanism of these interactions is unknown (97573). It is also unclear if these interactions are specific to NRTIs or if they are related to various components of antiretroviral therapy.
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Concomitant use of aminoglycoside antibiotics and magnesium can increase the risk for neuromuscular weakness.
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Both aminoglycosides and magnesium reduce presynaptic acetylcholine release, which can lead to neuromuscular blockade and possible paralysis. This is most likely to occur with high doses of magnesium given intravenously (13362).
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Use of acid reducers may reduce the laxative effect of magnesium oxide.
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A retrospective analysis shows that, in the presence of H2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs), a higher dose of magnesium oxide is needed for a laxative effect (90033). This may also occur with antacids. Under acidic conditions, magnesium oxide is converted to magnesium chloride and then to magnesium bicarbonate, which has an osmotic laxative effect. By reducing acidity, antacids may reduce the conversion of magnesium oxide to the active bicarbonate salt.
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Theoretically, magnesium may have antiplatelet effects, but the evidence is conflicting.
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In vitro evidence shows that magnesium sulfate inhibits platelet aggregation, even at low concentrations (20304,20305). Some preliminary clinical evidence shows that infusion of magnesium sulfate increases bleeding time by 48% and reduces platelet activity (20306). However, other clinical research shows that magnesium does not affect platelet aggregation, although inhibition of platelet-dependent thrombosis can occur (60759).
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Magnesium can decrease absorption of bisphosphonates.
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Cations, including magnesium, can decrease bisphosphonate absorption. Advise patients to separate doses of magnesium and these drugs by at least 2 hours (13363).
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Magnesium can have additive effects with calcium channel blockers, although evidence is conflicting.
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Magnesium inhibits calcium entry into smooth muscle cells and may therefore have additive effects with calcium channel blockers. Severe hypotension and neuromuscular blockades may occur when nifedipine is used with intravenous magnesium (3046,20264,20265,20266), although some contradictory evidence suggests that concurrent use of magnesium with nifedipine does not increase the risk of neuromuscular weakness (60831). High doses of magnesium could theoretically have additive effects with other calcium channel blockers.
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Magnesium salts may reduce absorption of digoxin.
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Gabapentin absorption can be decreased by magnesium.
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Clinical research shows that giving magnesium oxide orally along with gabapentin decreases the maximum plasma concentration of gabapentin by 33%, time to maximum concentration by 36%, and area under the curve by 43% (90032). Advise patients to take gabapentin at least 2 hours before, or 4 to 6 hours after, magnesium supplements.
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Magnesium might precipitate ketamine toxicity.
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In one case report, a 62-year-old hospice patient with terminal cancer who had been stabilized on sublingual ketamine 150 mg four times daily experienced severe ketamine toxicity lasting for 2 hours after taking a maintenance dose of ketamine following an infusion of magnesium sulfate 2 grams (105078). Since both magnesium and ketamine block the NMDA receptor, magnesium is thought to have potentiated the effects of ketamine.
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Magnesium can reduce the bioavailability of levodopa/carbidopa.
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Clinical research in healthy volunteers shows that taking magnesium oxide 1000 mg with levodopa 100 mg/carbidopa 10 mg reduces the area under the curve (AUC) of levodopa by 35% and of carbidopa by 81%. In vitro and animal research shows that magnesium produces an alkaline environment in the digestive tract, which might lead to degradation and reduced bioavailability of levodopa/carbidopa (100265).
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Potassium-sparing diuretics decrease excretion of magnesium, possibly increasing magnesium levels.
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Potassium-sparing diuretics also have magnesium-sparing properties, which can counteract the magnesium losses associated with loop and thiazide diuretics (9613,9614,9622). Theoretically, increased magnesium levels could result from concomitant use of potassium-sparing diuretics and magnesium supplements.
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Magnesium decreases absorption of quinolones.
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Magnesium can form insoluble complexes with quinolones and decrease their absorption (3046). Advise patients to take these drugs at least 2 hours before, or 4 to 6 hours after, magnesium supplements.
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Sevelamer may increase serum magnesium levels.
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In patients on hemodialysis, sevelamer use was associated with a 0.28 mg/dL increase in serum magnesium. The mechanism of this interaction remains unclear (96486).
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Parenteral magnesium alters the pharmacokinetics of skeletal muscle relaxants, increasing their effects and accelerating the onset of effect.
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Parenteral magnesium shortens the time to onset of skeletal muscle relaxants by about 1 minute and prolongs the duration of action by about 2 minutes. Magnesium potentiates the effects of skeletal muscle relaxants by decreasing calcium-mediated release of acetylcholine from presynaptic nerve terminals, reducing postsynaptic sensitivity to acetylcholine, and having a direct effect on the membrane potential of myocytes (3046,97492,107364). Magnesium also has vasodilatory actions and increases cardiac output, allowing a greater amount of muscle relaxant to reach the motor end plate (107364). A clinical study found that low-dose rocuronium (0.45 mg/kg), when given after administration of magnesium 30 mg/kg over 10 minutes, has an accelerated onset of effect, which matches the onset of effect seen with a full-dose rocuronium regimen (0.6 mg/kg) (96485). In another clinical study, onset times for rocuronium doses of 0.3, 0.6, and 1.2 mg/kg were 86, 76, and 50 seconds, respectively, when given alone, but were reduced to 66, 44, and 38 seconds, respectively, when the doses were given after a 15-minute infusion of magnesium sulfate 60 mg/kg (107364). Giving intraoperative intravenous magnesium sulfate, 50 mg/kg loading dose followed by 15 mg/kg/hour, reduces the onset time of rocuronium, enhances its clinical effects, reduces the dose of intraoperative opiates, and prolongs the spontaneous recovery time (112781,112782). It does not affect the activity of subsequently administered neostigmine (112782).
