Appendix -Drug Contraindications review of evidence
Cox Inhibitors – Issues
Aspirin and ibuprofen
Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation.
COX-1 enzymes also protect the natural mucus lining which protects the inner stomach. COX-1 inhibitors (aspirin) enzyme along with another enzyme, COX-2 (see below). When the COX-1 enzyme is blocked, inflammation is reduced, but the protective mucus lining of the stomach is also reduced, which can cause stomach upset, ulceration, and bleeding from the stomach and intestines. When the COX-2 enzyme is blocked, inflammation is reduced. Since the COX-2 enzyme does not play a role in the normal function of the stomach or intestinal tract, medications which selectively block COX-2 do not present the same risk of injuring the stomach or intestines. However COX- 2 inhibitors have been linked to increased myocardial infarction. Blood thinning effects however seem to be restricted to aspirin, not ibuprofen. In fact there is evidence ibuprofen may have the opposite effect and counteract the effects of aspirin if prescribed together.
Antiplatelets work in arterial circulation, where anticoagulants have little effect. Aspirin has an anti-platelet effect.
Interfere with vitamin K dependent clotting factors – acting on thrombin mechanisms.
Essentially both these and anti-platelet drugs thin blood viscosity (in different places?).
The potential for high omega-3 fatty acid intakes, especially EPA and DHA, to prolong bleeding times has been well studied, and may play a role in the cardioprotective effects of omega-3 fatty acids. Although excessively long bleeding times and increased incidence of hemorrhagic stroke have been observed in Greenland Eskimos with very high intakes of EPA + DHA (6.5 g/day), it is not known whether high intakes of EPA and DHA are the only factor responsible for these observations (1). The US FDA has ruled that intakes up to 3 g/day of long-chain omega-3 fatty acids (EPA and DHA) are Generally Recognized As Safe (GRAS) for inclusion in the diet, and available evidence suggests that intakes less than 3 g/day are unlikely to result in clinically significant bleeding (3). Although the Institute of Medicine did not establish a tolerable upper level of intake (UL) for omega-3 fatty acids, caution was advised with the use of supplemental EPA and DHA, especially in those who are at increased risk of excessive bleeding (see Drug Interactions below) (1).
High doses of black currant seed oil, borage seed oil, evening primrose oil, flaxseed oil and fish oil may inhibit platelet aggregation, and should be used with caution in people on anticoagulant medications. In particular, people taking fish oil or long-chain omega-3 fatty acid (EPA and DHA) supplements in combination with anticoagulant drugs, including aspirin, clopidogrel (Plavix), dalteparin (Fragmin), dipyridamole (Persantine), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid) and warfarin (Coumadin), should have their coagulation status monitored using a standardized prothrombin time assay (INR). One small study found that 3 g/day or 6 g/day of fish oil did not affect INR values in 10 patients on warfarin over a 4-week period (Bender NK, Kraynak MA, Chiquette E, Linn WD, Clark GM, Bussey HI. Effects of Marine Fish Oils on the Anticoagulation Status of Patients Receiving Chronic Warfarin Therapy. J Thromb Thrombolysis. 1998;5(3):257-261). However, a recent case report described an individual who required a reduction of her warfarin dose when she doubled her fish oil dose from 1 g/day to 2 g/day (Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother. 2004;38(1):50-52.).
Evidence of interactions between blood thinning meds and EFAs is not that conclusive. However, we should continue to suggest people only combine under medical supervision.
We should also add aspirin to our list of blood thinners, even low dose (75mg).
- Vitamin C Platelet aggregation has been reduced in two studies utilizing 2,000-3,000 milligrams of vitamin C daily for one to six weeks. No effect was noted on platelets in another study using 250 milligrams of vitamin C daily for eight weeks. Leukocyte adhesion to endothelium, an activity implicated in atherogenesis, was significantly inhibited in smokers receiving 2,000 milligrams of vitamin C daily for ten days.
