Two softgels contain: Vitamin E (from mixed natural tocopherols) 1 IU • Organic Flaxseed/Purifed Fish Oil Blend 2.5 g: Organic Flaxseed , Purified Fish Oil . Blend provides: Alpha Linoleic Acid (omega-3) 700 mg, EPA/DHA (omega-3) 300 mg, Oleic Acid (omega-9) 150 mg, Linoleic Acid (omega-6) 150 mg, Palmitic Acid 50 mg • Natural Mixed Tocopherols (gamma, delta, beta) 160 mg. Other Ingredients: Gelatin, Glycerin, Purified Water, Caramel.
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Below is general information about the effectiveness of the known ingredients contained in the product Flaxseed/Fish Oil Complex. 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
Below is general information about the safety of the known ingredients contained in the product Flaxseed/Fish Oil Complex. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when used orally and appropriately. Doses of 3 grams per day and less can be safely used by most people. Fish oil has Generally Recognized As Safe (GRAS) status in the US (1313,1024,2299,2300,2301,2302,2315,2317,4912,5702)(5705,5706,6394,6399,7368,7369,7380,12921,12922,13011)(13766,14382,16733,17408,17991,17992,66454,89325,89336,89346)(89351,89352,89373,89374,101543,103492,103499,103502,104546,105220)(107180,107181,113220). Although higher doses of fish oil, such as 6 grams daily for up to 1 year, have been used safely (89344), there are some safety concerns about using high doses of fish oil. Some older research suggests that doses greater than 3 grams per day can inhibit blood coagulation and potentially increase bleeding risk (8671,8679,8696,66258,21223,21224). However, the most rigorous research to date shows that short-term doses of fish oil 10 grams daily and long-term doses of 1.5 grams daily for up to 52 weeks do not increase the risk of bleeding or affect coagulation parameters in chronically ill and vulnerable patients (97180). Still, doses greater than 3 grams per day might suppress immune response (1313,7384). Patients should only take high-dose fish oil while under medical supervision.
POSSIBLY SAFE ...when parenteral nutrition supplemented with a lipid emulsion enriched in fish oil is used, short-term. Fish oil or omega-3 fatty acid lipid emulsions, administered intravenously for 1-4 weeks, have been safely used (1004,66042,66421,89323,103497).
POSSIBLY UNSAFE ...when fish oil from dietary sources is consumed in large amounts. Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. Very frequent consumption of contaminated fish can cause adverse effects such as tremor, numbness and tingling, difficulty concentrating, and vision problems. Avoid frequent consumption of swordfish, king mackerel, tilefish (also called golden bass or golden snapper), and farm-raised salmon (12964,12965,12966). There is insufficient reliable information available about the safety of fish oil when used topically.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately (5708,5711,65732,66070).
In adolescents 9 years of age and older, fish oil providing doses of up to 2250 mg omega-3 fatty acids daily have been used with apparent safety for up to 12 weeks (101543). Fish oil used in enteral feeds for up to 9 months has been shown to be safe in infants (13745). Young children should limit dietary consumption to no more than two ounces of fish per week (12967,12968). ...when given as part of parenteral nutrition in infants receiving long-term parenteral nutrition (96118,110340,110346,110352).
CHILDREN: POSSIBLY UNSAFE
when fish oil from dietary sources are consumed in large amounts.
Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. Frequent consumption of contaminated fish can cause brain damage, mental retardation, blindness, and seizures in children. Lower levels can cause more subtle problems such as learning disabilities (12964). Young children should limit consumption to no more than 2 ounces per week of fish (12967,12968).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately.
