Each capsule contains: Damiana Aphrodisiaca 110 mg • Mexican Yam (dioscorea) 100 mg • Panax ginseng 90 mg • Lecithin 50 mg • Vitamin E 20 mg • Zinc 7 mg • Vitamin B3 (Niacin) 5 mg • Vitamin B1 5 mg • Grape skin extract 2 mg • Peppermint 1 mg.
Brand name products often contain multiple ingredients. To read detailed information about each ingredient, click on the link for the individual ingredient shown above.
Below is general information about the effectiveness of the known ingredients contained in the product NaturaViga. 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
Below is general information about the safety of the known ingredients contained in the product NaturaViga. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Damiana has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).
POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (12,46933,11866).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Grapes and grape skin extracts have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).
POSSIBLY SAFE ...when the whole fruit of the grape, or extracts of the fruit, seed, or leaf, are used orally and appropriately in medicinal amounts. Grape seed extracts have been used with apparent safety in doses up to 200 mg daily for up to 11 months (9182,53016) and in doses up to 2000 mg daily for up to 3 months (53149,53190). Specific grape fruit extracts (Stilvid, Actafarma; Cognigrape, Bionap srl) have been used with apparent safety in doses up to 250-350 mg daily for 3-12 months or 700 mg daily for 6 months (53254,53256,96198). A specific grape leaf extract (AS 195, Antistax, Boehringer Ingelheim) has been used with apparent safety in doses up to 720 mg daily for up to 3 months (2538,52985,53005,53206). A preparation of dehydrated whole grapes, equivalent to 250 grams of fresh grapes daily, has also been used with apparent safety for up to 30 days (18228). A specific grape seed extract (Enovita; Indena SpA) 150 mg twice daily, standardized to provide at least 95% oligomeric proanthocyanins, has been used with apparent safety for up to 16 weeks (108091) ...when used topically and appropriately. Creams and ointments containing grape seed extract 2% or 5% have been used topically with apparent safety for up to 3 weeks (91539,100955). There is insufficient reliable information available about the safety of other grape plant parts when used topically.
CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods.
Grapes and grape skin extracts have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). However, whole grapes should be eaten with caution in children aged 5 years and under. Whole grapes can be a choking hazard for young children (96193). To reduce the risk of choking, whole grapes should be cut in half or quartered before being given to children. There is insufficient reliable information available about the safety of grape when used in medicinal amounts in children.
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods.
There is insufficient reliable information available about the safety of medicinal amounts during pregnancy and breast-feeding; avoid using in amounts greater than what is commonly found in foods.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Lecithin has Generally Recognized As Safe (GRAS) status in the US (2619,105544). ...when used orally and appropriately in medicinal amounts. Lecithin has been used safely in doses of up to 30 grams daily for up to 6 weeks (5140,5149,5152,5156,14817,14822,14838,19212). ...when used topically (4914).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in food amounts.
Lecithin has Generally Recognized As Safe (GRAS) status in the US (105544). There is insufficient reliable information available about the safety of medicinal amounts of lecithin during pregnancy or lactation; avoid using.
LIKELY SAFE ...when niacin is taken in food or as a supplement in amounts below the tolerable upper intake level (UL) of 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243). ...when prescription products are used orally and appropriately in doses of up to 2 grams daily (12033). CHILDREN:
LIKELY SAFE ...when used orally in amounts that do not exceed the tolerable upper intake level (UL). The ULs of niacin for children are: 1-3 years of age, 10 mg daily; 4-8 years of age, 15 mg daily; 9-13 years of age, 20 mg daily; 14-18 years of age, 30 mg daily (6243).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL).
The UL of niacin during pregnancy and lactation is 30 mg daily for 14-18 years of age and 35 mg daily for 19 years and older (6243).
There is insufficient reliable information available about the safety of larger oral doses of niacin during pregnancy or lactation; avoid using.
LIKELY SAFE ...when prescription products are used orally and appropriately (12033). ...when niacinamide supplements are taken orally in doses below the tolerable upper intake level (UL) set by the Institute of Medicine (IOM). The UL of niacinamide is 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243).
POSSIBLY SAFE ...when used orally in doses greater than 30 mg but less than 900 mg daily. The European Food Safety Authority has set the tolerable upper intake level (UL) of niacinamide at 900 mg daily (104937). However, oral niacinamide has been safely used in doses up to 1500 mg daily for 12 weeks in some clinical trials (25561,94188,98940,107709,110502) and up to 1000 mg daily for 12 months in other trials (93362,113559,113560). ...when used topically and appropriately for up to 16 weeks (5940,93360,110497,110498,110501,113681,113683,113684).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Niacinamide has been safely used in children for up to 7 years in doses below the tolerable upper intake level (UL) (4874,9957). The UL of niacinamide for children by age is: 1-3 years, 10 mg daily; 4-8 years, 15 mg daily; 9-13 years, 20 mg daily; 14-18 years, 30 mg daily (6243).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL) for niacinamide.
The UL of niacinamide during pregnancy and lactation is 30 mg daily for those 14-18 years of age and 35 mg daily for those 19 years and older (6243). There is insufficient reliable information available about the safety of larger oral doses of niacinamide or topical niacinamide; avoid using.
LIKELY SAFE ...when used orally and appropriately, short-term. Panax ginseng seems to be safe when used for up to 6 months (8813,8814,17736,89741,89743,89745,89746,89747,89748,103044)(103477,114980,114981,114984,114985). Panax ginseng sprout extract has also been used with apparent safety in doses up to 450 mg daily for up to 12 weeks (114983).
POSSIBLY UNSAFE ...when used orally, long-term. There is some concern about the long-term safety due to potential hormone-like effects, which might cause adverse effects with prolonged use (12537). Tell patients to limit continuous use to less than 6 months. There is insufficient reliable information available about the safety of Panax ginseng when used topically.
CHILDREN: LIKELY UNSAFE
when used orally in infants.
Use of Panax ginseng in newborns is associated with intoxication that can lead to death (12). There is limited reliable information available about use in older children (24109,103049); avoid using.
PREGNANCY: POSSIBLY UNSAFE
when used orally.
Ginsenoside Rb1, an active constituent of Panax ginseng, has teratogenic effects in animal models (10447,24106,24107); avoid using.
LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when peppermint oil is used orally, topically, or rectally in medicinal doses. Peppermint oil has been safely used in multiple clinical trials (3801,3804,6190,6740,6741,10075,12009,13413,14467,17681)(17682,68522,96344,96360,96361,96362,96363,96364,96365,99493).
POSSIBLY SAFE ...when peppermint leaf is used orally and appropriately, short-term. There is some clinical research showing that peppermint leaf can be used safely for up to 8 weeks (12724,13413). The long-term safety of peppermint leaf in medicinal doses is unknown. ...when peppermint oil is used by inhalation as aromatherapy (7107). There is insufficient reliable information available about the safety of using intranasal peppermint oil.
CHILDREN: POSSIBLY SAFE
when used orally for medicinal purposes.
Enteric-coated peppermint oil capsules have been used with apparent safety under medical supervision in children 8 years of age and older (4469).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (96361).
There is insufficient information available about the safety of using peppermint in medicinal amounts during pregnancy or lactation; avoid using.
LIKELY SAFE ...when used orally and appropriately. A tolerable upper intake level (UL) has not been established for thiamine, and doses up to 50 mg daily have been used without adverse effects (15,6243). ...when used intravenously or intramuscularly and appropriately. Injectable thiamine is an FDA-approved prescription product (15,105445).
CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts.
A tolerable upper intake level (UL) has not been established for healthy individuals (6243).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in dietary amounts of 1.
4 mg daily. A tolerable upper intake level (UL) has not been established for healthy individuals (3094,6243).