Perversely there is some evidence, though controversial, that vitamin C interacts with anticoagulant medications (blood thinners) such as warfarin (Coumadin) by blocking its action, requiring an increase in dose to maintain its effectiveness. Individuals on anticoagulants should limit their vitamin C intake to 1 gram/day and have their prothrombin time monitored by the clinician following their anticoagulant therapy.
Overall limit vitamin C to 1000mg on aspirin, warfarin as it might be affected either way. Warning as ‘May interact with aspirin or warfarin. Medical supervision.’ (1000 +)
- Garlic has been shown to help prevent atherosclerosis (hardening of the arteries), perhaps by reducing the ability of platelets to stick together.32 This can result in an increase in the tendency toward bleeding.33 Standardized extracts have, on rare occasions, been associated with bleeding in people.34 Garlic extracts have also been associated with two human cases of increased warfarin activity.35 The extracts were not definitively shown to be the cause of the problem. People taking warfarin should consult with a doctor before taking products containing standardized extracts of garlic or eating more than one clove of garlic daily. No warning needed. Evidence not strong enough.
- Vitamin E An isolated case was reported in 1974 of vitamin E (up to 1,200 IU per day) being associated with increased anticoagulation (blood thinning) in a patient treated with warfarin.11 A study of 12 people undergoing warfarin therapy found that additional vitamin E (100 IU or 400 IU per day) did not induce a clinical bleeding state.12 Moreover, a double-blind trial found that supplementation with vitamin E in amounts up to 1,200 IU per day had no effect on warfarin activity.13 It now appears safe for people taking warfarin to supplement vitamin E despite information to the contrary often provided by doctors about this purported interaction. These warnings are based on the isolated case report from 1974. However 50iu of vitamin E seems to increase risk of bleeding in smokers combined with aspirin, so keep this recommendation. REMOVE Warfarin WARNING FROM VITAMIN E Add aspirin.
- There have been at least five case reports suggesting that cranberry juice increases the activity of warfarin, possibly by inhibiting the breakdown of warfarin in the body.22 Because of this potential interaction, people taking warfarin should avoid, or limit the intake of, cranberry juice. Leave as no warning other than general.
- Asian ginseng was associated with a decrease in warfarin activity in a case report. Persons taking warfarin should consult with a physician knowledgeable about botanical medicines if they are considering taking Asian ginseng or eleuthero/Siberian ginseng (Eleutherococcus senticosus). A 1999 animal study did not reveal any significant interaction between warfarin and pure ginseng extract.
In a study of healthy human volunteers, supplementing with American ginseng reduced warfarin's anticoagulant effect, apparently by stimulating the body to accelerate the metabolism of warfarin. People taking warfarin should not take American ginseng, unless supervised by a doctor. A bit more persuasive WARNING????
- Ginkgo extracts may reduce the ability of platelets to stick together, possibly increasing the tendency toward bleeding. Standardized extracts of ginkgo have been associated with two cases of spontaneous bleeding, although the ginkgo extracts were not definitively shown to be the cause of the problem. There are two case reports of people taking warfarin in whom bleeding occurred after the addition of ginkgo. People taking warfarin should consult with a physician knowledgeable about botanical medicines if they are considering taking ginkgo. Isolated cases. No warning?
- Green tea (Camellia sinensis) One man taking warfarin and one-half to one gallon of green tea per day developed signs based on laboratory testing suggesting his blood was too thick because the green tea was blocking the effect of warfarin.42 Removal of the green tea caused normalization of his blood tests. Those taking green tea and warfarin together should have their blood monitored regularly to avert any problems and should consult with a doctor, healthcare practitioner and/or pharmacist before taking any medication. Isolated case
- According to a preliminary report, volunteers taking 900 mg per day of St. John’s wort were given a single dose of an anticoagulant similar in action to warfarin. There was a significant drop in the amount of the drug measured in the blood. Seven case studies reported to the Medical Products Agency in Sweden also found a decrease in the anticoagulant activity of warfarin when St. John’s wort was taken at the same time. This may have occurred because certain chemicals found in St. John’s wort activate liver enzymes that are involved in the elimination of some drugs. People taking warfarin should consult with their doctor before taking St. John’s wort.