Intake of fish oil during pregnancy does not appear to adversely affect the fetus or nursing infant (1026,1027,1042,8706,12969,12970,12971,12972,12973,14397)(15015,15162,101540,110338,113217,114181). One large clinical trial shows that intake of fish oil from the 24th week of gestation increases the odds of the child having overweight and having metabolic syndrome measurements at age 10 when compared with placebo (114181). More research is needed to confirm these findings. The adequate intake level of omega-3 fatty acids during pregnancy is 1.4 grams daily; the adequate intake level during lactation is 1.3 grams daily (89377). If possible, people who are trying to become pregnant, as well as those who are pregnant or lactating, should avoid swordfish, king mackerel, and tilefish (also called golden bass or golden snapper), as these may contain high levels of methylmercury. Pregnant individuals should also limit consumption of other fatty fish to 12 ounces, or about 3-4 servings, per week.
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when fish oil from dietary sources are consumed in large amounts.
Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. If possible, people who are trying to become pregnant, as well as those who are pregnant or lactating, should avoid swordfish, king mackerel, and tilefish (also called golden bass or golden snapper), as these may contain high levels of methylmercury. Pregnant individuals should also limit consumption of other fatty fish to 12 ounces, or about 3-4 servings, per week (12967,12968).
LIKELY SAFE ...when ground flaxseed is used orally and appropriately. Ground flaxseed has been safely used in numerous clinical trials in doses up to 30-60 grams daily for up to 1 year (6803,6808,8020,10952,10978,12908,12910) (16760,16761,16762,16765,16766,18224,21191,21194,21196,21198) (21199,21200,22176,22179,22180,22181,65866,66065) (101943,101949,101950).
POSSIBLY SAFE ...when flaxseed lignan extract or mucilage is used orally and appropriately. Some clinical research shows that a specific flaxseed lignan extract (Flax Essence, Jarrow Formulas) 600 mg daily can be used with apparent safety for up to 12 weeks (16768). Additional clinical research shows that other flaxseed lignin extracts can be used with apparent safety for up to 6 months (21193,21197,21200). In one clinical trial, flaxseed mucilage was used with apparent safety at a dose of up to 5120 mg daily for up to 12 weeks (108047)....when flaxseed is used topically in a warm poultice (101946).
POSSIBLY UNSAFE ...when raw or unripe flaxseed is used orally. Raw flaxseed contains potentially toxic cyanogenic glycosides (linustatin, neolinustatin, and linamarin); however, these glycosides have not been detected after flaxseed is baked (5899). Unripe flaxseeds are also thought to be poisonous when consumed due to cyanide content.
PREGNANCY: POSSIBLY UNSAFE
when used orally.
Flaxseed can have mild estrogenic effects. Theoretically, this might adversely affect pregnancy (9592,12907); however, there is no reliable clinical evidence about the effects of flaxseed on pregnancy outcomes.
LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally or topically and appropriately. Vitamin E is generally considered safe, even at doses exceeding the recommended dietary allowance (RDA); however, adverse effects are more likely to occur with higher doses. The tolerable upper intake level (UL) in healthy people is 1000 mg daily, equivalent to 1100 IU of synthetic vitamin E (all-rac-alpha-tocopherol) or 1500 IU of natural vitamin E (RRR-alpha-tocopherol) (4668,4681,4713,4714,4844,89234,90067,90069,90072,19206)(63244,97075). Although there is some concern that taking vitamin E in doses of 400 IU (form unspecified) per day or higher might increase the risk of adverse outcomes and mortality from all causes (12212,13036,15305,16709,83339), most of this evidence comes from studies that included middle-aged or older patients with chronic diseases or patients from developing countries in which nutritional deficiencies are prevalent.