LIKELY SAFE ...when used orally or topically and appropriately. Vitamin E is generally considered safe, even at doses exceeding the recommended dietary allowance (RDA); however, adverse effects are more likely to occur with higher doses. The tolerable upper intake level (UL) in healthy people is 1000 mg daily, equivalent to 1100 IU of synthetic vitamin E (all-rac-alpha-tocopherol) or 1500 IU of natural vitamin E (RRR-alpha-tocopherol) (4668,4681,4713,4714,4844,89234,90067,90069,90072,19206)(63244,97075). Although there is some concern that taking vitamin E in doses of 400 IU (form unspecified) per day or higher might increase the risk of adverse outcomes and mortality from all causes (12212,13036,15305,16709,83339), most of this evidence comes from studies that included middle-aged or older patients with chronic diseases or patients from developing countries in which nutritional deficiencies are prevalent.
POSSIBLY UNSAFE ...when used orally in high doses. Repeated doses exceeding the tolerable upper intake level (UL) of 1000 mg daily are associated with significant side effects in otherwise healthy people (4844). ...when used intravenously in large doses. Large repeated intravenous doses of all-rac-alpha-tocopherol (synthetic vitamin E) were associated with decreased activity of clotting factors and bleeding in one report (3074). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults who use e-cigarette, or vaping, products, which often contain vitamin E acetate. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Vitamin E acetate has been detected in most bronchoalveolar lavage samples taken from patients with EVALI. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. While this association shows a correlation between vitamin E acetate inhalation and lung injury, a causal link has not yet been determined, and it is not clear if other toxic compounds are also involved (101061,101062,102970).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Vitamin E has been safely used in children in amounts below the tolerable upper intake level (UL). The UL for healthy children is: 200 mg in children aged 1-3 years, 300 mg in children aged 4-8 years, 600 mg in children aged 9-13 years, and 800 mg in children aged 14-18 years. A UL has not been established for infants up to 12 months of age (23388).
CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL due to increased risk of adverse effects (23388).
...when alpha-tocopherol is used intravenously in large doses in premature infants. Large intravenous doses of vitamin E are associated with an increased risk of necrotizing enterocolitis and sepsis in this population (85062,85083). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adolescents and teenagers who use e-cigarette, or vaping, products. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Constituents in E-cigarette or vaping products with the potential to cause lung injury or impaired lung function include lipids, such as vitamin E acetate. Vitamin E acetate has been detected in all bronchoalveolar lavage samples taken from patients with EVALI. No other ingredient, including THC or nicotine, was found in all samples, and other ingredients, including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable This shows that vitamin E acetate is at the primary site of lung injury. A causal link has not yet been described and it is not clear if other compounds are also involved (101061,101062).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately.
The tolerable upper intake level (UL) during pregnancy is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older. However, maternal supplementation is not generally recommended unless dietary vitamin E falls below the RDA (4260). No serious adverse effects were reported with oral intake of 400 IU per day starting at weeks 9-22 of pregnancy in healthy patients or those at high risk for pre-eclampsia (3236,97075), or with 600-900 IU daily during the last two months of pregnancy (4260). However, some preliminary evidence suggests that taking vitamin E supplements might be harmful when taken in early pregnancy. A case-control study found that taking a vitamin E supplement during the first 8 weeks of pregnancy is associated with a 1.7-9-fold increase in odds of congenital heart defects (16823). However, the exact amount of vitamin E consumed during pregnancy in this study is unclear. Until more is known, advise patients to avoid taking a vitamin E supplement in early pregnancy unless needed for an appropriate medical indication.
LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL).
The UL during lactation is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older (4844).
LACTATION: POSSIBLY UNSAFE
when used orally in amounts that exceed the UL due to increased risk of adverse effects (4844).
POSSIBLY SAFE ...when used orally. A dose of 50 mg (containing 8 mg diosgenin) has been used with apparent safety for 12 weeks (12,96724). ...when used topically. A wild yam cream has been used with apparent safety for 3 months (10989).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
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 NaturaViga. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Theoretically, taking damiana with antidiabetes drugs might increase the risk of hypoglycemia.
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Theoretically, grape extracts may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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Ingesting grape juice with cyclosporine can reduce cyclosporine absorption.
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A small pharmacokinetic study in healthy young adults shows that intake of purple grape juice 200 mL along with cyclosporine can decrease the absorption of cyclosporine by up to 30% when compared with water (53177). Separate doses of grape juice and cyclosporine by at least 2 hours to avoid this interaction.
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Theoretically, grape juice might reduce the levels of CYP1A2 substrates.
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A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of CYP1A2 (2539).
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It is unclear if grape juice or grape seed extract inhibits CYP2C9; research is conflicting.
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In vitro evidence shows that grape seed extract or grape juice might inhibit CYP2C9 enzymes (11094,53011,53089). However, a small pharmacokinetic study in healthy adults shows that drinking 8 ounces of grape juice once does not affect the clearance of flurbiprofen, a probe-drug for CYP2C9 metabolism (11094). The effects of continued grape juice consumption are unclear.
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Theoretically, grape seed extract may increase the levels of CYP2D6 substrates.
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In vitro evidence suggests that grape seed extract might inhibit CYP2D6 enzymes (53011). However, this interaction has not been reported in humans.
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Theoretically, grape seed extract might increase the levels of CYP2E1 substrates.
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In vitro and animal research suggests that grape seed proanthocyanidin extract inhibits CYP2E1 enzymes (52949). However, this interaction has not been reported in humans.
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It is unclear if grape seed extract inhibits or induces CYP3A4; research is conflicting.
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Theoretically, long-term intake of grape seed extract might decrease the effects of midazolam.
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Animal research shows that subchronic ingestions of grape seed extract can increase the elimination of intravenous midazolam by increasing hepatic CYP3A4 activity. Single doses of grape seed extract do not appear to affect midazolam elimination (53011).
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Grape juice might decrease phenacetin absorption.
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A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of cytochrome P450 1A2 (CYP1A2) (2539).
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Concomitant use of alcohol and niacin might increase the risk of flushing and hepatotoxicity.
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Alcohol can exacerbate the flushing and pruritus associated with niacin (4458,11689). Large doses of niacin might also exacerbate liver dysfunction associated with chronic alcohol use. A case report describes delirium and lactic acidosis in a patient taking niacin 3 grams daily who ingested 1 liter of wine (14510). Advise patients to avoid large amounts of alcohol while taking niacin.
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Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as allopurinol.
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Large doses of niacin can reduce urinary excretion of uric acid, potentially resulting in hyperuricemia (4860,4863,12033). Doses of uricosurics such as allopurinol might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).
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Theoretically, niacin may have additive effects when used with anticoagulant or antiplatelet drugs.
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Niacin can increase blood glucose levels and may diminish the effects of antidiabetes drugs.
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Niacin impairs glucose tolerance in a dose-dependent manner, probably by causing or aggravating insulin resistance and increasing hepatic production of glucose (4860,4863,11692,11693). In diabetes patients, niacin 4.5 grams daily for 5 weeks can increase plasma glucose by an average of 16% and glycated hemoglobin (HbA1c) by 21% (4860). However, lower doses of 1.5 grams daily or less appear to have minimal effects on blood glucose (12033). In some patients, glucose levels increase when niacin is started, but then return to baseline when a stable dose is reached (12033,93344). Up to 35% of patients with diabetes may need adjustments in hypoglycemic therapy when niacin is added (4458,4860,4863,11689,12033).
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Theoretically, niacin may increase the risk of hypotension when used with antihypertensive drugs.
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The vasodilating effects of niacin can cause hypotension (4863,12033,93341). Furthermore, some clinical evidence suggests that a one-hour infusion of niacin can reduce systolic, diastolic, and mean blood pressure in hypertensive patients. This effect is not observed in normotensive patients (25917).
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Large doses of aspirin might alter the clearance of niacin.
