Kowalsky, Patricia E. PharmD
Section Editor(s): Alexander, Earnest PharmD; Susla, Gregory M. PharmD; Department Editors
Often when we ask our patients about their medications, they list the prescription drugs that they take. It seems common that over-the-counter products, vitamins, and herbal supplements are excluded from what patients typically think of as drugs. It is important, however, to ask detailed questions regarding medication history, because only then can we determine the complete list. This process is especially important when patients are admitted to the hospital. Because the elderly population consumes the most medications and is at the greatest risk for drug interactions, we must be diligent to investigate a complete medication history. Through the National Social Life, Health, and Aging Project, it was determined that more than half of the population aged 57 through 84 years was taking 5 or more medications, including prescription drugs, over-the-counter drugs, and dietary supplements. Of the population surveyed, 68% was taking over-the-counter products and dietary supplements in addition to prescription medications.1 The dietary supplement market is a large industry. For example, spending on dietary supplements totaled approximately $4.8 billion in 2008.2 With this popularity, we need to increase our understanding and awareness that patients may be using these products.
In 1994, the Food and Drug Administration (FDA) passed the Dietary Supplement Health and Education Act. Under this law, dietary supplements may be marketed without FDA approval unless the supplement contains a “new dietary ingredient,” defined as a product that contains “vitamins, minerals, herbs, or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites.”3 The FDA may not take action on an herbal supplement unless the product is deemed unsafe; only then can it be removed from the market. The other stipulation is that the manufacturer may only make claims referring to health, nutrients, or structure or function of the body. Therefore, the product must contain the following statement on the label if it purports to affect structure or function: “This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.”3 According to the FDA, only a prescription drug can treat a disease. A product would be considered an illegal drug if it stated claims such as “treatment, prevention, or cure for a specific disease or condition”3 on the label.
Patients need to understand that herbal products are not evaluated by the FDA unless there is sufficient evidence to prove that they are unsafe. The process for FDA approval of a prescription medication takes years because of the need for animal and human trials. The FDA does not approve a prescription medication unless there is evidence supporting the safety and efficacy of the product. There continues to be little scientific evidence behind herbal products. Even though there may be trials to assess the efficacy of these products, most are poorly designed and lack the rigor (eg, the number of participants) to definitively support their use for public health. Complementary and alternative medicine such as dietary supplements continues to be an area of controversy in the medical field.
It is hoped that this column will raise awareness of the prevalence of herbal supplement use and the dangers that can ensue from their combination with prescription medications. Common drug interactions are discussed with 10 of the top-20 herbal supplements purchased in 2009: garlic, echinacea, ginkgo, St John's wort, ginseng, saw palmetto, valerian, ginger, kava, and cranberry2 (see Table 1). The evidence supporting each supplement and the number and quality of clinical trials are described by MEDLINE. The 6 levels of scientific evidence from MEDLINE are (A) strong scientific evidence, (B) good scientific evidence, (C) unclear or conflicting scientific evidence, (D) fair negative scientific evidence, (E) strong negative scientific evidence, and (F) lack of evidence.4 The information contained here is not comprehensive of all interactions; if any doubts exist concerning a particular herbal-drug interaction, the health care professional should investigate additional sources.