POSSIBLY UNSAFE ...when used orally in high doses. Repeated doses exceeding the tolerable upper intake level (UL) of 1000 mg daily are associated with significant side effects in otherwise healthy people (4844). ...when used intravenously in large doses. Large repeated intravenous doses of all-rac-alpha-tocopherol (synthetic vitamin E) were associated with decreased activity of clotting factors and bleeding in one report (3074). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults who use e-cigarette, or vaping, products, which often contain vitamin E acetate. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Vitamin E acetate has been detected in most bronchoalveolar lavage samples taken from patients with EVALI. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. While this association shows a correlation between vitamin E acetate inhalation and lung injury, a causal link has not yet been determined, and it is not clear if other toxic compounds are also involved (101061,101062,102970).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Vitamin E has been safely used in children in amounts below the tolerable upper intake level (UL). The UL for healthy children is: 200 mg in children aged 1-3 years, 300 mg in children aged 4-8 years, 600 mg in children aged 9-13 years, and 800 mg in children aged 14-18 years. A UL has not been established for infants up to 12 months of age (23388).
CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL due to increased risk of adverse effects (23388).
...when alpha-tocopherol is used intravenously in large doses in premature infants. Large intravenous doses of vitamin E are associated with an increased risk of necrotizing enterocolitis and sepsis in this population (85062,85083). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adolescents and teenagers who use e-cigarette, or vaping, products. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Constituents in E-cigarette or vaping products with the potential to cause lung injury or impaired lung function include lipids, such as vitamin E acetate. Vitamin E acetate has been detected in all bronchoalveolar lavage samples taken from patients with EVALI. No other ingredient, including THC or nicotine, was found in all samples, and other ingredients, including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable This shows that vitamin E acetate is at the primary site of lung injury. A causal link has not yet been described and it is not clear if other compounds are also involved (101061,101062).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately.
The tolerable upper intake level (UL) during pregnancy is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older. However, maternal supplementation is not generally recommended unless dietary vitamin E falls below the RDA (4260). No serious adverse effects were reported with oral intake of 400 IU per day starting at weeks 9-22 of pregnancy in healthy patients or those at high risk for pre-eclampsia (3236,97075), or with 600-900 IU daily during the last two months of pregnancy (4260). However, some preliminary evidence suggests that taking vitamin E supplements might be harmful when taken in early pregnancy. A case-control study found that taking a vitamin E supplement during the first 8 weeks of pregnancy is associated with a 1.7-9-fold increase in odds of congenital heart defects (16823). However, the exact amount of vitamin E consumed during pregnancy in this study is unclear. Until more is known, advise patients to avoid taking a vitamin E supplement in early pregnancy unless needed for an appropriate medical indication.
LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL).
The UL during lactation is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older (4844).
LACTATION: POSSIBLY UNSAFE
when used orally in amounts that exceed the UL due to increased risk of adverse effects (4844).
Below is general information about the interactions of the known ingredients contained in the product Flaxseed/Fish Oil Complex. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Fish oil may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs. However, evidence is conflicting.
 Details
While fish oil may not be a potent inhibitor of platelet function, high doses of fish oil might have antiplatelet effects. Theoretically, concomitant use of fish oil with anticoagulant or antiplatelet drugs may increase the risk of bleeding (8671,8679,8696,13769,21223,21224,66258). However, the most rigorous research shows that short-term doses of fish oil 10 grams daily or long-term doses of 1.5 grams daily for up to 52 weeks does not increase the risk of bleeding or affect coagulation parameters in chronically ill and vulnerable patients (97180). Other controlled research shows that fish oil does not affect platelet function or increase the risk of bleeding (17990,17996,66105,66267,89374,107180). Some research even suggests that perioperative fish oil use decreases bleeding risk (89352). Some research suggests fish oil does not have additive antiplatelet effects when combined with aspirin (13769), but other clinical evidence suggests that adding fish oil to low-dose aspirin treatment increases antiplatelet effects in patients who are aspirin-resistant (21226). Also, some clinical research seems to show that fish oil has additive antiplatelet effects when used with aspirin and clopidogrel compared to aspirin and clopidogrel alone (21225).
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Theoretically, taking fish oil with antihypertensive drugs might increase the risk of hypotension.
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Theoretically, taking fish oil with contraceptive drugs might decrease the triglyceride-lowering effects of fish oil.