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Aspirin is often used with niacin to reduce niacin-induced flushing (4458,11689). Doses of 80-975 mg aspirin have been used, but 325 mg appears to be optimal (4458,4852,4853,11689). Aspirin also seems to reduce the clearance of niacin by competing for glycine conjugation. Taking aspirin 1 gram seems to reduce niacin clearance by 45% (14524). This is probably a dose-related effect and not clinically significant with the more common aspirin dose of 325 mg (11689,14524).
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Bile acid sequestrants can bind niacin and decrease absorption. Separate administration by 4-6 hours to avoid an interaction.
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In vitro studies show that colestipol (Colestid) binds about 98% of available niacin and cholestyramine (Questran) binds 10% to 30% (14511).
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Theoretically, concomitant use of niacin and gemfibrozil might increase the risk of myopathy in some patients.
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Theoretically, concomitant use of niacin and hepatotoxic drugs might increase the risk of hepatotoxicity.
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Niacin has been associated with cases of liver toxicity, especially when used in pharmacologic doses (4863,11689,11691,25929,25930,25931,113553). Sustained-release niacin preparations appear to be associated with a higher risk of hepatotoxicity than immediate-release niacin (11691,25930,25931,93342,113553).
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Theoretically, concomitant use of niacin and statins might increase the risk of myopathy and rhabdomyolysis in some patients.
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Some case reports have raised concerns that niacin might increase the risk of myopathy and rhabdomyolysis when combined with statins (14508,25918). However, a significantly increased risk of myopathy has not been demonstrated in clinical trials, including those using an FDA-approved combination of lovastatin and niacin (Advicor) (7388,11689,12033,14509).
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Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as probenecid.
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Large doses of niacin reduce urinary excretion of uric acid, potentially causing hyperuricemia (4863,12033). Doses of uricosurics such as probenecid might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).
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Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as sulfinpyrazone.
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Large doses of niacin reduce urinary excretion of uric acid, potentially causing hyperuricemia (4863,12033). Doses of uricosurics such as sulfinpyrazone might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).
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Theoretically, niacin might antagonize the therapeutic effects of thyroid hormones.
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Clinical research and case reports suggests that taking niacin can reduce serum levels of thyroxine-binding globulin by up to 25% and moderately reduce levels of thyroxine (T4) (25916,25925,25926,25928). Patients taking thyroid hormone for hypothyroidism might need dose adjustments when using niacin.
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Theoretically, concomitant use of niacin and transdermal nicotine might increase the risk of flushing and dizziness.
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Theoretically, niacinamide may have additive effects when used with anticoagulant or antiplatelet drugs, especially in patients on hemodialysis.
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Niacinamide might increase the levels and adverse effects of carbamazepine.
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Plasma levels of carbamazepine were increased in two children given high-dose niacinamide, 60-80 mg/kg/day. This might be due to inhibition of the cytochrome P450 enzymes involved in carbamazepine metabolism (14506). There is not enough data to determine the clinical significance of this interaction.
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Niacinamide might increase the levels and adverse effects of primidone.
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Case reports in children suggest niacinamide 60-100 mg/kg/day reduces hepatic metabolism of primidone to phenobarbital, and reduces the overall clearance rate of primidone (14506); however, there is not enough data to determine the clinical significance of this potential interaction.
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Although Panax ginseng has shown antiplatelet effects in the laboratory, it is unlikely to increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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In vitro evidence suggests that ginsenoside constituents in Panax ginseng might decrease platelet aggregation (1522,11891). However, research in humans suggests that ginseng does not affect platelet aggregation (11890). Animal research indicates low oral bioavailability of Rb1 and rapid elimination of Rg1, which might explain the discrepancy between in vitro and human research (11153). Until more is known, use with caution in patients concurrently taking anticoagulant or antiplatelet drugs.
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Theoretically, taking Panax ginseng with antidiabetes drugs might increase the risk of hypoglycemia.
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Clinical research suggests that Panax ginseng might decrease blood glucose levels (89740). Monitor blood glucose levels closely.
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Theoretically, taking Panax ginseng with caffeine might increase the risk of adverse stimulant effects.
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Theoretically, Panax ginseng might decrease levels of drugs metabolized by CYP1A1.
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In vitro research shows that Panax ginseng can induce the CYP1A1 enzyme (24104).
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Theoretically, Panax ginseng might increase levels of drugs metabolized by CYP2D6. However, research is conflicting.
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There is some evidence that Panax ginseng can inhibit the CYP2D6 enzyme by approximately 6% (1303,51331). In addition, in animal research, Panax ginseng inhibits the metabolism of dextromethorphan, a drug metabolized by CYP2D6, by a small amount (103478). However, contradictory research suggests Panax ginseng might not inhibit CYP2D6 (10847). Until more is known, use Panax ginseng cautiously in patients taking drugs metabolized by these enzymes.
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Theoretically, Panax ginseng might increase or decrease levels of drugs metabolized by CYP3A4.
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Panax ginseng may affect the clearance of drugs metabolized by CYP3A4. One such drug is imatinib. Inhibition of CYP3A4 was believed to be responsible for a case of imatinib-induced hepatotoxicity (89764). In contrast, Panax ginseng has been shown to increase the clearance of midazolam, another drug metabolized by CYP3A4 (89734,103478). Clinical research shows that Panax ginseng can reduce midazolam area under the curve by 44%, maximum plasma concentration by 26%, and time to reach maximum plasma concentration by 29% (89734). Midazolam metabolism was also increased in animals given Panax ginseng (103478). Until more is known, use Panax ginseng cautiously in combination with CYP3A4 substrates.
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Theoretically, concomitant use of large amounts of Panax ginseng might interfere with hormone replacement therapy.
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Theoretically, Panax ginseng might decrease blood levels of oral or intravenous fexofenadine.
Details
Animal research suggests that taking Panax ginseng in combination with oral or intravenous fexofenadine may reduce the bioavailability of fexofenadine. Some scientists have attributed this effect to the ability of Panax ginseng to increase the expression of P-glycoprotein (24101).
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Theoretically, Panax ginseng might reduce the effects of furosemide.
Details
There is some concern that Panax ginseng might contribute to furosemide resistance. There is one case of resistance to furosemide diuresis in a patient taking a germanium-containing ginseng product (770).
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Theoretically, Panax ginseng might increase the effects and adverse effects of imatinib.
Details
A case of imatinib-induced hepatotoxicity has been reported for a 26-year-old male with chronic myelogenous leukemia stabilized on imatinib for 7 years. The patient took imatinib 400 mg along with a Panax ginseng-containing energy drink daily for 3 months. Since imatinib-associated hepatotoxicity typically occurs within 2 years of initiating therapy, it is believed that Panax ginseng affected imatinib toxicity though inhibition of cytochrome P450 3A4. CYP3A4 is the primary enzyme involved in imatinib metabolism (89764).
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Theoretically, Panax ginseng use might interfere with immunosuppressive therapy.
Details
Panax ginseng might have immune system stimulating properties (3122).
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Theoretically, taking Panax ginseng with insulin might increase the risk of hypoglycemia.
Details
Clinical research suggests that Panax ginseng might decrease blood glucose levels (89740). Insulin dose adjustments might be necessary in patients taking Panax ginseng; use with caution.
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Although Panax ginseng has demonstrated variable effects on cytochrome P450 3A4 (CYP3A4), which metabolizes lopinavir, Panax ginseng is unlikely to alter levels of lopinavir/ritonavir.
Details
Lopinavir is metabolized by CYP3A4 and is administered with the CYP3A4 inhibitor ritonavir to increase its plasma concentrations. Panax ginseng has shown variable effects on CYP3A4 activity in humans (89734,89764). However, taking Panax ginseng (Vitamer Laboratories) 500 mg twice daily for 14 days did not alter the pharmacokinetics of lopinavir/ritonavir in 12 healthy volunteers (93578).