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Magnesium increases the systemic absorption of sulfonylureas, increasing their effects and side effects.
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Clinical research shows that administration of magnesium hydroxide with glyburide increases glyburide absorption, increases maximal insulin response by 35-fold, and increases the risk of hypoglycemia, when compared with glyburide alone (20307). A similar interaction occurs between magnesium hydroxide and glipizide (20308). The mechanism of this effect appears to be related to the elevation of gastrointestinal pH by magnesium-based antacids, increasing solubility and enhancing absorption of sulfonylureas (22364).
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Magnesium decreases absorption of tetracyclines.
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Magnesium can form insoluble complexes with tetracyclines in the gut and decrease their absorption and antibacterial activity (12586). Advise patients to take these drugs 1 hour before or 2 hours after magnesium supplements.
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Selenium may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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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, vanadium might increase the risk of bleeding when taken with anticoagulant/antiplatelet drugs.
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In vitro research shows that the sodium orthovanadate form of vanadium prolongs clotting time, likely through inhibition of thrombin and factor Xa (3054).
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Theoretically, vanadium might increase the risk of hypoglycemia when taken with antidiabetes drugs.
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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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Vitamin D might increase aluminum absorption and toxicity, but this has only been reported in people with renal failure.
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The protein that transports calcium across the intestinal wall can also bind and transport aluminum. This protein is stimulated by vitamin D, which may therefore increase aluminum absorption (11595,11597,22916). This mechanism may contribute to increased aluminum levels and toxicity in people with renal failure, when they take vitamin D and aluminum-containing phosphate binders chronically (11529,11596,11597).
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Vitamin D might reduce absorption of atorvastatin.
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A small, low-quality clinical study shows that taking vitamin D reduces levels of atorvastatin and its active metabolites by up to 55%. However, while atorvastatin levels decreased, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels did not substantially change (16828). Atorvastatin is metabolized in the gut by CYP3A4 enzymes, and researchers theorized that vitamin D might induce CYP3A4, causing reduced levels of atorvastatin. However, this proposed mechanism was not specifically studied.
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Taking calcipotriene with vitamin D increases the risk for hypercalcemia.
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Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (15). Theoretically, combining calcipotriene with vitamin D supplements might increase the risk of hypercalcemia.
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Vitamin D might induce CYP3A4 enzymes and reduce the bioavailability of CYP3A4 substrates.
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There is some concern that vitamin D might induce CYP3A4. In vitro research suggests that vitamin D induces CYP3A4 transcription. Additionally, observational research has found that increased UV light exposure and serum vitamin D levels are associated with decreased serum levels of CYP3A4 substrates such as tacrolimus and sirolimus, while no association between UV light exposure or vitamin D levels and levels of mycophenolic acid, a non-CYP3A4 substrate, was found (110539). A small, low-quality clinical study shows that taking vitamin D reduces levels of the CYP3A4 substrate atorvastatin and its active metabolites by up to 55%; however, the clinical effects of atorvastatin were not reduced (16828). While researchers theorized that vitamin D might induce CYP3A4, this proposed mechanism was not specifically studied.
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Theoretically, hypercalcemia induced by high-dose vitamin D can increase the risk of arrhythmia from digoxin.
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High doses of vitamin D can cause hypercalcemia. Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (15). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and digoxin concurrently.
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Theoretically, hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of diltiazem for arrhythmia.
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High doses of vitamin D can cause hypercalcemia. Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically this could also occur with diltiazem. Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and diltiazem concurrently.
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Theoretically, taking thiazide diuretics and high-dose vitamin D can increase the risk of hypercalcemia.
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Thiazide diuretics decrease urinary calcium excretion, which could lead to hypercalcemia if vitamin D supplements are taken concurrently (3072,11541,69580). This has been reported in people being treated with vitamin D for hypoparathyroidism, and also in elderly people with normal parathyroid function who were taking a thiazide, vitamin D, and calcium-containing antacids daily (11539,11540).
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Hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of verapamil for arrhythmia.
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Hypercalcemia due to high doses of vitamin D can reduce the effectiveness of verapamil in atrial fibrillation (10574). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and verapamil concurrently.
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Amiloride can modestly reduce zinc excretion and increase zinc levels.
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Clinical research shows that amiloride can reduce urinary zinc excretion, especially at doses of 10 mg per day or more. This zinc-sparing effect can help to counteract zinc losses caused by thiazide diuretics, but it is unlikely to cause zinc toxicity at usual amiloride doses (830,11626,11627,11634). The other potassium-sparing diuretics, spironolactone (Aldactone) and triamterene (Dyrenium), do not seem to have a zinc-sparing effect.