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There is some evidence that contraceptive drugs might interfere with the triglyceride lowering effects of fish oils (8694).
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Taking fish oil with cyclosporine might increase levels and adverse effects of cyclosporine.
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In kidney transplant recipients on a general immunosuppressive regimen, taking omega-3 fatty acids daily seems to increase peak blood levels of cyclosporine when compared with placebo. This increase was as much as 20% after one month. However, the area under the curve was not significantly affected (66472).
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Theoretically, taking fish oil with orlistat might decrease the absorption of fish oil fatty acids.
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Orlistat binds lipase in the gastrointestinal tract and reduces fat absorption. Theoretically, taking fish oil with orlistat might decrease absorption of fish oil fatty acids. To avoid this potential interaction, recommend separating administration of orlistat and fish oil by at least 2 hours.
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Theoretically, taking fish oil with platinum agents can cause resistance to platinum agents, potentially decreasing their effectiveness.
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Platinum-induced fatty acids (PIFAs) are fatty acids secreted from human and mouse stem cells when exposed to platinum-based chemotherapy. Animal research suggests that PIFAs cause resistance to chemotherapy by stimulating lysophospholipid production in the spleen, which interferes with the DNA damage caused by certain chemotherapy drugs (92076). One PIFA, known as 16:4(n-3), has been found in both raw fish and some commercially available fish oil products. Mackerel and herring have high PIFA concentrations, while salmon and tuna have low PIFA concentrations. Levels of PIFA in commercial fish oil products ranged from 0.2- 5.7 microMol. Animal research shows that PIFA-containing fish oil products cause resistance to cisplatin, fluorouracil, irinotecan, and oxaliplatin (91250,92075). It is unclear if all commercially available fish oil products contain PIFAs. Additionally, it is argued that levels of PIFA found in some fish oil products are too low to be of clinical concern. Furthermore, a lack of chemotherapy resistance in countries with high fish intake, such as Greenland, Japan, and Norway, suggest that this interaction may not be clinically significant (91288,91289).
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Taking fish oil with sirolimus might increase levels and adverse effects of sirolimus.
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Pharmacokinetic research shows that omega-3 fatty acids increase exposure to sirolimus in kidney transplant patients on a calcineurin inhibitor-free immunosuppressive regimen. A 25% dose reduction in sirolimus was required to keep patients within the expected trough-concentration window (105232). Researchers hypothesize that this may be due to inhibition of cytochrome P450 3A4 (CYP3A4) by fish oil, although this has not been confirmed in clinical research.
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Taking fish oil with tacrolimus might increase levels and adverse effects of tacrolimus.
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In a small group of patients, taking fish oil 2.6 grams (Omacor) daily for 4 weeks increased the 8-hour area under the curve of tacrolimus by 25% when compared with baseline. Peak levels were increased by approximately 22% (105212). Researchers hypothesize that this may be due either to an increase in bioavailability or to inhibition of cytochrome P450 3A4 (CYP3A4) by fish oil, although this has not been confirmed in clinical research.
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Fish oil may have antiplatelet effects and might increase the risk of bleeding if used with warfarin.
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Theoretically, antibiotics might interfere with the metabolism of flaxseed constituents, which could potentially alter the effects of flaxseed.
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Some potential benefits of flaxseed are thought to be due to its lignan content. Secoisolariciresinol diglucoside (SDG), a major lignan precursor, is found in high concentrations in flaxseed. SDG is converted by bacteria in the colon to the lignans enterolactone and enterodiol (5897,8022,8023,9592). Antibiotics alter the flora of the colon, which could theoretically alter the metabolism of flaxseed.
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Theoretically, using flaxseed in combination with anticoagulant or antiplatelet drugs might have additive effects and increase the risk of bleeding.
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Theoretically, flaxseed might have additive effects when used with antidiabetes drugs and increase the risk for hypoglycemia.