- Coenzyme Q10 (CoQ10) is structurally similar to vitamin K and may affect blood coagulation. Four case reports describe possible interference by CoQ10 with warfarin activity. It remains unknown how common or rare this interaction is. Aspirin ok in this case as slightly different action – antiplatelet. Those taking warfarin should only take CoQ10 with the guidance of their doctor.
- OPCs – probably high levels only eg bioflavone, oligopin
Taking the pill can reduce levels of vitamin C.
However, it has been generally recognised that taking one gram (1000 milligrams) of vitamin C a day will increase the amount of synthetic estradiol (an estrogen absorbed by the digestive system) by 50 percent . Both ascorbic acid and paracetamol give rise to increased blood concentrations of ethinylestradiol (?due to competition for sulphation. If the vitamin C has not been metabolized, it may be reabsorbed rather than excreted..)
However a study by Zamah et al., on 37 women found that the competition between vitamin C (ascorbic acid) and ethinylestradiol for sulfation did not lead to an increase in the bioavailability of ethinylestradiol. A reduction in levels of circulating ethinylestadiol was also not found when these women stopped taking the high doses (1g) of vitamin C. (Zamah NM, Hümpel M, Kuhnz W, Louton T, Rafferty J, Back DJ. Contraception. 1993 Oct;48(4):377-91. Absence of an effect of high vitamin C dosage on the systemic availability of ethinyl estradiol in women using a combination oral contraceptive) Despite this, the latest Stockley IH (1999 Drug Interactions, A Source Book of Adverse Interactions, Their Mechanisms, Clinical Importance and Management. Pharmaceutical Press, London) continues to assert that ascorbic acid (1 g) can interfere with oral contraceptive metabolism, leading to higher blood levels of estradiol.
Most women who are on the pill will not notice any adverse effects from megadosing with vitamin C; some women, however, may experience spotting and other high oestrogen symptoms eg PMT. This should be restricted to restricted to oestrogen based pills.
Agnus castus - may rebalance oestrogen and progesterone and could counteract the effects of the pill.
Evidence is therefore conflicting, but keep warning for high doses of 1000+ .
May be dose/person dependent? If it has an effect it is to increase the levels of oestrogen in the pill, not to increase natural oestrogen. It should not reduce the effectiveness of the pill, contrary to popular belief.
Eight cases reported to the Medical Products Agency of Sweden suggest that St. John’s wort may interact with oral contraceptives and cause intramenstrual bleeding and/or changes in menstrual bleeding.14 One reviewer has suggested that St. John’s Wort may reduce serum levels of estradiol.15 It should be noted, however, that only three of the eight Swedish women returned to normal menstrual cycles after stopping St. John’s Wort. Women taking oral contraceptives for birth control should consult with their doctor before taking St.John’s Wort.
Because of case reports that supplementation with evening primrose oil induced seizure activity in people with undiagnosed temporal lobe epilepsy (150. Vaddadi KS. The use of gamma-linolenic acid and linoleic acid to differentiate between temporal lobe epilepsy and schizophrenia. Prostaglandins Med. 1981;6(4):375-379.), people with a history of seizures or seizure disorder are generally advised to avoid evening primrose oil and other gamma-linolenic acid-rich oils (Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.).
Used for Cancer and as an anti-inflammatory in psoriasis/arthritis.
Works by interfering with folic acid metabolism. Folic acid deficiency signs. Folic acid at 1g plus in cancer tx (will reduce efficacy of drug). I can’t actually find the reference for why only 1 gram plus. Some recommend no folic acid unless agreed by a Doctor, but this would be covered by our general statement on being under the care of a medical practitioner.
Works differently if used in arthritis and psoriasis tx, but still depletes folic acid, so taking folic acid is fine and in fact necessary in this case.