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Zinc modestly reduces levels of atazanavir, although this effect does not seem to be clinically significant.
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Clinical research shows that zinc might decrease serum atazanavir levels by chelating with atazanavir in the gut and preventing its absorption (93578). Although a single dose of zinc sulfate (Solvazinc tablets) 125 mg orally does not affect atazanavir concentrations in patients being treated with atazanavir/ritonavir, co-administration of zinc sulfate 125 mg daily for 2 weeks reduces plasma levels of atazanavir by about 22% in these patients. However, despite this decrease, atazanavir levels still remain at high enough concentrations for the prevention of HIV virus replication (90216).
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Zinc might decrease cephalexin levels by chelating with cephalexin in the gut and preventing its absorption.
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A pharmacokinetic study shows that zinc sulfate 250 mg taken concomitantly with cephalexin 500 mg decreases peak levels of cephalexin by 31% and reduces the exposure to cephalexin by 27%. Also, taking zinc sulfate 3 hours before cephalexin decreases peak levels of cephalexin by 11% and reduces the exposure to cephalexin by 18%. By decreasing cephalexin levels, zinc might increase the risk of treatment failure. This effect does not occur when zinc is taken 3 hours after the cephalexin dose (94163). To avoid an interaction, advise patients take zinc sulfate 3 hours after taking cephalexin.
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Theoretically, zinc might interfere with the therapeutic effects of cisplatin.
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Animal research suggests that zinc stimulates tumor cell production of the protein metallothionein, which binds and inactivates cisplatin (11624,11625). It is not known whether zinc supplements or high dietary zinc intake can cause clinically significant interference with cisplatin therapy. Cisplatin might also increase zinc excretion.
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Theoretically, taking zinc along with integrase inhibitors might decrease the levels and clinical effects of these drugs.
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Zinc might reduce the levels and clinical effects of penicillamine.
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By forming an insoluble complex with penicillamine, zinc interferes with penicillamine absorption and activity. Zinc supplements reduce the efficacy of low-dose penicillamine (0.5-1 gram/day), but do not seem to affect higher doses (1-2.75 gram/day), provided dosing times are separated (2678,4534,11605). Advise patients to take zinc and penicillamine at least 2 hours apart.
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Zinc can decrease the levels and clinical effects of quinolones antibiotics.
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Zinc modestly reduces levels of ritonavir.
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Clinical research shows that zinc might reduce serum ritonavir levels by chelating with ritonavir in the gut and preventing its absorption (93578). In patients with HIV, ritonavir is taken with atazanavir to prevent the metabolism and increase the effects of atazanavir. A pharmacokinetic study shows that, in patients being treated with atazanavir/ritonavir, co-administration of zinc sulfate (Solvazinc tablets) 125 mg as a single dose or as multiple daily doses for 2 weeks reduces plasma levels of ritonavir by about 16% (90216). However, atazanavir levels still remains high enough to prevent HIV virus replication. Therefore, the decrease in ritonavir levels is not likely to be clinically significant.
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Zinc might reduce levels of tetracycline antibiotics.
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Tetracyclines form complexes with zinc in the gastrointestinal tract, which can reduce absorption of both the tetracycline and zinc when taken at the same time (3046,4945). Taking zinc sulfate 200 mg with tetracycline reduces absorption of the antibiotic by 30% to 40% (11615). Demeclocycline and minocycline cause a similar interaction (4945). However, doxycycline does not seem to interact significantly with zinc (11615). Advise patients to take tetracyclines at least 2 hours before, or 4-6 hours after, zinc supplements to avoid any interactions.
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Below is general information about the adverse effects of the known ingredients contained in the product Phytocal A. 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, betaine hydrochloride is generally well tolerated when taken as a single dose.
Gastrointestinal ...Theoretically, the hydrochloric acid produced from betaine hydrochloride might irritate gastric or duodenal ulcers or impede ulcer healing. It might also cause heartburn.
General
...Orally, boron is generally well tolerated when used in doses below the tolerable upper intake level (UL) of 20 mg.
Vaginally, boron is well tolerated.
Most Common Adverse Effects:
Orally: Anorexia, dermatitis, erythema, indigestion.
Vaginally: Burning and pain.
Dermatologic
...Orally, chronic use of 1 gram daily of boric acid or 25 grams daily of boric tartrate can cause dermatitis and alopecia (7135).
Larger doses can result in acute poisoning. Symptoms of poisoning in adults and children may include skin erythema, desquamation, and exfoliation (17).
Gastrointestinal
...Orally, chronic use of 1 gram daily of boric acid or 25 grams daily of boric tartrate can cause anorexia and indigestion (7135).
Larger doses can result in acute poisoning. Children who have ingested 5 grams or more of borates can have persistent nausea, vomiting, and diarrhea leading to acute dehydration, shock, and coma. Adults who have ingested 15-20 grams of borate can exhibit nausea, vomiting, diarrhea, epigastric pain, hematemesis, and a blue-green discoloration of feces and vomit (17).
Genitourinary ...Vaginally, boric acid can cause vulvovaginal burning and dyspareunia in males if intercourse occurs shortly after vaginal treatment (15447).
