A continuing pharmacy education activity for pharmacists. Popular Herbal and Dietary Supplements Monograph 7

Transcription

1 Popular Herbal and Dietary Supplements Monograph 7 A continuing pharmacy education activity for pharmacists Supported by an independent educational grant from

2 Provider: American Pharmacists Association Target Audience: Pharmacists Release Date: July 30, 2010 Expiration Date: July 30, 2013 ACPE Number: H01-P CPE Credit Hours: 2.5 hours (0.25 CEUs) ACPE Activity Type: Knowledge-based Fee: There is no fee associated with this activity. Activity Preview Americans spend an estimated $15 billion each year on herbal products and other nonvitamin, nonmineral dietary supplements. Many consumers view dietary supplements as milder, safer alternatives to conventional prescription and nonprescription medications; few are aware that dietary supplements are not subject to the same standards of safety and efficacy as conventional medications. As the health care professional most likely to be accessible at the point of purchase, pharmacists are well positioned to talk with consumers about dietary supplements, provide evidence-based recommendations for the use of dietary supplements, and discourage the use of potentially unsafe products and practices. This monograph addresses the use of herbal products and other nonvitamin, nonmineral dietary supplements that are available without a prescription. The regulation and marketing of dietary supplements is reviewed and contrasted with regulations governing prescription and nonprescription medications. A framework for engaging patients in productive, evidence-based discussions about dietary supplement use is presented. The monograph concludes with an overview of selected dietary supplements that are used widely in the United States. Learning Objectives At the completion of this activity, the pharmacist will be able to: 1. Summarize federal regulations governing dietary supplements. 2. Identify common misperceptions concerning the extent of regulation regarding the safety and efficacy of dietary supplements. 3. Outline a strategy for guiding patient selection and use of dietary supplements. 4. Provide examples of reputable sources of evidence-based information about dietary supplements. 5. Discuss the efficacy and safety of popular dietary supplements, including black cohosh, coenzyme Q 10, echinacea, evening primrose oil, fish oil, garlic, ginkgo, ginseng, kava, melatonin, phytoestrogens, probiotics, St. John s wort, and saw palmetto. Advisory Board Bella Mehta, PharmD Associate Professor of Clinical Pharmacy Director, Clinical Partners Program The Ohio State University College of Pharmacy Columbus, Ohio Carol Rollins, MS, RD, PharmD, BCNSP Associate Clinical Professor Coordinator, Nutrition Support Pharmacy University Medical Center University of Arizona College of Pharmacy Tucson, Arizona Accreditation Information The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (CPE). The ACPE Universal Activity Number assigned to this activity by the accredited provider is H01-P. To obtain 2.5 hours of CPE credit (0.25 CEUs) for this activity, complete the CPE exam and submit it online at education. A Statement of Credit will be awarded for a passing grade of 70% or better. You have two opportunities to successfully complete the CPE exam. Pharmacists who successfully complete this activity before July 30, 2013, can receive credit. Your Statement of Credit will be available online immediately upon successful completion of the CPE exam. Development This home-study CPE activity was developed by the American Pharmacists Association. Support This activity is supported by an independent educational grant from Procter & Gamble. Disclosures Bella Mehta, PharmD, declares that her husband owns stock in Pfizer Inc. Carol Rollins, MS, RD, PharmD, BCNSP, declares no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. APhA s editorial staff declares no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. This publication was prepared by Cynthia Knapp Dlugosz, BPharm, of CKD Associates, LLC, on behalf of the American Pharmacists Association.