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Theoretically, flaxseed might have additive effects when used with antihypertensive drugs and increase the risk of hypotension.
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Theoretically, taking flaxseed might decrease the effects of estrogens.
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Flaxseed contains lignans with mild estrogenic and possible antiestrogenic effects. The lignans seem to compete with circulating endogenous estrogen and might reduce estrogen binding to estrogen receptors, resulting in an anti-estrogen effect (8868,9593). It is unclear if this effect transfers to exogenously administered estrogens.
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of alkylating agents.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Due to interference with production of vitamin K-dependent clotting factors, use of more than 400 IU of vitamin E daily with warfarin might increase prothrombin time (PT), INR, and the risk of bleeding, (91,92,93). At a dose of 1000 IU per day, vitamin E can antagonize vitamin K-dependent clotting factors even in people not taking warfarin (11999). Limited clinical evidence suggests that doses up to 1200 IU daily may be used safely by patients taking warfarin, but this may not be applicable in all patient populations (90).
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Below is general information about the adverse effects of the known ingredients contained in the product Flaxseed/Fish Oil Complex. 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 and parenterally, fish oil is generally well-tolerated.
Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Abdominal pain, bad breath, fishy aftertaste, heartburn, increased low-density lipoprotein (LDL) cholesterol levels, loose stools, nausea, and rash.
Serious Adverse Effects (Rare):
Orally: Atrial fibrillation. When taken in doses of 3 grams or more daily, there are rare reports of increased risk of bleeding and stroke, as well as immune suppression.
Cardiovascular
...Orally, fish oil supplements in doses of 3-10 grams daily can cause a dose-dependent increase in low-density lipoprotein (LDL) cholesterol levels in some people (2299,2318,8678,8698,15734,15735,48120,65729) by increasing the size of LDL particles (9771).
Therefore, LDL levels should be monitored in people who take fish oil supplements (15734). But fish oil doesn't seem to cause development of atherosclerosis, despite earlier concerns that polyunsaturated fatty acids, such as omega-3 fatty acids, might increase the oxidation of LDL (1011,2323,7165,7366,8695,8700,9771).
There is concern that fish oil supplements may be associated with an increased risk for atrial fibrillation (AF). In one large clinical study (the STRENGTH trial), taking a prescription fish oil product (Epanova) 4 grams daily for up to 5 years was associated with an increased risk for AF, with a number needed to harm of 114 when compared with a corn oil control. The patients in this study were considered to be at high risk for future cardiovascular disease (CVD) (103491). Also, one large population study in adults without CVD suggests that regular use of fish oil supplements is associated with a modestly higher risk of both atrial fibrillation and stroke when compared with non-use of fish oil supplements (114182).
In a secondary analysis of the Omega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trial, adults aged 70-82 years with recent myocardial infarction supplementing with 1.8 grams daily of n-3 PUFA (EPA/DHA) for 24 months had a 90% increased risk of developing AF or micro-AF, which is characterized by short, AF-like activity lasting less than 30 seconds. Changes in serum EPA levels seem to mediate this risk, with higher serum EPA levels predictive of an increased risk of AF and intermediate serum EPA levels predictive of an increased risk of micro-AF (112469).
Meta-analyses of randomized controlled trials show that taking omega-3 fatty acid supplements increases the incidence rate ratio for AF by up to 37% when compared with placebo, with an increased incidence rate associated with doses of more than 1 gram daily. One study in these analyses used eicosapentaenoic acid (EPA) alone as purified icosapent ethyl (106075,107171,107181).
In 2023, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency issued a public statement on the use of omega-3-acid ethyl esters, concluding that exposure to omega-3-acid ethyl esters for the treatment of hypertriglyceridemia is associated with a dose-dependent increased risk of AF in patients with established cardiovascular disease or risk factors for cardiovascular disease when compared with placebo. The highest risk of AF is associated with a dose of 4 grams daily. If AF occurs, treatment should be permanently discontinued (112467).