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Theoretically, Panax ginseng may increase the clearance of midazolam.
Details
Midazolam is metabolized by cytochrome P450 3A4 (CYP3A4). Clinical research suggests that Panax ginseng can reduce midazolam area under the curve by 44%, maximum plasma concentration by 26%, and time to reach maximum plasma concentration by 29% (89734). Midazolam metabolism was also increased in animals given Panax ginseng (103478).
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Theoretically, Panax ginseng can interfere with MAOI therapy.
Details
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Theoretically, taking Panax ginseng with nifedipine might increase serum levels of nifedipine and the risk of hypotension.
Details
Preliminary clinical research shows that concomitant use can increase serum levels of nifedipine in healthy volunteers (22423). This might cause the blood pressure lowering effects of nifedipine to be increased when taken concomitantly with Panax ginseng.
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Theoretically, Panax ginseng has an additive effect with drugs that prolong the QT interval and potentially increase the risk of ventricular arrhythmias. However, research is conflicting.
Details
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Theoretically, taking Panax ginseng with raltegravir might increase the risk of liver toxicity.
Details
A case report suggests that concomitant use of Panax ginseng with raltegravir can increase serum levels of raltegravir, resulting in elevated liver enzymes levels (23621).
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Theoretically, Panax ginseng might increase or decrease levels of selegiline, possibly altering the effects and side effects of selegiline.
Details
Animal research shows that taking selegiline with a low dose of Panax ginseng extract (1 gram/kg) reduces selegiline bioavailability, while taking a high dose of Panax ginseng extract (3 grams/kg) increases selegiline bioavailability (103053). More research is needed to confirm these effects.
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Theoretically, taking Panax ginseng with stimulant drugs might increase the risk of adverse stimulant effects.
Details
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Panax ginseng might affect the clearance of warfarin. However, this interaction appears to be unlikely.
Details
There has been a single case report of decreased effectiveness of warfarin in a patient who also took Panax ginseng (619). However, it is questionable whether Panax ginseng was the cause of this decrease in warfarin effectiveness. Some research in humans and animals suggests that Panax ginseng does not affect the pharmacokinetics of warfarin (2531,11890,17204,24105). However, other research in humans suggests that Panax ginseng might modestly increase the clearance of the S-warfarin isomer (15176). More evidence is needed to determine whether Panax ginseng causes a significant interaction with warfarin.
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Theoretically, peppermint oil might increase the levels and adverse effects of cyclosporine.
Details
In animal research, peppermint oil inhibits cyclosporine metabolism and increases cyclosporine levels. Inhibition of cytochrome P450 3A4 (CYP3A4) may be partially responsible for this interaction (11784). An interaction between peppermint oil and cyclosporine has not been reported in humans.
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Theoretically, peppermint might increase the levels of CYP1A2 substrates.
Details
In vitro and animal research shows that peppermint oil and peppermint leaf inhibit CYP1A2 (12479,12734). However, in clinical research, peppermint tea did not significantly affect the metabolism of caffeine, a CYP1A2 substrate. It is possible that the 6-day duration of treatment may have been too short to identify a difference (96359).
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Theoretically, peppermint might increase the levels of CYP2C19 substrates.
Details
In vitro research shows that peppermint oil inhibits CYP2C19 (12479). So far, this interaction has not been reported in humans.
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Theoretically, peppermint might increase the levels of CYP2C9 substrates.
Details
In vitro research shows that peppermint oil inhibits CYP2C9 (12479). So far, this interaction has not been reported in humans.
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Theoretically, peppermint might increase the levels of CYP3A4 substrates.
Details
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Trimethoprim might increase blood levels of thiamine.
Details
In vitro, animal, and clinical research suggest that trimethoprim inhibits intestinal thiamine transporter ThTR-2, hepatic transporter OCT1, and renal transporters OCT2, MATE1, and MATE2, resulting in paradoxically increased thiamine plasma concentrations (111678).
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of alkylating agents.
Details
There's concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.
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Concomitant use of vitamin E and anticoagulant or antiplatelet agents might increase the risk of bleeding.
Details
Vitamin E seems to inhibit of platelet aggregation and antagonize the effects of vitamin K-dependent clotting factors (4733,4844,11580,11582,11583,11584,11586,112162). These effects appear to be dose-dependent, and are probably only likely to be clinically significant with doses of at least 800 units daily (11582,11585). Mixed tocopherols, such as those found in food, might have a greater antiplatelet effect than alpha-tocopherol (10364). RRR alpha-tocopherol (natural vitamin E) 1000 IU daily antagonizes vitamin K-dependent clotting factors (11999). Advise patients to avoid high doses of vitamin E, especially in people with low vitamin K intake or other risk factors for bleeding.
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of antitumor antibiotics.
Details
There's concern that antioxidants could reduce the activity of antitumor antibiotic drugs such as doxorubicin, which generate free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy involving antitumor antibiotics. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.
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A specific form of vitamin E might increase absorption and levels of cyclosporine.
Details
There is some evidence that one specific formulation of vitamin E (D-alpha-tocopheryl-polyethylene glycol-1000 succinate, TPGS, tocophersolan, Liqui-E) might increase absorption of cyclosporine. This vitamin E formulation forms micelles which seems to increase absorption of cyclosporine by 40% to 72% in some patients (624,625,10368). However, this interaction is unlikely to occur with the usual forms of vitamin E.
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Theoretically, vitamin E might induce metabolism of CYP3A4, possibly reducing the levels CYP3A4 substrates.
Details
Vitamin E appears to bind with the nuclear receptor, pregnane X receptor (PXR), which results in increased expression of CYP3A4 (13499,13500). Although the clinical significance of this is not known, use caution when considering concomitant use of vitamin E and other drugs affected by these enzymes.
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Vitamin E might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.
Details
A combination of niacin and simvastatin (Zocor) effectively raises high-density lipoprotein (HDL) cholesterol levels in people with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% (7388,11537). Vitamin E alone combined with a statin does not seem to decrease HDL levels (11286,11287). It is not known whether the adverse effect on HDL is due to one of the other antioxidants or to the combination. It also is not known whether it will occur in other patient populations.
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Taking selumetinib with vitamin E can result in a total daily dose of vitamin E that exceeds safe limits and therefore might increase the risk of bleeding.
Details
Selumetinib contains 48-54 IU vitamin E per capsule (102971). The increased risk of bleeding with vitamin E appears to be dose-dependent (11582,11585,34577). Be cautious when using selumetinib in combination with supplemental vitamin E, especially in patients at higher risk of bleed, such as those with chronic conditions and those taking antiplatelet drugs (102971).
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Using vitamin E with warfarin might increase the risk of bleeding.
Details
Due to interference with production of vitamin K-dependent clotting factors, use of more than 400 IU of vitamin E daily with warfarin might increase prothrombin time (PT), INR, and the risk of bleeding, (91,92,93). At a dose of 1000 IU per day, vitamin E can antagonize vitamin K-dependent clotting factors even in people not taking warfarin (11999). Limited clinical evidence suggests that doses up to 1200 IU daily may be used safely by patients taking warfarin, but this may not be applicable in all patient populations (90).
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Theoretically, wild yam might increase or decrease the effects of estrogen.
Details
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Amiloride can modestly reduce zinc excretion and increase zinc levels.
Details
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.
Details
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.
Details
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.
Details
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.
Details
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Zinc might reduce the levels and clinical effects of penicillamine.
Details
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.
Details
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Zinc modestly reduces levels of ritonavir.
Details
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.
Details
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 NaturaViga. 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, adverse effects to damiana seem to be rare; however, a thorough safety evaluation has not been conducted.
Neurologic/CNS ...Orally, 200 grams of damiana extract has caused tetanus-like convulsions and paroxysms resulting in symptoms similar to rabies or strychnine poisoning (4).