3 Introduction The term complementary and alternative medicine (CAM) refers to a group of diverse medical and health care systems, practices, and products that are not generally considered to be part of conventional medicine. Complementary medicine is used as an adjunct to conventional medicine, whereas alternative medicine is used in place of conventional medicine. This monograph addresses one aspect of CAM: the use of herbal products and other nonvitamin, nonmineral dietary supplements that are available without a prescription. According to data from the 2007 National Health Interview Survey, Americans spent an estimated $14.8 billion on nonvitamin, nonmineral dietary supplements during the previous 12 months an amount equivalent to approximately one third of total outof-pocket spending on prescription medications (Figure 1). An analysis of earlier National Health Interview Survey data found that nearly one in five adults in the United States more than 38 million people used an herbal product for health promotion or treatment of a specific health condition. Regulation and Marketing of Dietary Supplements Many consumers view dietary supplements as substitutes for conventional prescription and nonprescription medications. Unfortunately, consumers as well as many health care professionals often are unaware of important differences between these categories of products. acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. A new dietary ingredient is a dietary ingredient that was not sold as a dietary supplement in the United States before October 15, Manufacturers may market a combination of dietary ingredients as a proprietary blend. The DSHEA places dietary supplements in a special category under the general umbrella of foods, not drugs. Within the U.S. Food and Drug Administration (FDA), dietary supplements fall under the purview of the Center for Food Safety and Applied Nutrition. As a result, dietary supplements are excluded from the strict standards applied to prescription and nonprescription medications regulated through the Center for Drug Evaluation and Research. Under the DSHEA, firms that manufacture or distribute a dietary supplement are responsible for: Determining that the product is safe. Ensuring that any representations or claims made about the product are substantiated by adequate evidence to show that they are not false or misleading. In stark contrast to prescription and nonprescription medications, dietary supplements do not need to be approved by the FDA before they are marketed. Thus, firms are not required to submit or disclose any of the evidence used to substantiate product safety or claims either before or after a product is marketed, unless the product contains a new dietary ingredient. Manufacturers or distributors of dietary supplements that contain new dietary ingredients must notify the FDA of the intent to market the product 75 days in advance; they also must submit a premarket safety report establishing that the new dietary ingredient is reasonably expected to be safe under the conditions recommended or suggested in the labeling. However, because there is no Figure 1. Total 2007 Out-of-Pocket Health Care Costs for Conventional Health Care and Complementary and Alternative Medicine Dietary Supplement Health and Education Act of 1994 The Dietary Supplement Health and Education Act of 1994 (DSHEA) amended the Federal Food, Drug, and Cosmetic (FD&C) Act to create a distinct regulatory framework for dietary supplements. The DSHEA defines a dietary supplement as a product taken by mouth that contains a dietary ingredient intended to supplement the diet. Dietary ingredients include vitamins, minerals, herbs or other botanicals, amino OTC Advisor: Popular Herbal and Dietary Supplements 1

4 authoritative list of dietary ingredients that were available before October 15, 1994, the responsibility for determining whether a product contains a new dietary ingredient lies with the manufacturer or distributor. Moreover, there are no specific criteria for what constitutes acceptable evidence that a new dietary ingredient poses no significant or unreasonable risk. Labeling of Dietary Supplements The labels of dietary supplements are not required to provide the comprehensive user information that appears on labels of nonprescription medications. Information that must appear on a dietary supplement label includes: The name of the product and identification of the product as a dietary supplement. The name and place of business of the manufacturer, packer, or distributor. A complete list of ingredients. The net contents of the product. Most dietary supplements also must include a Supplement Facts panel similar to the Nutrition Facts panel on foods that identifies each dietary ingredient contained in the product. Botanical dietary supplements should indicate the scientific (i.e., Latin binomial) name of the plant as well as the specific plant part used (e.g., Echinacea purpurea aerial parts, which refers to the aboveground parts of the plant). For proprietary blends of dietary ingredients, the DSHEA requires that the product label include the total weight of the blend and the components of the blend, in order of predominance by weight. The actual quantity of each ingredient need not be disclosed. Dietary Supplement Claims In the United States, only prescription and nonprescription drugs may