Neurologic/CNS ...Orally, large doses can result in acute poisoning. Poisoning with boron can cause hyperexcitability, irritability, tremors, convulsions, weakness, lethargy, and headaches (17).
Ocular/Otic ...Exposure to boric acid or boron oxide dust has been reported to cause eye irritation (36852).
Pulmonary/Respiratory ...Exposure to boric acid and boron oxide dust has been reported to cause mouth and nasal passage irritation, sore throat, and productive cough (36852).
General
...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.
Cardiovascular
...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI).
Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).
Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).
Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.
Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).
General
...Orally, gentian root, in combination with other herbs, seems to be generally well tolerated.
There is insufficient reliable information available about the adverse effects of gentian when taken as a medicine alone.
Most Common Adverse Effects:
Orally: Allergic skin reactions, gastrointestinal discomfort.
Gastrointestinal ...Orally, gentian root, in combination with other herbs, has been reported to cause gastrointestinal adverse effects (374,379). Gastrointestinal intolerance occurred in patients with cancer-associated anorexia who took gentian tincture 1 mL three times daily, in conjunction with turmeric 1 gram and ginger 1 gram twice daily, for 14 days. Six of 17 patients discontinued the regimen due to nausea, 3 due to vomiting, 2 due to diarrhea, and 2 due to bloating. It is unclear if this gastrointestinal intolerance was caused by gentian, the other herbs, or the patients' predisposing conditions (96263).
Immunologic ...Orally, gentian root, in combination with other herbs, has been reported to cause allergic skin reactions (374,379). It is unclear if these reactions were caused by gentian, the other herbs, or the combination.
General
...There is limited clinical research evaluating the safety of horsetail.
Most Common Adverse Effects:
Orally: Abdominal distension, increased bowel movements, and nausea.
Dermatologic ...In one case report, a patient developed seborrheic dermatitis after topical application of horsetail, requiring treatment with local epinephrine and oral antihistamines. The nicotine component of horsetail was determined to be the likely cause of this reaction (13563).
Gastrointestinal ...Orally, horsetail has been associated with mild gastrointestinal side effects including abdominal distension, increased frequency of bowel movements, and nausea (55576). Orally, chronic consumption of horsetail infusion has been associated with acute pancreatitis. In a case report, a 56-year-old female presenting with recurrent mild acute pancreatitis every 6-7 months, previously thought to be drug-induced, discontinued ingesting horsetail infusions. The patient had a history of bilateral adrenal gland removal and was being treated for hypertension, dyslipidemia, and hormone replacement, and then self-medicated with horsetail infusions. After discontinuing horsetail infusions, there were no further recurrences of pancreatitis during a 14-month follow-up (97574).
Hepatic ...In one case report, a patient with asymptomatic hepatitis B developed symptomatic liver failure following consumption of boiled horsetail juice 500 mL daily for 2 weeks. Liver enzymes returned to normal following discontinuation of the juice (92291). It is not known if the horsetail juice was contaminated or mixed with other ingredients.
Immunologic ...Horsetail has been associated with cross-allergenicity with carrots (13577).
Renal ...There are at least 4 case reports of hyponatremia thought to be at least partially associated with horsetail consumption. In one case report, an elderly patient who had taken oral horsetail 15 mg daily for 10 years presented with hyponatremia and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) secondary to reduced oral intake and nausea for the previous 2 days. Horsetail was thought to be a contributing factor. The patient's symptoms resolved after 5 days of treatment with oral sodium chloride and fluid restriction (108851).
Other ...Crude horsetail contains thiaminase, which can cause thiamine deficiency with prolonged consumption. Canadian Equisetum arvense products are required to be certified as free from thiaminase-like activity (55579,105301). In one case report, the development of autism in a child exposed to both horsetail and alcohol during pregnancy was thought to be caused by thiamine deficiency attributed to this combination (92292). However, it is not known if other genetic or environmental factors were involved in the development of this condition in utero.
General
...No adverse effects have been reported in adults.
However, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal adverse effects, such as necrotizing enterocolitis, when recombinant human bile salt-stimulated lipase is used in premature infants.
Gastrointestinal ...Orally, when added to the formula or pasteurized breast milk consumed by premature infants, recombinant human bile salt-stimulated lipase (rhBSSL) can cause gastrointestinal adverse effects, including abdominal distension, flatulence, constipation, colic, abdominal pain, gastroenteritis, vomiting, regurgitation, and rectal bleeding (101940). Premature infants receiving rhBSSL also had a slightly higher rate of necrotizing enterocolitis (NEC) when compared with those receiving placebo. After review by a panel of experts, it was determined that the rate of confirmed or suspected NEC in infants consuming rhBSSL was 3.3%, compared with 0.5% in those receiving placebo. Although this rate of NEC is lower than the historical rate of occurrence in premature infants (11%), a possible increased risk for NEC cannot be ruled out (101940).
General
...Magnesium is generally well tolerated.
Some clinical research shows no differences in adverse effects between placebo and magnesium groups.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal irritation, nausea, and vomiting.
Intravenously: Bradycardia, dizziness, flushing sensation, hypotension, and localized pain and irritation. In pregnancy, may cause blurry vision, dizziness, lethargy, nausea, nystagmus, and perception of warmth.