General
...Orally, the whole fruit, as well as the seed, fruit, and leaf extracts, seem to be well tolerated.
Topically, grape seed extracts seem to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, dry mouth, dyspepsia, headache, joint pain, and nausea.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis to grape skin has been reported.
Dermatologic ...Orally, mild hair thinning has been reported in a patient taking a specific grape leaf extract AS195 KG) (2538). Urticaria (hives) has also been reported with this same extract (53206). Cases of contact dermatitis have been reported in grape workers, including those working in California vineyards (53270,53272,53275).
Gastrointestinal ...Orally, abdominal pain and nausea have been reported with use of grape seed extract, but these effects typically occur at rates similar to placebo (9182,13162). In a case report of a 57-year-old man, intermittent nausea, vomiting, and diarrhea occurred over a 10-day period and improved once grape seed extract was stopped (96764). Gastrointestinal adverse effects have also been reported with use of a different grape seed extract (Entelon, Hanlim Pharm). However, the specific types of gastrointestinal effects were not described (100954). A specific grape leaf extract AS195 (Antistax, Boehringer Ingelheim Pharma GmbH & Co. KG) has reportedly caused flatulence, mild constipation, gastrointestinal discomfort, diarrhea, dyspepsia, dry mouth, and retching (2538,52985,53206). Diarrhea, gastrointestinal distress, indigestion, and aversion to taste have been reported with use of Concord grape juice (52972,53166,53175,53181,53199). Loose stools have been reported in a clinical trial of grape pomace (99270). Bowel obstruction caused by intact grapes and grape seeds has been described in case reports (53241,53284,53278). Excessive consumption of grapes, dried grapes, raisins, or sultanas might cause diarrhea due to laxative effects (4201).
Hematologic ...Orally, one case of leg hematoma following a minor trauma was reported in a person using grape leaf extract (2538). Also, one case of bruising was reported in a person drinking Concord grape juice daily for 2 weeks (52972).
Immunologic ...Orally, there is one report of an anaphylactic reaction to oral grape skin extract, which included urticaria and angioedema (4073).
Musculoskeletal ...Orally, musculoskeletal disorders, including back pain, have been reported with use of a specific grape leaf extract AS195 KG) (2538,53206). Joint pain and lumbago have been reported with use of grape seed extract, but these effects occur at rates similar to placebo (91541).
Neurologic/CNS ...Orally, headache has been reported with use of grape seed extract, but this effect occurs at rates similar to placebo (9182,91541). A specific grape leaf extract AS195 (Antistax, Boehringer Ingelheim Pharma GmbH & Co. KG) has reportedly caused dizziness, tiredness, headache, and sleep problems (2538,53206). As a class, nervous system adverse effects have been reported with use of a specific grape seed extract (Entelon, Hanlim Pharm). However, the specific types of adverse neurologic effects were not described (100954).
Ocular/Otic ...Orally, ocular adverse effects have been reported with use of a specific grape seed extract (Entelon, Hanlim Pharm). However, the specific types of ocular adverse effects were not described (100954).
Pulmonary/Respiratory ...Orally, nasopharyngitis and oropharyngeal pain have been reported with use of a specific grape leaf extract AS195 KG) (53206). Sore throat, cough, allergic rhinitis, and nasopharyngitis have been reported with use of grape seed extract, but these effects occur at rates similar to placebo (9182,91541). One case report describes a 16-year-old female who developed increased levels of immunoglobulin E (IgE) following skin-prick exposure to grape vine pollen, as well as positive test responses following bronchial and conjunctival provocation (53301). Reduced forced vital capacity has been described in California grape workers (53080,53081). Occupational eosinophilic lung was diagnosed in a grape grower with a history of asthma. Respiratory exposure to sulfites in grape was implicated as the cause of the adverse reaction (53285).
Other
...Orally, grape products can cause adverse effects due to contamination with pesticides or mycotoxins.
Some evidence has shown that pesticides used in vineyards may remain on grape surfaces post-harvesting. For example, the fungicide folpet sprayed on grapevines has been shown to remain on the grape surface. Although there was minimal penetration of the epicuticular wax, it showed high resistance to washing (52935). Carbaryl has been identified in over 58% of juice samples collected in Canada. This pesticide reportedly occurred more frequently in grape than in other juices. However, estimates of short-term intake were below proposed acute reference doses (53003).
Ochratoxin A is a mycotoxin that is suspected to be nephrotoxic, teratogenic, hepatotoxic and carcinogenic and has been identified in grape juice, frozen grape pulps, and red and white wine sold in Rio de Janeiro, Brazil. However, the highest levels identified in grape products were lower than the established virtually safe dose of 5 ng/kg of body weight daily (53010,53004). Ochratoxin A has also been identified in red, but not white, grape juice marketed in Switzerland, Canada, and the U.S. (53292,53020).
General
...Orally, lecithin is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, fullness, and nausea.
Dermatologic ...Orally, lecithin can cause allergic skin reactions in people with egg or soy allergies (15705).
Gastrointestinal ...Orally, lecithin may cause abdominal pain, diarrhea, fullness, and nausea (5140,6243,14817,14822,14838,19204,59281).
Neurologic/CNS ...Orally, lecithin caused CNS complaints and agitation in one patient in a clinical trial (59261).
General
...Orally, niacin is well tolerated in the amounts found in foods.
It is also generally well tolerated in prescription doses when monitored by a healthcare provider.
Most Common Adverse Effects:
Orally: Flushing, gastrointestinal complaints (abdominal pain, constipation, diarrhea, heartburn, nausea, vomiting), and elevated liver enzymes.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity, myopathy, thrombocytopenia, and vision changes.
Cardiovascular
...Orally, flushing is a common dose-related adverse reaction to niacin.
A large meta-analysis of clinical studies shows that up to 70% of patients may experience flushing (96211). Although flushing can occur with doses of niacin as low as 30 mg daily, it is more common with the larger doses used for treatment of dyslipidemia. The flushing reaction is due to prostaglandin-induced blood vessel dilation and can also include symptoms of burning, tingling, urticaria, erythema, pain, and itching of the face, arms, and chest. There may also be increased intracranial blood flow and headache (4889,26089,93341,104933). Onset is highly variable and ranges from within 30 minutes to as long as 6 weeks after the initial dose (6243). Flushing can be minimized via various strategies, including taking doses with meals, slow dose titration, using extended release formulations, pretreating with non-steroidal anti-inflammatory drugs, taking regular-release niacin with meals, or taking the sustained-release product at bedtime (4852,4853,4854,4857,4858,25922,26073,26084). Flushing often diminishes with continued use but can recur when niacin is restarted after missed doses (4863,6243,26081). The vasodilating effects of niacin can also cause hypotension, dizziness, tachycardia, arrhythmias, syncope, and vasovagal attacks, especially in patients who are already taking antihypertensive drugs (4863,12033,93341,110494).
High doses of niacin can raise homocysteine levels. A 17% increase has been reported with 1 gram daily and a 55% increased has been reported with 3 grams daily. Elevated homocysteine levels are an independent risk factor for cardiovascular disease (490); however, the clinical significance of this effect is unknown. A large-scale study (AIM-HIGH) found that patients receiving extended-release niacin (Niaspan) 1500-2000 mg daily with a statin had an over two-fold increased risk of ischemic stroke (1.6%) when compared with those receiving only simvastatin (0.7%). However, when the risk was adjusted for confounding factors, niacin was not found to be associated with increased stroke risk (17627,93354). A meta-analysis of three clinical trials conducted in approximately 29,000 patients showed a higher risk of mortality in patients taking niacin in addition to a statin when compared with a statin alone. However, with a p-value of 0.05 and confidence interval including 1, the validity of this finding remains unclear (97308).
Endocrine
...Orally, niacin can impair glucose tolerance in a dose-dependent manner.