Dermatologic
...Orally, skin rashes, itching, and skin irritation have been reported (66498,66492,66488,89369,104551).
A case of severe tissue inflammation and breast tissue necrosis has been reported for a female who injected fish oil from capsules subcutaneously for breast augmentation (89371).
Gastrointestinal
...Orally, most adverse effects of omega-3 fatty acids are gastrointestinal in nature (12915,65599,65728,65770,65780,65904,66061,66104,66164,66488)(89347,89357,103491,103551,107172,114184).
Gastrointestinal upset is common with the use of fish oil supplements, occurring in up to 5% of patients in clinical trials, with nausea in up to 1.5% of patients (2307,16733,65599,65732,65762,65830,65886,65925,65974)(66020,66042,66083,66104,66130,66164,66169,66358,66370,66488)(66494,66498,89347,103491,104551,110353,114184). Diarrhea and loose stools may also occur (6257,10871,65599,65648,65830,65935,66042,66061,66104,66119)(66130,66173,66492,89347,89359,103491,104551,107172,110353), with potentially severe diarrhea at very high doses (12986,16901,66093,66356). There have also been reports of increased burping (17963,65648,65729,65770,65830,66020,66042,66077,66164,66169)(66492,66494,104551,114184), acid reflux, heartburn (104551,110338), indigestion (65566,65830,66061,66104,66173,89359,114184), abdominal bloating (66083,66104), abdominal or gastrointestinal pain or discomfort (8680,17996,66119,66492,103491), anorexia (62390,89359), flatulence (66492), constipation (16901), nausea and vomiting (65728,65830,66104,66130,66488,103491,104551), steatorrhea (66119,66354,66356), fishy hiccups (66488), metallic taste (66488), and a fishy breath odor and aftertaste (16901,65648,65729,65762,66020,66042,66061,66077,66083,66104)(66130,66164,66172,66173,66424,66488,66494,89369,104551,107172). Also, some preliminary evidence suggests that increased serum levels of omega-3 fatty acids, especially DHA, might increase the risk for atrophic gastritis (8709).
Gastrointestinal side effects may be minimized if fish oils are taken with meals and if doses are started low and gradually increased. Taking supplements with meals or freezing them seems to help decrease these side effects for some patients (12975). Enteric coated fish products might also help reduce side effects (6258).
Hematologic
...Orally, 3 grams or greater of omega-3 fatty acids daily may inhibit platelet aggregation and increase the risk of bleeding; however, there is little evidence of statistically significant bleeding risk at lower doses (1313,8699,66500,66501,66334,101543).
Very large intakes of fish oil or omega-3 fatty acids (more than 46 grams per day) may increase the risk of ischemic or hemorrhagic (bleeding) stroke (7603,66502).
A case of hemolytic anemia has been reported for an infant with short bowel syndrome who developed liver disease from total parenteral nutrition (TPN) and was switched to a specific TPN with fish oil (Omegaven, Fresenius-Kabi, Graz, Austria) instead. After stopping the fish oil-TPN, the anemia was reversed suggesting that parenteral fish oil might cause hemolytic anemia (66022).
Hepatic ...Orally, mild elevations in liver function tests, such as alanine aminotransferase and aspartate aminotransferase, have been reported rarely (66353,113218).
Immunologic
...A case of anaphylaxis following ingestion of a fish oil capsule has been reported for a female patient with a history of allergy to crab.
The patient was treated successfully with epinephrine, but had several recurrences of stridor over the next 2 days (89378).
There is also some evidence that fish oil in doses greater than 3 grams per day might adversely affect immune function. Fish oil appears to suppress T- and B-cell function and to reduce the production of cytokines, which might be detrimental to elderly people and people with suppressed immune function such as patients with human immunodeficiency virus (HIV) infection (1313,7383,7384).