Table 1: Summary of ...Image Tools
Garlic has been primarily used for the treatment of high cholesterol, and there is good scientific evidence (grade B) to support its role.4 However, trials were conducted only for a short period of time (4–12 weeks), and the decrease in total cholesterol and low-density lipoprotein was minor. Garlic has also been used in myriad other disorders (cancer, fungal infections, atherosclerosis, myocardial infarction, hypertension, peripheral vascular disease, and diabetes) with little scientific evidence supporting its benefits. The main serious adverse effect with garlic is bleeding, especially in patients taking anticoagulants, antiplatelet agents such as aspirin and clopidogrel (Plavix), and nonsteroidal anti-inflammatory drugs (NSAIDs).4 The mechanism behind this effect is the inhibition of platelet aggregation by allicin, a component of garlic.5 Bleeding has been associated with this herbal supplement even without concomitant anticoagulant use.6 According to a study involving the use of garlic, ginkgo, and ginseng with FDA-approved medications, the interaction between garlic and warfarin (Coumadin) is one of the higher-risk combinations resulting in bleeding.7 Garlic has also been shown to decrease the levels of antiretroviral drugs such as saquinavir (Invirase) and ritonavir (Norvir) and cause “severe gastrointestinal toxicity” when used with ritonavir.8 Patients taking diabetes medications should be cautioned because of the possibility of hypoglycemia. Garlic also may affect thyroid medications and has the potential to cause hypothyroidism. Theoretically, any drug relying on the cytochrome P450 (CYP450) enzyme system for liver metabolism can be affected by the use of garlic.4
Echinacea is so popular for the use of prevention and treatment of upper respiratory tract infection (grade B) that it is said to “represent approximately ten percent of the dietary supplement market.”9 The data are conflicting as to whether this herb can decrease the length and severity of symptoms of respiratory tract infections (immune stimulation grade C). As with all other herbal supplements, more clinical trials that are properly designed to determine whether the use of this product is effective and safe are needed. Theoretically, immunosuppressive drugs would be affected by echinacea, causing leukopenia with long-term use. In turn, it is not recommended for use in immunocompromised patients, such as transplant patients or those with human immunodeficiency virus (HIV) or cancer.9 It has been shown that prolonged use may result in hepatotoxicity; therefore, it should not be used concomitantly with other hepatotoxic drugs.10 However, another source reports that echinacea, even in combination with other drugs, is most likely safe for patients.8 This herbal product should still be used with caution as more data are needed to confirm its safety and efficacy.
Ginkgo has been used because of strong scientific evidence for claudication to decrease leg pain (grade A). Among many other “indications,” patients may also use it for age-associated memory impairment, but the data are conflicting (grade C).11 It is no surprise that ginkgo can have interactions with prescription drugs, because it contains more than 40 different chemicals.12 Although it is generally well tolerated, the main serious adverse effect associated with ginkgo is bleeding, even in the absence of other drugs.6,11 Therefore, bleeding risk increases when ginkgo is used concomitantly with anticoagulants, NSAIDs, and antiplatelet agents.11 There has even been a report of “spontaneous bilateral subdural hematoma associated with long-term ginkgo ingestion.”6 The other drug interaction of note involves anticonvulsant medications, especially in patients eating ginkgo seeds specifically.11 Ginkgo was implicated in a case report to have caused a fatal seizure because of subtherapeutic levels of valproic acid (Depakote) and phenytoin (Dilantin).8 Other potential drug interactions include concomitant use with hypoglycemic agents (resulting in hyperglycemia), blood pressure medications (ginkgo was shown to increase the blood pressure of a patient taking a thiazide diuretic in one case report, although it is a peripheral vasodilator), selective serotonin reuptake inhibitors (SSRIs) (increased risk of serotonin syndrome), monoamine oxidase inhibitors (MAOIs) (further inhibition of monoamine oxidase), acetylcholinesterase inhibitors like donepezil (Aricept) leading to increased adverse effects, and drugs used for erectile dysfunction (increased action of drugs for erectile dysfunction).6,8,11,13
St John's Wort