Dosages of 3-4 grams daily appear to increase blood glucose in patients with or without diabetes, while dosages of 1.5 grams daily or less have minimal effects (12033). Niacin is thought to impair glucose tolerance by increasing insulin resistance or increasing hepatic output of glucose (4863,11692,11693). In patients with diabetes, niacin 4.5 grams daily for 5 weeks has been associated with an average 16% increase in plasma glucose and 21% increase in glycated hemoglobin (HbA1C) (4860). Up to 35% of patients with diabetes may need to increase the dose or number of hypoglycemic agents when niacin is started (4458,4860,4863,11689,12033). Occasionally, severe hyperglycemia requiring hospitalization can occur (11693). In patients with impaired fasting glucose levels, niacin may also increase fasting blood glucose, and adding colesevelam might attenuate this effect (93343).
Although patients without diabetes seem to only experience small and clinically insignificant increases in glucose (4458), niacin might increase their risk of developing diabetes. A meta-analysis of clinical research involving over 26,000 patients shows that using niacin over 5 years is associated with increased prevalence of new onset type 2 diabetes at a rate of 1 additional case of diabetes for every 43 patients treated with niacin (96207). This finding is limited because the individual trials were not designed to assess diabetes risk and the analysis could not be adjusted for confounding factors like obesity. One small clinical study shows that taking extended-release niacin with ezetimibe/simvastatin does not increase the risk of a new diagnosis of diabetes or need for antidiabetic medication when compared with ezetimibe/simvastatin alone after 16 months (93344). This may indicate that the increased risk of developing diabetes is associated with niacin use for more than 16 months.
Niacin therapy has also been linked with hypothyroidism and its associated alterations in thyroid hormone and binding globulin tests (such as decreased total serum thyroxine, increased triiodothyronine, decreased thyroxine-binding globulin levels, and increased triiodothyronine uptake) (25916,25925,25926,25928).
Gastrointestinal ...Orally, large doses of niacin can cause gastrointestinal disturbances including nausea, vomiting, bloating, heartburn, abdominal pain, anorexia, diarrhea, constipation, and activation of peptic ulcers (4458,4863,12033,26083,93341,96211). These effects may be reduced by taking the drug with meals or antacid, and usually disappear within two weeks of continued therapy (4851,26094). Gastrointestinal effects may be more common with time-release preparations of niacin (11691).
Hematologic ...Orally, sustained-release niacin has been associated with cases of reversible coagulopathy, mild eosinophilia, and decreased platelet counts (4818,25915,26097,93340). Also, there have been reports of patients who developed leukopenia while taking niacin for the treatment of hypercholesterolemia (25916).
Hepatic ...Orally, niacin is associated with elevated liver function tests and jaundice, especially with doses of 3 grams/day or more, and when doses are rapidly increased (4458,4863,6243). The risk of hepatotoxicity appears to be higher with slow-release and extended-release products (4855,4856,4863,6243,11691,12026,12033,93342). Niacin should be discontinued if liver function tests rise to three times the upper limit of normal (4863). There are rare cases of severe hepatotoxicity with fulminant hepatitis and encephalopathy due to niacin (4863,6243,11691). In one case, a patient taking extended-release niacin 2500 mg daily for 15 years developed decompensating cirrhosis and was diagnosed with chronic, toxic, metabolic liver injury. Despite medical intervention, the patient died (113553). Also, there is at least one case of niacin-induced coagulopathy resulting from liver injury without liver enzyme changes (93340).
Musculoskeletal ...Orally, niacin has been associated with elevated creatine kinase levels (4818,4888). Also, several cases of niacin-induced myopathy have been reported (26100,26111). Concomitant administration of niacin and HMG-CoA reductase inhibitors may increase the risk of myopathy and rhabdomyolysis (14508,25918,26111); patients should be monitored closely.
Neurologic/CNS ...Orally, high-dose niacin has been associated with cases of neuropsychiatric adverse events such as extreme pain and psychosis. Two 65-year-old males taking niacin orally for 5 months for the treatment of dyslipidemias developed severe dental and gingival pain. The pain was relieved by the discontinuation of niacin. The pain was thought to be due to inflammation and pain referral to the teeth (4862). In one case report, a 52-year-old male with no history of psychiatric illness who initially complained of hot flushes when taking niacin 500 mg daily, presented with an acute psychotic episode involving mania after niacin was increased to 1000 mg daily (93350).
Ocular/Otic ...Orally, chronic use of large amounts of niacin has been associated with dry eyes, toxic amblyopia, blurred vision, eyelid swelling, eyelid discoloration, loss of eyebrows and eyelashes, proptosis, keratitis, macular edema, and cystic maculopathy, which appear to be dose-dependent and reversible (4863,6243,26112).
General
...Orally, niacinamide is well tolerated in amounts typically found in food.
When used topically and orally in higher doses, niacinamide seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, itching, gastrointestinal disturbances, headache, and rash.
Topically: Burning sensation, itching, and mild dermatitis.
Dermatologic ...Orally, large doses of niacinamide are associated with occasional reports of rashes, itching, and acanthosis nigricans (4880,11695,11697,14504,107709), though a meta-analysis of 19 clinical studies suggests that dermatological adverse event rates are similar between niacinamide and control (110497). Topically, application of niacinamide in a cream has been reported to cause a burning sensation, itching and pruritus, crusting, and mild dermatitis (93357,93360,110501,110498).
Endocrine ...Orally, niacinamide in high doses, 50 mg/kg daily, has been associated with modestly higher insulin requirements in patients with type 1 diabetes, when compared with taking niacinamide 25 mg/kg daily. Theoretically, high-dose niacinamide might increase insulin resistance, although to a lesser extent than niacin (4881,14512).
Gastrointestinal ...Orally, large doses of niacinamide can cause gastrointestinal disturbances including nausea, vomiting, heartburn, anorexia, epigastric pain, flatulence, and diarrhea (6243,11694,11695,11696,11697,107709,110497,113682).
Hematologic ...Orally, niacinamide supplementation might increase the risk for thrombocytopenia in patients undergoing hemodialysis (98940,107709). A meta-analysis of small clinical studies shows that taking niacinamide during hemodialysis to reduce phosphate levels is associated with a 2.8-fold increased risk for thrombocytopenia when compared with placebo. In one of the included studies, platelet levels returned to normal within 20 days after niacinamide discontinuation (98940).
Hepatic ...Orally, older reports of elevated liver function tests with high doses of niacinamide (3 grams or more daily) have raised concerns about liver toxicity. However, newer studies have not reported this concern; it is possible that some of these cases were due to contamination with niacin (4880,11694,11695,14503).
Neurologic/CNS ...Orally, large doses of niacinamide can cause dizziness, drowsiness, and headaches (11694,11695,11696,11697,107709).
General
...Orally, Panax ginseng is generally well tolerated when used for up to 6 months.
There is some concern about the long-term safety due to potential hormone-like effects.
Topically, no adverse effects have been reported when ginseng is used as a single ingredient. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Insomnia.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis, arrhythmia, ischemia, Stevens-Johnson syndrome.
Cardiovascular ...Panax ginseng may cause hypertension, hypotension, and edema when used orally in high doses, long-term (3353). However, single doses of Panax ginseng up to 800 mg are not associated with changes in electrocardiogram (ECG) parameters or increases in heart rate or blood pressure (96218). There is a case report of menometrorrhagia and tachyarrhythmia in a 39-year-old female who took Panax ginseng 1000-1500 mg/day orally and also applied a facial cream topically that contained Panax ginseng. Upon evaluation for menometrorrhagia, the patient also reported a history of palpitations. It was discovered that she had sinus tachycardia on ECG. However, the patient was a habitual consumer of coffee 4-6 cups/day and at the time of evaluation was also mildly anemic. The patient was advised to discontinue taking Panax ginseng. During the 6 month period following discontinuation the patient did not have any more episodes of menometrorrhagia or tachyarrhythmia (13030). Also, a case of transient ischemic attack secondary to a hypertensive crisis has been reportedly related to oral use of Panax ginseng (89402).