Neurologic/CNS ...Orally, fish oil may cause headache, dizziness, and inability to sleep (65599,65648,89359,103491,104551). Also, restlessness and formication have been reported in less than 1% of studied cases of patients taking fish oil (66498).
Oncologic ...There is some concern that high fish intake may increase the risk for certain types of cancer. One large epidemiological study has found that dietary intake of fish oil from fatty fish twice a week or more is associated with a 16% increased risk of breast cancer when compared with eating fatty fish less than twice weekly (107175). Additionally, an analysis of the NIH-AARP Diet and Health Study, a prospective cohort study in over 491,000 older adults, has found that total intake of fish is associated with increased melanoma risk over a median follow-up of 15.5 years. When the lowest and highest quintiles of intake are compared, there is a 22% increase in the risk for malignant melanoma and a 28% increase in the risk for melanoma in situ. In sub-group analyses, all melanoma incidence is positively associated with tuna intake or non-fried fish intake, but malignant melanoma incidence is inversely associated with fried fish intake (108509). It was suggested that the positive associations could be due to contaminants in fish such as polychlorinated biphenyls, dioxins, arsenic, and mercury.
Pulmonary/Respiratory ...Orally, fish oil has been reported to cause nasopharyngitis and upper respiratory tract infections in 3. 3% of patients in one clinical trial (65798). Exacerbation of asthma and apnea have been reported for patients using fish oil (1040,66061,66119,66354).
Other ...Fish oil can contribute to caloric intake and may cause weight gain if used long-term. One gram of fat or oil provides 9 kcal (6871). Fish oil capsules containing 500 mg omega-3 fatty acids in 1 gram of oil would supply about 13.5 kcal per capsule (6871,6874). Fish oil supplements also contain cholesterol in amounts from 1-6 mg per gram of fish oil (3022,6871).
General
...Orally, flaxseed is usually well-tolerated.
Most Common Adverse Effects:
Orally: Bloating, diarrhea, gastrointestinal complaints.
Serious Adverse Effects (Rare):
Orally: Severe allergic reactions such as and anaphylaxis.
Gastrointestinal
...Integrating flaxseed in the diet can cause digestive symptoms similar to other sources of dietary fiber including bloating, fullness, flatulence, abdominal pain, diarrhea, constipation, dyspepsia, and nausea (12910,16761,16765,21198,21200,22176,22179,65866,101943).
Higher doses are likely to cause more gastrointestinal side effects. Flaxseed can significantly increase the number of bowel movements and the risk for diarrhea (6803,8021,16765). Doses greater than 45 grams per day may not be tolerated for this reason (6802). Metallic aftertaste and bowel habit deterioration have also been reported in a clinical trial (21198).
There is some concern that taking large amounts of flaxseed could result in bowel obstruction due to the bulk forming laxative effects of flaxseed. Bowel obstruction occurred in one patient in a clinical trial (65866). However, this is not likely to occur if flaxseed is consumed with an adequate amount of fluids.
Immunologic ...Occasionally, allergic and anaphylactic reactions have been reported after ingestion of flaxseed (16761). Handling and processing flaxseed products might increase the risk of developing a positive antigen test to flaxseed and hypersensitivity (6809,12911,26471,26482).
Oncologic ...Flaxseed contains alpha-linolenic acid (ALA). High dietary intake of ALA has been associated with increased risk for prostate cancer (1337,2558,7823,7147,12978). However, ALA from plant sources, such as flaxseed, does not seem to increase this risk (12909).
Other ...Orally, partially defatted flaxseed, which is flaxseed with less alpha-linolenic acid, might increase triglyceride levels (6808). Raw or unripe flaxseed contains potentially toxic cyanogenic glycosides (linustatin, neolinustatin, and linamarin). These chemicals can increase blood levels and urinary excretion of thiocyanate in humans. However, these glycosides have not been detected after flaxseed is baked (5899).
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).