legally claim to diagnose, cure, mitigate, treat, or prevent illness. The DSHEA permits three types of claims on the labels of dietary supplements: nutrient content claims, health claims, and structure/function claims. Nutrient content claims describe the amount of a nutrient or dietary substance in a product. They must be made in accordance with the FDA s authorizing regulations. Health claims describe a relationship between a dietary ingredient and a disease or health-related condition. These claims also are subject to FDA review and authorization; diets high in calcium may reduce the risk of osteoporosis is an example of an authorized health claim. Structure/function claims describe the role of a dietary ingredient in maintaining normal healthy structures or functions of the body. For example, echinacea may claim to support the healthy defense mechanisms of the body. These claims are not subject to FDA review and authorization; the manufacturer is responsible for ensuring the accuracy and truthfulness of Homeopathy Homeopathy is a distinct system of medicine with its own pharmacopoeia and philosophy of practice. It is based on the principle of like cures like, or the law of similars. This principle states that if a substance produces a specific symptom or set of symptoms when administered in large doses to a healthy person, that same substance can cure the specific symptom or symptoms when administered in a very minute dose. A second principle holds that as a substance becomes more dilute, it becomes more potent. Unlike herbs and dietary supplements, homeopathic preparations are not regulated under the Dietary Supplement Health and Education Act. Instead, substances included in the Homeopathic Pharmacopoeia of the United States are recognized as drugs under the Federal Food, Drug, and Cosmetic Act. Because homeopathic products contain little or no active ingredient, they do not have to undergo the same safety and efficacy testing as prescription and nonprescription medications. Homeopathic preparations can be sold over the counter if they are intended to treat self-limiting conditions such as headaches or the common cold. Preparations that are intended to treat serious conditions such as cancer must be obtained by prescription from a licensed practitioner. these claims. Manufacturers must submit the text of structure/function claims to the FDA within 30 days after marketing a dietary supplement. When a structure/function claim is made, the product label also must include the following disclaimer: This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. The FDA and the Federal Trade Commission (FTC) work together to enforce regulations governing dietary supplement claims. The FDA has primary responsibility for regulating claims found on packaging, package labeling, inserts, and other promotional materials that are distributed at the point of sale. The FTC has primary responsibility for advertising claims made though print and broadcast advertisements, infomercials, catalogs, and other direct marketing materials. The FTC s truth-in-advertising law requires that advertising claims must be truthful and not misleading. In addition, claims about the efficacy or safety of dietary supplements must be supported by competent and reliable scientific evidence. This evidence is defined as tests, analyses, research, studies, or other evidence based on the expertise of professionals in the relevant area, that have been conducted and evaluated in an objective manner by persons qualified to do so, using procedures generally accepted in the profession to yield accurate and reliable results. Manufacturers who make dietary supplement health claims sometimes ignore the regulations established by the FDA and FTC and market products using false or misleading claims. Manufacturers of dietary supplements for weight loss are frequent culprits. The FTC consumer publication Weighing the Evidence in Diet Ads (available at pubs/consumer/health/hea03.shtm) provides examples of some common false and misleading claims that patients may encounter. Quality Control Considerations Although the DSHEA required the establishment of Current Good Manufacturing Practice (CGMP) standards 2 American Pharmacists Association

5 for dietary supplements, the FDA did not issue a final rule until June 2007, and manufacturers were not required to comply with the standards until June 2008 or later. (The standards were implemented in a rolling fashion; companies with 500 or more employees were given 1 year to comply, companies with 20 to 500 employees had 2 years, and companies with fewer than 20 employees had 3 years.) Before this final rule went into effect, many dietary supplements were found to have significant variability in content, purity, potency, consistency, and actual identity. In just one recent example, a widespread outbreak of acute selenium poisoning that began in March 2008 in the United States was traced to a liquid dietary supplement that contained 200 times the labeled concentration of selenium. The final rule requires certain activities in the manufacturing, packaging, labeling, and holding of dietary supplements to ensure that products (1) contain what they are represented to contain (i.e., are not misbranded) and (2) are not contaminated with harmful or undesirable substances (i.e., are not adulterated). The final rule further requires