Dermatologic
...Orally, Panax ginseng may cause itching or an allergic response consisting of systemic rash and pruritus (89743,89760,104953,114984,114985).
Skin eruptions have also been reported with use of Panax ginseng at high dosage, long-term (3353). Uncommon side effects with oral Panax ginseng include Stevens-Johnson syndrome (596).
In one case report, a 6-year-old male with a previous diagnosis of generalized pustular psoriasis, which had been in remission for 18 months, presented with recurrent pustular lesions after consuming an unspecified dose of Panax ginseng. The patient was diagnosed with pityriasis amiantacea caused by subcorneal pustular dermatosis. Treatment with oral dapsone 25 mg daily was initiated, and symptoms resolved after 4 weeks (107748). In another case report, a 26-year-old female presented with itchy exanthem and oval erythematous lesions on the face, neck, and abdomen after consuming a decoction containing Panax ginseng, aconite, ginger, licorice, Cassia cinnamon, goldthread, and peony 400 mL twice daily for 1 week. Pityriasis rosea-like eruption was suspected, but the patient refused topical or oral antihistamines or corticosteroids. The patient continued taking the decoction but with Panax ginseng and aconite removed. After 6 days, symptoms began to resolve, and by 17 days symptom improvement was significant (114986). It is unclear if this reaction was due to Panax ginseng, aconite, the combination, or some other factor. Pityriasis rosea typically resolves spontaneously.
Topically, when a specific multi-ingredient cream preparation (SS Cream) has been applied to the glans penis, mild pain, local irritation, and burning have occurred (2537).
Endocrine
...The estrogenic effects of ginseng are controversial.
Some clinical evidence suggests it doesn't have estrogen-mediated effects (10981). However, case reports of ginseng side effects such as postmenopausal vaginal bleeding suggest estrogenic activity (590,591,592,10982,10983).
In a 12-year-old Korean-Japanese male, enlargement of both breasts with tenderness in the right breast (gynecomastia) occurred after taking red ginseng extract 500 mg daily orally for one month. Following cessation of the product, there was no further growth or pain (89733). Swollen and tender breasts also occurred in a 70-year-old female using Panax ginseng orally (590).
Gastrointestinal ...Orally, Panax ginseng can cause decreased appetite (3353), constipation, diarrhea, dyspepsia (3353,89734,103477,112841,114980,114985), abdominal pain (89734,87984,112841,114985), and nausea (589,87984). However, these effects are typically associated with long-term, high-dose usage (3353). Some evidence suggests that fermented Panax ginseng is more likely to cause abdominal pain and diarrhea when compared with unfermented Panax ginseng (112841).
Genitourinary
...Amenorrhea has been reported with oral use of Panax ginseng (3353).
Topically, when a specific multi-ingredient cream preparation (SS Cream) has been applied to the glans penis, sporadic erectile dysfunction and excessively delayed ejaculation have occurred (2537). Less commonly, patients can experience vaginal bleeding (591,592,3354,23630).
Hepatic ...It is unclear if Panax ginseng is associated with adverse hepatic effects. Cholestatic hepatitis has been reported in a 65-year old male following oral use of a combination product containing Panax ginseng and other ingredients (Prostata). However, it is unclear if this adverse effect was due to Panax ginseng, other ingredients, or the combination (598). An elevation in liver enzymes has been rarely reported in clinical research (114985).
Immunologic ...A case of anaphylaxis, with symptoms of hypotension and rash, has been reported following ingestion of a small amount of Panax ginseng syrup (11971).
Neurologic/CNS ...Orally, one of the most common side effects to Panax ginseng is insomnia (589,89734,111336,114985). Headache (594,23638,112840,114985), vertigo, euphoria, and mania (594) have also been reported. Migraine and somnolence occurred in single subjects in a clinical trial (87984). In a case report of a 46-year-old female, orobuccolingual dyskinesia occurred following oral use of a preparation containing black cohosh 20 mg and Panax ginseng 50 mg twice daily for menopausal symptoms. The patient's condition improved once the product was stopped and treatment with baclofen 40 mg and clonazepam 20 mg daily was started (89735).
General
...Orally, topically, or rectally, peppermint oil is generally well tolerated.
Inhaled,
peppermint oil seems to be well tolerated. Intranasally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted. Orally, peppermint leaf seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, anal burning, belching, diarrhea, dry mouth, heartburn, nausea, and vomiting.
Topically: Burning, dermatitis, irritation, and redness.
Dermatologic
...Topically, peppermint oil can cause skin irritation, burning, erythema, and contact dermatitis (3802,11781,31528,43338,68473,68457,68509,96361,96362).
Also, a case of severe mucosal injury has been reported for a patient who misused an undiluted over the counter mouthwash that contained peppermint and arnica oil in 70% alcohol (19106).
In large amounts, peppermint oil may cause chemical burns when used topically or orally. A case of multiple burns in the oral cavity and pharynx, along with edema of the lips, tongue, uvula, and soft palate, has been reported for a 49-year-old female who ingested 40 drops of pure peppermint oil. Following treatment with intravenous steroids and antibiotics, the patient's symptoms resolved over the course of 2 weeks (68432). Also, a case of chemical burns on the skin and skin necrosis has been reported for a 35-year-old male who spilled undiluted peppermint oil on a previous skin graft (68572). Oral peppermint oil has also been associated with burning mouth syndrome and chronic mouth ulceration in people with contact sensitivity to peppermint (6743). Also, excessive consumption of mint candies containing peppermint oil has been linked to cases of stomatitis (13114).
Gastrointestinal ...Orally, peppermint oil can cause heartburn, nausea and vomiting, anal or perianal burning, abdominal pain, belching, dry mouth, diarrhea, and increased appetite (3803,6740,6741,6742,10075,11779,11789,17682,68497,68514)(68532,68544,96344,96360,102602,104219,107955). Enteric-coated capsules might help to reduce the incidence of heartburn (3802,4469,6740,11777). However, in one clinical study, a specific enteric-coated formulation of peppermint oil (Pepogest; Nature's Way) taken as 180 mg three times daily was associated with a higher rate of adverse effects when compared with placebo (48% versus 31%, respectively). Specifically, of the patients consuming this product, 11% experienced belching and 26% experienced heartburn, compared to 2% and 12%, respectively, in the placebo group (107955). A meta-analysis of eight small clinical studies in patients with irritable bowel syndrome shows that taking enteric-coated formulations of peppermint oil increases the risk of gastroesophageal reflux symptoms by 67% when compared with a control group (109980). Enteric-coated capsules can also cause anal burning in people with reduced bowel transit time (11782,11789).
Genitourinary ...Orally, a sensitive urethra has been reported rarely (102602).
Hepatic ...One case of hepatocellular liver injury has been reported following the oral use of peppermint. Symptoms included elevated liver enzymes, fatigue, jaundice, dark urine, and signs of hypersensitivity. Details on the dosage and type of peppermint consumed were unavailable (96358).
Immunologic ...One case of IgE-mediated anaphylaxis, characterized by sudden onset of lip and tongue swelling, tightness of throat, and shortness of breath, has been reported in a 69-year-old male who consumed peppermint candy (89479). An allergic reaction after use of peppermint oil in combination with caraway oil has been reported in a patient with a history of bronchial asthma (96344). It is not clear if this reaction occurred in response to the peppermint or caraway components.
Neurologic/CNS ...Orally, headache has been reported rarely (102602).
Ocular/Otic ...Orally, peppermint has been reported to cause blurry vision (3803).
General
...Orally and parenterally, thiamine is generally well tolerated.
Serious Adverse Effects (Rare):
Parenterally: Hypersensitivity reactions including angioedema and anaphylaxis.