St John's wort is well known for its use in mild to moderate depression. In fact, there is strong scientific evidence (grade A) to support its use from studies lasting 1 to 3 months, which showed that it was more effective than placebo and equivalent in efficacy to tricyclic antidepressants (TCAs). However, its use has not been compared with that of SSRIs.14 At one time, the active ingredient in preparations causing the antidepressant effect was thought to be hypericin. Now, however, data suggest that hyperforin is responsible for the antidepressant effect. Even in light of this, manufacturers vary the amounts of hyperforin and may even use different parts of the plant and combine other ingredients in the preparation.15 St John's wort is associated with many drug interactions, especially with those drugs affected by the CYP450 enzyme system (eg, carbamazepine [Tegretol], cyclosporine [Gengraf, Neoral, Sandimmune], simvastatin [Zocor], theophylline, and warfarin).14 The half-life may vary from 6 to 48 hours in individuals after regular use.12 The FDA issued a public health advisory in 2000 regarding the use of St John's wort with indinavir (Crixivan) and other drugs. The concomitant use of the herbal supplement and indinavir, a protease inhibitor used to treat HIV, resulted in a significant decrease in plasma concentrations of indinavir. Therefore, the use of St John's wort with other protease inhibitors and drugs called nonnucleoside reverse transcriptase inhibitors (for HIV treatment) is not recommended.16
Numerous other drug interactions can occur when used concurrently with SSRIs, TCAs, MAOIs, birth-control drugs (decreased effectiveness), warfarin, triptans (used for migraine headaches), chemotherapy drugs (especially increased clearance of imatinib [Gleevec]), NSAIDs, and cyclooxygenase 2 (COX-2) inhibitors (increased anti-inflammatory effects). Caution is also advised with the use of benzodiazepines, opioids, P-glycoprotein drugs, antibiotics, antivirals, anesthetic agents, antifungals, sedatives, anxiolytics, anticonvulsants, and heart medications.14 Also of note, St John's wort decreased digoxin absorption by approximately 25% in a study of healthy participants when administered for 10 days; this is most likely caused by the induction of P-glycoprotein, of which digoxin is a substrate.6,15 It has also been shown to decrease the levels of simvastatin (Zocor) because of interactions through the CYP450 enzyme system.6 With respect to critical care, 2 separate case reports showed a decrease in patient response to vasopressors and a prolongation in the effects of anesthesia. It may also decrease methadone and midazolam (Versed) concentrations.8
Ginseng has been used with good scientific evidence (grade B) for its antioxidant effects on heart disease, hypoglycemic effects on diabetes mellitus, and its immune system enhancement. It has also been used for many other disorders but with conflicting scientific evidence.17 Caution should be exercised in patients with diabetes because of hypoglycemia and those with bleeding disorders, because ginseng affects platelet function by inhibiting COX and thromboxane A2 synthase.5,17 Therefore, it should not be taken with anticoagulants, because it has been shown to either increase or decrease the anticoagulant effects of warfarin; increased risk of bleeding may result if taken with NSAIDs or antiplatelet agents. Patients should also avoid ginseng if they have “hormone-sensitive conditions such as breast cancer, uterine cancer, or endometriosis.”17 Ginseng can interact with loop diuretics such as furosemide (Lasix) and cause drug resistance.18 Concomitant use with MAOIs can result in headache, tremors, mania, insomnia, agitation, and depression.17,18 Two case reports have reported an interaction with phenelzine (Nardil), an MAOI, resulting in insomnia, headache, tremors, and irritability.8 Other drug interactions include ginseng's use with opioids (possible inhibition of analgesic effects), digoxin (increased digoxin levels), calcium channel blockers, drugs metabolized by the CYP450 enzyme system, drugs used in hypercholesterolemia, chemotherapy drugs, antivirals, antipsychotic medications, immunomodulators, and glucocorticoids.6,17
Saw palmetto has been used with strong scientific evidence (grade A) for benign prostatic hypertrophy; it is reported to “improve symptoms such as nighttime urination, urinary flow, and overall quality of life” and be similar in effectiveness to finasteride (Proscar) with fewer adverse drug effects.19 Saw palmetto should not be used in combination with other androgens, finasteride, or flutamide (Eulexin). It may increase the risk of bleeding when taken with NSAIDs, warfarin, or antiplatelet agents.19 However, Izzo and Ernst's review of the literature from 2009 regarding herbal interactions with prescribed medications reported that there are no significant interactions with saw palmetto.8 This herbal supplement may prolong bleeding time, although, as found in one case report, animal studies have shown that it inhibits COX.5 It would be prudent to exercise caution when combining this product with drugs that can affect bleeding.