Serious Adverse Effects (Rare):
All ROAs: With toxic doses, loss of reflexes and respiratory depression can occur. High doses in pregnancy can increase risk of neonatal mortality and neurological defects.
Cardiovascular
...Intravenously, magnesium can cause bradycardia, tachycardia, and hypotension (13356,60795,60838,60872,60960,60973,60982,61001,61031,114681).
Inhaled magnesium administered by nebulizer may also cause hypotension (113466). Magnesium sulfate may cause rapid heartbeat when administered antenatally (60915,114681).
In one case report, a 99-year-old male who took oral magnesium oxide 3000 mg daily for chronic constipation was hospitalized with hypermagnesemia, hypotension, bradycardia, heart failure, cardiomegaly, second-degree sinoatrial block, and complete bundle branch block. The patient recovered after discontinuing the magnesium oxide (108966).
Dermatologic ...Intravenously, magnesium may cause flushing, sweating, and problems at the injection site (including burning pain) (60960,60982,111696,114681). In a case study, two patients who received intravenous magnesium sulfate for suppression of preterm labor developed a rapid and sudden onset of an urticarial eruption (a skin eruption of itching welts). The eruption cleared when magnesium sulfate was discontinued (61045). Orally, magnesium oxide may cause allergic skin rash, but this is rare. In one case report, a patient developed a rash after taking 600 mg magnesium oxide (Maglax) (98291).
Gastrointestinal
...Orally, magnesium can cause gastrointestinal irritation, nausea, vomiting, and diarrhea (1194,4891,10661,10663,18111,60951,61016,98290).
In rare cases, taking magnesium orally might cause a bezoar, an indigestible mass of material which gets lodged in the gastrointestinal tract. In a case report, a 75-year-old female with advanced rectal cancer taking magnesium 1500 mg daily presented with nausea and anorexia from magnesium oxide bezoars in her stomach (99314). Magnesium can cause nausea, vomiting, or dry mouth when administered intravenously or by nebulization (60818,60960,60982,104400,113466,114681). Antenatal magnesium sulfate may also cause nausea and vomiting (60915,114681). Two case reports suggest that giving magnesium 50 grams orally for bowel preparation for colonoscopy in patients with colorectal cancer may lead to intestinal perforation and possibly death (90006).
Delayed meconium passage and obstruction have been reported rarely in neonates after intravenous magnesium sulfate was given to the mother during pregnancy (60818). In a retrospective study of 200 neonates born prematurely before 32 weeks of gestation, administration of prenatal IV magnesium sulfate, as a 4-gram loading dose and then 1-2 grams hourly, was not associated with the rate of meconium bowel obstruction when compared with neonates whose mothers had not received magnesium sulfate (108728).
Genitourinary ...Intravenously, magnesium sulfate may cause renal toxicity or acute urinary retention, although these events are rare (60818,61012). A case of slowed cervical dilation at delivery has been reported for a patient administered intravenous magnesium sulfate for eclampsia (12592). Intravenous magnesium might also cause solute diuresis. In a case report, a pregnant patient experienced polyuria and diuresis after having received intravenous magnesium sulfate in Ringer's lactate solution for preterm uterine contractions (98284).
Hematologic ...Intravenously, magnesium may cause increased blood loss at delivery when administered for eclampsia or pre-eclampsia (12592). However, research on the effect of intravenous magnesium on postpartum hemorrhage is mixed. Some research shows that it does not affect risk of postpartum hemorrhage (60982), while other research shows that intrapartum magnesium administration is associated with increased odds of postpartum hemorrhage, increased odds of uterine atony (a condition that increases the risk for postpartum hemorrhage) and increased need for red blood cell transfusions (97489).
Musculoskeletal
...Intravenously, magnesium may cause decreased skeletal muscle tone, muscle weakness, or hypocalcemic tetany (60818,60960,60973).
Although magnesium is important for normal bone structure and maintenance (272), there is concern that very high doses of magnesium may be detrimental. In a case series of 9 patients receiving long-term tocolysis for 11-97 days, resulting in cumulative magnesium sulfate doses of 168-3756 grams, a lower bone mass was noted in 4 cases receiving doses above 1000 grams. There was one case of pregnancy- and lactation-associated osteoporosis and one fracture (108731). The validity and clinical significance of this data is unclear.
Neurologic/CNS
...Intravenously, magnesium may cause slurred speech, dizziness, drowsiness, confusion, or headaches (60818,60960,114681).
With toxic doses, loss of reflexes, neurological defects, drowsiness, confusion, and coma can occur (8095,12589,12590).
A case report describes cerebral cortical and subcortical edema consistent with posterior reversible encephalopathy syndrome (PRES), eclampsia, somnolence, seizures, absent deep tendon reflexes, hard to control hypertension, acute renal failure and hypermagnesemia (serum level 11.5 mg/dL), after treatment with intravenous magnesium sulfate for preeclampsia in a 24-year-old primigravida at 39 weeks gestation with a previously uncomplicated pregnancy. The symptoms resolved after 4 days of symptomatic treatment in an intensive care unit, and emergency cesarian delivery of a healthy infant (112785).