certain activities intended to ensure the identity, purity, quality, strength, and composition of dietary supplements. The CGMPs established by the final rule apply to all domestic and foreign manufacturers, as well as any company involved in the testing, quality control, packaging and labeling, or distribution of dietary supplements in the United States. Before the FDA issued its final rule, several organizations developed voluntary programs for verifying and certifying the quality of dietary supplement products. These organizations include the U.S. Pharmacopeia (USP), ConsumerLab.com, NSF International, and the Natural Products Association. The programs administered by these organizations remain active; they address product quality only, not the safety or efficacy of specific dietary supplement ingredients. USP Programs USP offers two programs for dietary supplements and each awards a distinctive USP Verified Mark (Figure 2). These programs encompass Adulteration and Contamination of Dietary Supplements According to the Dietary Supplement Health and Education Act, a dietary supplement is considered to be adulterated if it: Presents a significant or unreasonable risk of illness or injury when used in accordance with the suggested labeling (or, if unlabeled, under ordinary conditions of use). Is a new entity and lacks adequate evidence to ensure its safety of use. Has been declared an imminent hazard by the Secretary of the Department of Health and Human Services. Contains a dietary ingredient that is present in sufficient quantities to render the product poisonous or deleterious to human health, as described for adulterated foods in the Federal Food, Drug, and Cosmetic Act. Adulteration of dietary supplements may be intentional or unintentional. Unintentional adulteration often reflects contamination of products by substances such as natural toxins, bacteria, pesticides, glass, or heavy metals (e.g., lead) that are introduced at the time of cultivation or during manufacturing processes. It also is possible for a dietary supplement to be cross-contaminated by chemicals, drugs, or dietary ingredients present at the manufacturing site. Intentional adulteration is a deliberate act. For example, a manufacturer may use a different substance in place of a dietary ingredient that is in short supply or is too expensive. Alternatively, a manufacturer may choose to add an ingredient to intensify a specific pharmacologic effect. In one notable case, a manufacturer allegedly added pharmaceutical-grade ephedrine and caffeine to a dietary supplement that was represented to contain ma huang and kola nut (and concealed the addition by falsifying records). If only ma huang and kola had been used, the volume of those ingredients needed to achieve the labeled strength of the supplement would have resulted in capsules too large to ingest by mouth. finished products (i.e., marketed dietary supplement products purchased by consumers) and ingredients (i.e., ingredients used to manufacture dietary supplement products). The program for finished products is the USP Dietary Supplement Verification Program. It verifies the quality, purity, and potency of dietary supplement products through comprehensive laboratory testing, review of manufacturing and quality control documents, on-site manufacturing facility audits, and random off-the-shelf testing. Finished products that meet the program s stringent criteria are permitted to display the USP Dietary Supplement Verification Program certification mark. These products are certified to contain the listed ingredients in the indicated amounts, to be bioavailable, to be free of contaminants, and to have been manufactured under appropriate conditions. A list of USP Verified dietary supplements also is maintained on the USP Web site ( dietarysupplements/supplements. html). The USP Verified Dietary Supplement Ingredients Program verifies active and inactive ingredients used in the dietary supplement manufacturing process. It ensures that ingredients are consistent in quality from batch to batch; meet label or certificate of analysis claims for identity, strength, purity, and quality; are prepared in accordance with accepted manufacturing processes; and meet requirements for acceptable limits of contamination. Verified ingredients may carry the USP Verified Dietary Supplement Ingredient Mark on their containers. ConsumerLab.com Programs ConsumerLab.com, LLC, is a privately held company that provides test results and information to help consumers and health care professionals evaluate health, wellness, and nutrition products, including dietary supplements. Products are tested through two programs: (1) Product Reviews and (2) a Voluntary Certification Program for manufacturers and distributors. Product Reviews are independent tests of multiple brands of dietary OTC Advisor: Popular Herbal and Dietary Supplements 3