(Extract from foetal-exposure.org)
Case reports and anecdotal studies suggest vitamin A intake of 25,000 IU or more during pregnancy increases the risk for congenital anomalies (Rosa et al., 1986). Rothman et al. (1995) undertook a study in order to clarify the issue of what dose of vitamin A begins to pose an increased risk for congenital anomalies. Between October 1984 and June 1987 22,748 pregnant women were identified of which 339 babies had birth defects; 121 of these infants had defects in sites arising from the cranial neural crest. The trend for the risk for musculoskeletal and urogenital tract defects was less apparent, and no discernible risk was observed for neural tube defects. Women who consumed more than 15,000 IU of preformed vitamin A from food and supplements had infants with defects associated with cranial-neural-crest tissue 3.5 times greater than women who consumed 5000 IU or less (95% CI, 1.7-7.3). The prevalence ratio of these defects for women who consumed more than 10,000 IU/day compared to women who consumed less than 5000 IU/day from supplement alone was 4.8 (95% CI, 2.2-10.5). Rothman et al. (1995) reported finding a threshold for supplemental vitamin A near 10,000 IU/day. The increased frequency of malformations was observed more frequently among infants born to women ingesting large amounts of vitamin A before the seventh week of gestation. The authors of this study concluded that approximately 1 in 57 infants would have malformations attributable to vitamin A supplements at doses above 10,000 IU/day.
The study by Rothman et al. (1995) is not without controversy over the results. Oakley and Erickson (1995) expressed concern about the need for more detailed data on the amount of vitamin A consumed by women who took 10,000 IU or more during pregnancy. The mean vitamin A intake in this group was 21,675 IU/day, which suggests some fetuses were exposed to more than 25,000 IU/day. Specific exposure information is necessary before it is recommended that the dose-response threshold curve described in the paper by Rothman et al. (1995) be utilized. In responding to this criticism the authors state, "the curve shows about a 5-fold increase in birth defects for women taking daily doses of retinol, and is fitted through individual data points."
Several studies have assessed the risk to a pregnancy with maternal intake of 8000 IU or less of preformed vitamin A during pregnancy. Khoury et al. (1996) examined data from a large population-based case control study of major birth defects conducted by the Center for Disease Control. Mothers of infants with serious birth defects were compared to mothers of infants without birth defects. No increased risk was observed among vitamin A and multivitamin users or among women who took both multivitamins and vitamin A supplements together (OR .54, 95% CI .22-1.33). These authors also reviewed numerous case studies in order to assess whether specific phenotypes were associated with vitamin A use. They compared case studies of babies with birth defects whose mothers used vitamin A supplements with babies with birth defects whose mothers reported not using any vitamin A supplements during pregnancy. No differences were observed between the two groups when looking at patterns and types of birth defects, presence of multiple congenital anomalies and recognizable phenotypes. They did not have information on the amount of vitamin A ingested, but most multivitamins and supplements during that time period contained 8000 IU of retinol. The authors state that "these data should provide reassurance that vitamin A supplements under 8000 IU do not increase the risk for birth defects (Khoury, 1996)".
Several studies have been reported revealing no increase in congenital anomalies after prenatal exposure to large amounts of vitamin A. These include 1203 infants exposed to 6000 IU daily during the first trimester of gestation (Dudas and Czeizel, 1992); and, a case control study of 11,293 children with minor and major malformations and maternal use of 10,000 IU or more of vitamin A per day (Martinez-Frias and Salvador, 1988, 1990).
The recommended daily allowance for preformed vitamin A is 2700 IU/day or 8000 IU of beta-carotene. In 1987 the CDC, Teratology Society and Council for Responsible Nutrition independently published recommendations for use of vitamin A during pregnancy. These were made because teratogenicity appears to occur at some undetermined level above 8000 IU and pregnant women in the United States do not seem to benefit from additional vitamin A. They recommend limiting vitamin A in prenatal vitamins to 5000-8000 IU and vitamin A content of all multivitamins to 10,000 IU; therein suggesting women should not ingest more than 10,000 IU prior to consulting a physician.
Summary The above information is for information purposes only and is correct at the time of publishing. However, more research becomes available to us on a daily basis, so please always consult your G.P or Consultant if you have any concerns about any possible interactions with any prescribed medication you may be taking currently.