Ocular/Otic ...Intravenously, magnesium may cause blurred vision (114681). Additionally, cases of visual impairment or nystagmus have been reported following magnesium supplementation, but these events are rare (18111,60818).
Psychiatric ...A case of delirium due to hypermagnesemia has been reported for a patient receiving intravenous magnesium sulfate for pre-eclampsia (60780).
Pulmonary/Respiratory ...Intravenously, magnesium may cause respiratory depression and tachypnea when used in toxic doses (12589,61028,61180).
Other ...Hypothermia from magnesium used as a tocolytic has been reported (60818).
General ...Orally, molybdenum is generally well tolerated when used appropriately in amounts that do not exceed the Tolerable Upper Intake Level (UL) of 2 mg/day (7135).
Genitourinary ...Environmental exposure to molybdenum has been reported to be a reproductive toxicant in men. Circulating levels of molybdenum are inversely associated with testosterone levels and sperm concentration (63482,63484).
Hematologic ...Orally, in an area of Armenia, a very high dietary molybdenum intake of 10 to 15 mg/day due to high local soil levels has resulted in an increased incidence of hyperuricemia (7135,16478,16487). The mechanism likely involves increased xanthine oxidase activity, leading to increased uric acid production (2663).
Immunologic ...Molybdenum is present in some stainless steel angioplasty stents. Multiple cases report on patients with these stents who have developed a contact allergy to molybdenum, as indicated by positive skin patch tests. It is suggested that this increases the risk for restenosis of the stented artery (16485).
Musculoskeletal ...Orally, in an area of Armenia, a very high dietary molybdenum intake of 10 to 15 mg/day due to high local soil levels has resulted in an increased incidence of hyperuricemia, gout, and arthralgias (7135,16478,16487). There is also a case report of gout in a man with industrial exposure to molybdenum metal dust (16480). The mechanism likely involves increased xanthine oxidase activity, leading to increased uric acid production (2663).
Neurologic/CNS ...In one case report of a man in his late thirties, dietary supplementation with molybdenum 300-800 micrograms daily for a cumulative dose of 13. 5 mg over 18 days resulted in acute psychosis with visual and auditory hallucinations, petit mal seizures, and a life-threatening grand mal attack, related to frontal cortical damage. Chelation therapy with calcium ethylene diamine tetraacetic acid (CaEDTA) was required. A year later, the man was diagnosed with toxic encephalopathy with executive deficiencies, learning disability, major depression, and post-traumatic stress disorder (63368).
Psychiatric ...In one case report of a man in his late thirties, dietary supplementation with molybdenum 300-800 micrograms daily for a cumulative dose of 13. 5 mg over 18 days resulted in acute psychosis with visual and auditory hallucinations, petit mal seizures, and a life-threatening grand mal attack, related to frontal cortical damage. Chelation therapy with calcium ethylene diamine tetraacetic acid (CaEDTA) was required. A year later, the man was diagnosed with toxic encephalopathy with executive deficiencies, learning disability, major depression, and post-traumatic stress disorder (63368).
Pulmonary/Respiratory ...Pneumoconiosis has been reported with excessive intake of molybdenum or exposure in the workplace (63365,63547,63510).
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, vanadium is well tolerated when taken in amounts below the tolerable upper intake level (UL) of 1.
8 mg daily. Higher doses may cause adverse effects.
Most Common Adverse Effects:
Orally: Gastrointestinal adverse effects, including abdominal discomfort, diarrhea, flatulence, and nausea, when taken at doses above the UL.
Serious Adverse Effects (Rare):
Orally: Kidney damage, when taken long-term at high doses.
Topically: Contact dermatitis and other allergic reactions in sensitive individuals.
Cardiovascular ...Higher levels of vanadium in the body have been associated with a greater risk for hypertension (107923). However, it is unclear if oral supplementation with vanadium causes elevated blood pressure.
Dermatologic ...Allergic reactions to vanadium metal have been reported (99051,102095). A 68-year-old female developed an itchy, erythematous rash, ocular pruritus, and a positive skin test to vanadium after implantation of a vanadium-containing knee prosthesis (99051). Contact dermatitis, presenting as pruritic eczema of the hand, and a positive skin patch test to vanadium was reported in a 39-year-old male who worked with vanadium-containing tools (102095).
Endocrine ...In some cases, patients with diabetes have used very high doses (100 mg daily) safely for up to 4 weeks (3055,3056,3057). However, high body levels of vanadium have been associated with an increased incidence malnutrition-related diabetes mellitus (3020).
Gastrointestinal ...Orally, vanadium most commonly causes mild gastrointestinal upset (7135). There is concern that taking doses exceeding the tolerable upper intake level (UL) of 1.8 mg per day can increase the risk of gastrointestinal side effects and possibly lead to more severe toxicity. At higher doses, vanadium frequently causes gastrointestinal effects including abdominal discomfort, diarrhea, nausea, and flatulence (3012,3055,3056,3057,12557,12558). Doses of 22.5 mg daily can also cause cramps (3012). Vanadium has also been associated with green discoloration of the tongue, which is unrelated to dose (7135).
Immunologic
...Allergic reactions to vanadium metal have been reported (99051,102095).