Immunologic
...Orally, thiamine might rarely cause dermatitis and other allergic reactions.
Parenterally, thiamine can cause anaphylactoid and hypersensitivity reactions, but this is also rare (<0.1%). Reported symptoms and events include feelings of warmth, tingling, pruritus, urticaria, tightness of the throat, cyanosis, respiratory distress, gastrointestinal bleeding, pulmonary edema, angioedema, hypotension, and death (15,35585,105445).
In one case report, a 46-year-old female presented with systemic allergic dermatitis after applying a specific product (Inzitan, containing lidocaine, dexamethasone, cyanocobalamin and thiamine) topically by iontophoresis; the allergic reaction was attributed to thiamine (91170).
General
...Orally and topically, vitamin E is generally well-tolerated.
Serious Adverse Effects (Rare):
Orally: Bleeding, hemorrhagic stroke, cardiovascular complications.
Inhaled: Vitamin E acetate is thought to be responsible for e-cigarette, or vaping, product-use associated lung injury (EVALI).
Cardiovascular
...Some evidence suggests that taking vitamin E supplements, especially greater than or equal to 400 IU taken by mouth daily for over one year, might also increase the risk of mortality in non-healthy patients (12212,13036,15305,16709,83339).
A population study shows that vitamin E use is associated with a significantly increased risk of mortality in people with a history of severe cardiovascular disease such as stroke or myocardial infarction (16709). In an analysis of clinical trials, patients who took either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) in doses of 400 IU/day or higher had an increased risk of mortality from all causes. The risk of mortality seems to increase when higher doses are used (12212). A large-scale study also suggests that patients with diabetes or cardiovascular disease who take RRR-alpha-tocopherol (natural vitamin E) 400 IU daily have an increased risk of heart failure and heart failure-related hospitalization (13036). However, in another large scale study, taking 600 IU vitamin E every other day for 10 years did not increase the risk of heart failure in healthy females over 45 years of age (90068). There is speculation that high-dose vitamin E might disrupt the normal antioxidant balance and result in pro-oxidant rather than antioxidant effects.
There is some evidence that vitamin E in combination with simvastatin (Zocor), niacin, selenium, vitamin C, and beta-carotene might lower high density lipoprotein-2 (HDL-2) by 15%. HDL-2 is considered to be the most cardioprotective component of HDL (7388). However, vitamin E and a statin alone don't seem to negatively affect HDL (11286,11287). In addition, vitamin E has been associated with increased triglycerides (85215). Although only certain isomers of vitamin E are included for determination of dietary requirements, all isomers are considered for determining safe intake levels. All the isomers are thought to potentially contribute to toxicity.
Dermatologic
...Topically, vitamin E has been associated with contact dermatitis, inflammatory reactions, and eczematous lesions (11998,85066,85285).
Dermatitis, often associated with moisturizers containing vitamin E, has a scattered generalized distribution, is more common on the face than the hands, and is more common in females with a history of atopic dermatitis. In a retrospective analysis of results of patch tests for DL-alpha-tocopherol sensitivity, 0.9% of patients had a definite positive reaction, while over 50% had a weakly positive, non-vesicular erythematous reaction (107869).
Orally, vitamin E has been associated with pruritus in one clinical trial (34596).
Subcutaneously, vitamin E has been associated with reports of lipogranuloma (85188,112331). In one case, subcutaneous injection of a specific supplement (1Super Extenze), containing mineral oil and tocopherol acetate, into the penile tissue resulted in penile disfigurement due to sclerosing lipogranuloma (85188). In another case, a 50-year-old Iranian female presented with lipogranuloma of the face, characterized by severe facial erythema, edema, and tenderness, 3 months after receiving subcutaneous injections of vitamin E to the cheeks for "facial rejuvenation." The patient had noticed initial symptoms within 3 days, and her symptoms progressively worsened over time (112331).
Gastrointestinal ...Orally, vitamin E supplementation has been associated with abdominal pain, nausea, diarrhea, or flu-like symptoms (85040,85323). Intravenously, large doses of vitamin E in premature infants are associated with an increased risk of necrotizing enterocolitis and sepsis (85083,85231).
Genitourinary ...There is contradictory evidence about the effect of vitamin E on prostate cancer risk. One large-scale population study shows that males who take a multivitamin more than 7 times per week and who also take a separate vitamin E supplement have a significantly increased risk of developing prostate cancer (15607). In a large-scale clinical trial (The SELECT trial) in males over the age of 50 years, taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily increased the risk of developing prostate cancer by 17% when compared with placebo. However, the difference in prostate cancer risk between vitamin E and placebo became significant only 3 years after patients stopped taking supplementation and were followed in an unblinded fashion. Interestingly, patients taking vitamin E plus selenium did not have a significantly increased risk of prostate cancer (17688).
Hematologic ...High doses of vitamin E might increase the risk of bleeding due to antagonism of vitamin K-dependent clotting factors and platelet aggregation. Patients with vitamin K deficiencies or taking anticoagulant or antiplatelet drugs are at a greater risk for bleeding (4098,4844,11999,34596,34538,34626,34594,112162).
Neurologic/CNS ...There is concern that vitamin E might increase the risk of hemorrhagic stroke (16708,34594,34596,108641). In one clinical study, there was a higher incidence of hemorrhagic stroke in male smokers taking all-rac-alpha-tocopherol (synthetic vitamin E) for 5-8 years compared to those not taking vitamin E (3949). Other studies lasting from 1.4-4.5 years and using either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) showed no significantly increased risk for stroke (2307,3896,3936). A meta-analysis of studies shows that vitamin E in doses of 300-800 IU daily, including both natural and synthetic forms, does not significantly affect total stroke risk. However, it significantly increases the risk of hemorrhagic stroke by 22%. This means that there will be one additional hemorrhagic stroke for every 1250 patients taking vitamin E. In contrast to this finding, the analysis also found that vitamin E significantly reduces the risk of ischemic stroke by 10%. This means that one ischemic stroke will be prevented for every 476 patients taking vitamin E (14621). In patients with moderately severe Alzheimer disease, taking vitamin E 2000 IU for 2 years has been associated with a modest, but significant, increase in falls and episodes of syncope when compared to placebo (4635).
Pulmonary/Respiratory ...When inhaled, vitamin E acetate is thought to play a role in the development of e-cigarette, or vaping, product-use associated lung injury (EVALI). Although a causal link has not yet been determined, in two case series, vitamin E acetate has been found in most bronchoalveolar lavage samples taken from the primary site of lung injury in patients with EVALI, whereas no vitamin E was found in healthy control samples. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. EVALI has resulted in death in some patients (101062,102970).
Other ...In an analysis of 3 trials, taking vitamin E 400 IU with vitamin C 1000 mg daily for 14-22 weeks during gestation appears to increase the risk of gestational hypertension by 30% compared to placebo in patients at risk of pre-eclampsia. However, the risk of pre-eclampsia itself was not increased (83450).
General
...Orally, wild yam is generally well tolerated.
Most Common Adverse Effects:
Orally: Fever, headache, upset stomach, and vomiting.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis.
Gastrointestinal ...Orally, wild yam can cause upset stomach and vomiting, especially at higher doses (12,86450).
Hematologic ...In one case report, a 55-year-old female with protein S deficiency and systemic lupus erythematosus (SLE) had temporary vision loss in the left eye from hemiretinal vein thrombosis 3 days after taking a combination phytoestrogen product containing wild yam 276 mg, dong quai 100 mg, red clover 250 mg, and black cohosh 250 mg (13155). It is unclear if wild yam contributed to this event.
Immunologic ...There are three case reports of anaphylaxis after ingestion of cooked wild yam (96722).
Neurologic/CNS ...Orally, wild yam can cause headache and fever, especially at higher doses (86450).
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).