Valerian has been used with conflicting scientific evidence (grade C) for anxiety disorder, depression, insomnia, menopausal symptoms, and sedation. Although it seems to be well-tolerated for up to 4 to 6 weeks, long-term use may actually cause insomnia, and patients may go through a type of withdrawal if the product is stopped abruptly after high-dose, long-term use.20 Liver function also should be monitored with long-term use.12 Caution should be exercised when combining this supplement with other drugs such as benzodiazepines, opioids, and anticonvulsants that cause sedation.12,20 Concurrent use with statins may result in increased statin levels.12
Ginger has been used with good scientific evidence (grade B) for nausea and vomiting associated with pregnancy and with conflicting evidence (grade C) for nausea and vomiting that are chemotherapy related. For use in pregnancy, it may be safe at low doses for a short period of time, but more data are required to verify safety in this population.21 Ginger does have antiplatelet effects because it inhibits thromboxane synthetase, which is evidence against its use in pregnancy.10,21 As with many other herbals discussed here, concomitant use with NSAIDs, warfarin, and clopidogrel (Plavix) increases the risk of bleeding. Conflicting evidence exists about ginger's effect on stomach acid production; it may increase acid production, but it may also protect the stomach. Therefore, potential interactions exist with antacids, histamine-2 blockers, and proton pump inhibitors. Myriad other possible interactions are noted in the literature, a few of which include immunosuppressants, CYP450 drugs, xanthine oxidase drugs (such as allopurinol), statins, hypotensive medications (either increasing or decreasing blood pressure), and digoxin.21
Several studies reported on MEDLINE support the use of kava to treat anxiety (grade A evidence). Human studies have shown that it has moderate benefits and may be similar to benzodiazepines and buspirone. However, the FDA has issued a consumer advisory regarding kava's association with severe liver injury.22 Given the data from more than 25 reports in other countries, the FDA cautions patients who have liver disease or those who take drugs that can affect the liver to consult their physician before taking such supplements. There has been at least one associated case in the United States involving a healthy young female patient who needed a liver transplantation.23 Some kava-containing products have been removed from the market.22 It is estimated that the FDA receives notification of only 1% or less of severe adverse events that occur with dietary supplements.24 Therefore, one should be cautious of this herbal supplement as we can assume that there are many other cases of liver injury.
When used concomitantly with other sedative agents, additive effects can cause further sedation (eg, benzodiazepines, barbiturates, alcohol, and antidepressants).12 Two separate case reports support this theory. One showed that the use of kava, combined with alprazolam, resulted in a lethargic and disoriented state, and another showed that its use with paroxetine also resulted in a lethargic state.8 Other potential drug interactions may result when kava is used concomitantly with the following: drugs that affect the liver or kidneys, sedatives/hypnotics, TCAs or those with similar properties (eg, cyclobenzaprine [Flexeril]), diuretics and angiotensin-converting enzyme inhibitors (additive effects resulting in further diuresis), Parkinson disease medications, SSRIs (drowsiness), opioids (additive effects), hormones (of note, oral contraceptives), and chemotherapy drugs. Some health care professionals recommend holding kava 2 to 3 weeks before surgery because it may prolong the effects of anesthesia; an increased risk of bleeding associated with kava also exists.22
Cranberry is commonly thought to treat (grade C evidence) and/or prevent (grade B evidence) urinary tract infections. However, there are conflicting data supporting its use in this disorder. For urinary tract infection prevention, more data are needed, but it is thought to “prevent bacteria from sticking to cells that line the bladder.”25 In terms of drug interactions, cranberry may increase the international normalized ratio in patients taking warfarin, but this is controversial. It may also increase vitamin B12 absorption in patients taking proton pump inhibitors. Other potential interacting drugs include those used for Alzheimer disease, those used in diabetes mellitus, antifungals, antiulcer drugs, drugs used to lower cholesterol, antivirals, chemotherapy drugs, clarithromycin (Biaxin), diuretics, salicylate, and those drugs that are eliminated by the liver or kidneys. Cranberry may increase the excretion of some drugs in the urine.25
Herbal supplement use is more common than we think. As health care professionals, we must assess whether each drug that a patient takes is safe and effective. There is a scarcity of strong evidence on which to evaluate the risks and benefits of herbal supplement use. Ideally, randomized controlled trials would determine safety and efficacy. However, many trials involving herbal supplements are not designed appropriately or have little statistical power to apply the results to the general population.