A 68-year-old female developed an itchy, erythematous rash, ocular pruritus, and a positive skin test to vanadium after implantation of a vanadium-containing knee prosthesis (99051). Contact dermatitis, presenting as pruritic eczema of the hand, and a positive skin patch test to vanadium was reported in a 39-year-old male who worked with vanadium-containing tools (102095).
Higher levels of vanadium in the body have been associated with a weakened immune system in children, as measured by reductions in CD3+ and CD4+ cell counts (107924). However, it is unclear if oral supplementation with vanadium causes a weakened immune system or increases the risk of infection.
Neurologic/CNS ...Orally, vanadium has been rarely associated with fatigue, lethargy, and focal neurological lesions, which are unrelated to dose (7135).
Pulmonary/Respiratory ...Severe and chronic respiratory tract disorders have been reported from occupational exposure to vanadium dusts (17).
Renal ...In some cases, patients with diabetes have used very high doses (100 mg daily) of vanadium safely for up to 4 weeks (3055,3056,3057). However, there is concern based on animal research that prolonged use of high doses might cause serious side effects including kidney damage (7135). High body levels of vanadium have also been associated with an increased incidence of kidney stones, distal renal tubular acidosis, hypokalemic periodic paralysis, and sudden unexplained nocturnal death (3020).
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 or intramuscularly, vitamin D is well tolerated.
Serious Adverse Effects (Rare):
Orally or intramuscularly: Excessive doses can lead to vitamin D toxicity with symptoms of hypercalcemia, and also sometimes azotemia and anemia.
Cardiovascular ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Rarely, people develop hypertension (10142). An analysis of clinical research suggests that, when taken orally, vitamin D might modestly increase levels of low-density lipoprotein (LDL)-cholesterol. However, it is not clear if this increase is clinically significant (84642).
Gastrointestinal ...Orally, vitamin D may cause dry mouth. In clinical research, intake of vitamin D 50,000 IU weekly for 4 weeks followed by 50,000 IU monthly for 5 months thereafter was associated with a 3.7-fold increase in reports of dry mouth compared with placebo (91348).Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Symptoms of vitamin D toxicity include pancreatitis (10142,84433). Vomiting occurred in one patient given a single dose of 200,000 IU (104624).
Genitourinary ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Advanced symptoms may include decreased libido (10142). Vaginal discharge and itching have been reported in a clinical trial following oral use (91348).
Hematologic
...Lab values of urinary and blood calcium, phosphate, albumin, blood urea nitrogen, serum cholesterol, aspartate aminotransferase, and alanine aminotransferase concentrations might increase with vitamin D use, especially with high doses (10142,91349,93943).
A case of elevated international normalized ration (INR) has been reported for an 84 year-old patient who took vitamin D 50,000 IU daily for 2 months. The patient's serum levels of vitamin D increased from <7 ng/mL to 100 ng/mL over 6 months. To resolve symptoms, vitamin D supplementation was discontinued (84433).
Musculoskeletal ...Vitamin D intoxication can occur when vitamin D supplements are taken in excessive doses (10142,17506). Symptoms of vitamin D toxicity include osteoporosis in adults and decreased growth in children (10142).
Ocular/Otic ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses (10142,17506). Symptoms of vitamin D toxicity include calcific conjunctivitis and photophobia (10142).
Psychiatric ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses (10142,17506). In rare cases, symptoms of vitamin D toxicity include psychosis (10142,93002).
Pulmonary/Respiratory ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Advanced symptoms of vitamin D toxicity may include runny nose (10142,17506,93002).
Renal ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Symptoms of vitamin D toxicity include azotemia. Vitamin D may also cause hypercalcemia, with advanced symptoms including kidney stones or kidney insufficiency due to precipitation of calcium phosphate in the tubules. Symptoms of renal impairment include frequency, nighttime awakening to urinate, thirst, inability to concentrate urine, and proteinuria. Renal impairment is usually reversible with discontinuation of vitamin D supplements (10142,93002,93943,110831,110833).
General
...Orally, zinc is well tolerated in doses below the tolerable upper intake level (UL), which is 40 mg daily for adults.
Topically, zinc is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, diarrhea, metallic taste, nausea and vomiting (dose-related).
Topically: Burning, discoloration, itching, stinging, and tingling when applied to irritated tissue.
Intranasally: Bad taste, dry mouth, headache, irritation, reduced sense of smell.
Serious Adverse Effects (Rare):
Orally: There have been cases of acute renal tubular necrosis, interstitial nephritis, neurological complications, severe vomiting, and sideroblastic anemia after zinc overdose.
Intranasally: There have been cases where intranasal zinc caused permanent loss of smell (anosmia).
Dermatologic
...Topically, zinc can cause burning, stinging, itching, and tingling when applied to inflamed tissue (6911,8623,87297).
Zinc oxide can be deposited in the submucosal tissue and cause dark discoloration of the skin. This can occur with prolonged topical application to intact skin, application to eroded or ulcerated skin, or penetrating traumatic exposure, and also parenteral administration (8618).
In rare cases, oral zinc has resulted in worsened acne (104056), skin sensitivity (6592), a leishmanial reaction with a macular rash that occurred on exposed parts of the body (86935), eczema (104055), systemic contact dermatitis (109457), and the development of severe seborrheic dermatitis (86946).
Gastrointestinal
...Orally, zinc can cause nausea (338,2663,2681,6592,6700,18216,106230,106233,106227,113661), vomiting (2663,2681,6519,6592,96069,96074), a metallic or objectionable taste in the mouth (336,338,6700,11350,18216,106902,113661), abdominal cramping (6592,96069), indigestion (87227), heartburn (96069), dry mouth (87533), and mouth irritation (336,2619).
When used orally in amounts above the tolerable upper intake level, zinc may cause irritation and corrosion of the gastrointestinal tract (331,86982,87315,106902), watery diarrhea (1352), epigastric pain (2663,2681), and severe vomiting (2663,2681).
Intranasally, zinc can cause bad taste, dry mouth, and burning and irritation of the throat (8628,8629).
When used topically as a mouth rinse, zinc may cause tooth staining (90206).
Hematologic ...There is concern that high daily doses of zinc, above the tolerable upper intake level (UL) of 40 mg per day, might increase the risk of copper deficiency, potentially leading to anemia and leukopenia (7135,112473). To prevent copper deficiency, some clinicians give a small dose of copper when zinc is used in high doses, long-term (7303).
Hepatic ...There are two cases of liver deterioration in patients with Wilson disease following initiation of treatment with zinc 50-200 mg three times daily. The mechanism of action is not understood, and the event is extremely uncommon (86927,87470).
Immunologic ...Daily doses of 300 mg of supplemental zinc for 6 weeks appear to impair immune response (7135). A case of erythematosus-like syndrome, including symptoms such as fever, leg ulcers, and rash, has been reported following intake of effervescent tablets (Solvezink) containing zinc 45 mg (87506). In another case, severe neutropenia was reported after taking supplemental zinc 900 mg daily for an unknown duration (112473).
Musculoskeletal ...Orally, zinc may cause body aches in children (113661).
Neurologic/CNS
...Zinc-containing denture adhesives can cause toxicity if used more frequently than recommended for several years.
Case reports describe hyperzincemia, low copper levels, blood dyscrasias, and neurological problems, including sensory disturbances, numbness, tingling, limb weakness, and difficulty walking in patients applying denture adhesive multiple times daily for several years (17092,17093,90205,90233). Due to reports of zinc toxicity associated with use of excessive amounts of zinc-containing denture adhesives for several years, GlaxoSmithKline has reformulated Polygrip products to remove their zinc content (17092,17093).
Intranasally (8628) and orally (87534), zinc can cause headache. When used orally in amounts above the tolerable upper intake level (UL), zinc may cause central nervous system (CNS) symptoms including lethargy, fatigue, neuropathy, dizziness, and paresthesia (2663,2681,87369,87470,87533,87534,112473).
Oncologic ...There is concern that zinc might worsen prostate disease. For example, some preliminary evidence suggests that higher dietary zinc intake increases the risk for benign prostatic hyperplasia (6908). Epidemiological evidence suggests that taking more than 100 mg of supplemental zinc daily or taking supplemental zinc for 10 or more years doubles the risk of developing prostate cancer (10306). Another large-scale population study also suggests that men who take a multivitamin more than 7 times per week and who also take a separate zinc supplement have a significantly increased risk of prostate cancer-related mortality (15607). However, a large analysis of population research suggests that there is no association between zinc intake and the risk of prostate cancer (96075).
Pulmonary/Respiratory
...There are several hundred reports of complete loss of sense of smell (anosmia) that may be permanent with use of zinc gluconate nasal gel, such as Zicam (11306,11155,11707,16800,16801,17083,86999,87535).
Loss of sense of smell is thought to be dose related but has also been reported following a single application (11306,11155,11707,16800). Patients often report having sniffed deeply when applying the gel, then experiencing an immediate burning sensation, and noticing anosmia within 48 hours (17083). On June 16, 2009, the US Food and Drug Administration (FDA) advised patients not to use a specific line of commercial zinc nasal products (Zicam) after receiving 130 reports of loss of smell (16800). The manufacturer of these products had also received several hundred reports of loss of smell related to its intranasal zinc products (16801). Zinc sulfate nasal spray was used unsuccessfully for polio prophylaxis before the polio vaccine was developed. It caused loss of smell and/or taste, which was sometimes permanent (11713). Animal studies suggest that zinc sulfate negatively affects smell, possibly by damaging the olfactory epithelium and neurons (11156,11703,11704,11705,11706). Zinc gluconate nasal spray has not been tested for safety in animals or humans. The clinical studies of intranasal zinc have not described anosmia as an adverse effect, but testing was not done to see if zinc use adversely affected sense of smell (6471,8628,8629,10247). Also, these clinical studies reported tingling or burning sensation in the nostril, dry nose, nose pain, and nosebleeds.
When used in amounts above the tolerable upper intake level (UL), zinc may cause flu-like symptoms including coughing (2663).
Renal ...In overdose, zinc can cause acute renal tubular necrosis and interstitial nephritis (331,1352,87338).
Other ...Occupational inhalation of zinc oxide fumes can cause metal fume fever with symptoms including fatigue, chills, fever, myalgias, cough, dyspnea, leukocytosis, thirst, metallic taste, and salivation (331).