Another problem with data supporting the use of herbal supplements involves the underreporting of adverse events. Patients using these products assume that “natural” is equivalent to safe, and they are biased toward associating adverse effects with prescription medications. Underreporting is also compounded by a lack of awareness of all of the products that patients are taking.15 Clinicians then have difficulty linking adverse drug events to the herbal supplement. There are more potential interactions that were not included in this review, in addition to those that are yet to be discovered. Health care professionals should be cautious about starting or resuming herbal supplements in patients before researching the current data supporting their use. To find the most up-to-date information, the following Web sites are good resources for information on herbal supplements: http://www.nlm.nih.gov/medlineplus/druginfo/herb_All.html and http://www.fda.gov/Food/DietarySupplements/ConsumerInformation/ucm110417.htm#getinfo.
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2. Cavaliere C, Rea P, Lynch ME, et al. Herbal supplement sales experience slight increase in 2008. HerbalGram. 2009 82: 58–61.
5. Becker BW, Concannon MJ, Henry SL, et al. The effect of herbal medicines on platelet function: an in vivo experiment and review of the literature. Plast Reconstr Surg. 2007 120(7): 2044–2050.
6. Izzo AA, Di Carlo G, Borrelli F, Ernst E Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction. Int J Cardiol. 2005 98: 1–14.
7. Elmer GW, Lafferty WE, Tyree PT, Lind BK Potential interactions between complementary/alternative products and conventional medicines in a Medicare population. Ann Pharmacother. 2007 41(10): 1617–1624.
8. Izzo AA, Ernst E Interactions between herbal medicines and prescribed drugs (an updated systematic review). Drugs. 2009 69(13): 1777–1798.
10. Miller LG Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998 158(20): 2200–2211.
12. Holcomb SS Common herb drug interactions: what you should know. Nurse Pract. 2009 34(5): 21–29.
13. Mechanick JI, Brett EM, Chausmer AB, et al. American Association of Clinical Endocrinologists medical guidelines for the clinical use of dietary supplements and nutraceuticals. Endocr Pract. 2003 9(5): 417–470.
15. Goldman P Herbal medicines today and the roots of modern pharmacology. Ann Intern Med. 2001 135: 594–600.
17. Natural Standard The Authority on Integrative Medicine. Ginseng (American ginseng, Asian ginseng, Chinese ginseng, Korean red ginseng, Panax ginseng: Panax spp., including P. ginseng C.C. Meyer and P. quinquefolius L., excluding Eleutherococcus senticosus). http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-ginseng.html
. Updated August 26, 2009. Accessed February 28, 2010.
18. Herbal medicine guide In: Physician's Desk Reference for Nonprescription Drugs, Dietary Supplements, and Herbs. Montvale, NJ: Thomson Healthcare Inc; 2007.
24. Centers for Disease Control and Prevention Hepatic toxicity possibly associated with kava-containing products—United States, Germany, and Switzerland, 1999–2002. MMWR Morb Mortal Wkly Rep. 2002 51(47): 1065–1067. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5147a1.htm
. Accessed March 4, 2010.