6 Figure 2. Logos Associated With Voluntary Programs for Verifying and Certifying Dietary Supplement Quality supplement products that claim to have the same key ingredient. ConsumerLab.com purchases a sampling of products at the retail level (e.g., stores, mail order, online) to reflect both popular brands and smaller brands; no samples are accepted from product manufacturers. Blind samples are sent to select commercial and academic laboratories for testing; products with questionable results are retested in a different laboratory using similar methods and instrumentation. The results are compiled in Product Reviews that are available to ConsumerLab.com Web site subscribers (a 1-year subscription costs approximately $30). Products deemed to pass testing are permitted to carry the ConsumerLab. USP Verified Dietary Supplement Mark USP Verified Dietary Supplement Ingredient Mark Sample ConsumerLab.com Approved Quality Product Seal NSF Certification Mark Natural Products Association GMP Certification Program GMP = Good Manufacturing Practice; USP = United States Pharmacopeia. com Approved Quality Product Seal (Figure 2). Product Reviews typically are updated every 24 to 36 months, although the company states that it may retest brands at any time. Products in the Voluntary Certification Program undergo similar testing. Although test results are proprietary to the manufacturer, products that pass are listed in the respective Product Review with a footnote indicating that they were tested through the Voluntary Certification Program. Products that pass also are eligible to carry the ConsumerLab.com Seal. NSF International Dietary Supplements Certification Program NSF International originally founded as the National Sanitation Foundation is a not-for-profit, nongovernmental organization engaged in standards development, product certification, education, and risk management for public health and safety. It offers a Dietary Supplements Certification Program to manufacturers and suppliers on a voluntary, fee-forservice basis. As part of the certification process, NSF: Reviews product formulations and labels to determine appropriate testing. Inspects manufacturing facilities. Obtains products and tests them at NSF laboratories to verify conformance to the NSF Dietary Supplement Standard. Products that meet all of the requirements are permitted to carry the NSF Certification Mark (Figure 2). Certified dietary supplements can be found by searching the NSF listings at Natural Products Association GMP Certification Program The Natural Products Association Good Manufacturing Practice (GMP) Certification Program is designed to verify that member companies manufacturing practices for dietary supplements conform to a standardized set of GMPs developed and approved by the association. The Natural Products Association GMPs meet or exceed all current FDA requirements for dietary supplements; they also incorporate some industry best practices. Certification is based on third-party inspection of manufacturing facilities and review of GMP-related documentation. The program represents facility and process certification rather than product certification. Companies that achieve a high level of compliance are permitted to use the Natural Products Association GMP Certification Mark (Figure 2). All companies are re-audited every 2 years. Unsafe Dietary Supplements and Adverse Event Reporting The FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market. However, the burden of proof rests with the agency; the FDA must be able to show that a dietary supplement is unsafe before it can 4 American Pharmacists Association

7 restrict the product s use or remove the product from the marketplace. Evidence that a product is unsafe typically comes from sources such as safety literature, adverse event reports, and product information (e.g., labeling, claims, package inserts, accompanying literature). One example of an FDA action against unsafe dietary supplements is the 2004 market withdrawal of ephedra and other products (e.g., ma huang) that contain ephedrine alkaloids. On February 11, 2004, the FDA published a final rule declaring these products adulterated under the Federal FD&C Act (and therefore illegal to market). The final rule became effective on April 12, According to the FDA, dietary supplements containing ephedrine alkaloids are adulterated because they present an unreasonable risk of illness or injury under the conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in labeling, under ordinary conditions of use. The agency based its action on the wellknown pharmacology of ephedrine alkaloids, the peer-reviewed scientific literature on the effects of ephedrine alkaloids, and the adverse events reported to have occurred in individuals following consumption of dietary supplements containing ephedrine alkaloids. Among the reported adverse events subjectively determined to be definitely, probably, or possibly associated with ephedra use were 17 cases of hypertension, 13 cases of palpitations or tachycardia, 10 cases of stroke, and 7 cases of seizures. Ten of these events resulted in death. Under the DSHEA, the reporting of adverse events associated with the use of dietary supplements was voluntary. Adverse event reporting became mandatory when the Dietary Supplement and Nonprescription Drug Consumer Protection Act was signed into law in December Specifically, that law requires manufacturers, packers, and distributors of dietary supplements to record, investigate, and forward to the FDA any reports they receive of serious adverse events associated with the use of their products that are reported to them directly. A serious adverse event is an adverse event that: Results in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect. Requires, based on reasonable medical judgment, a medical or surgical intervention to prevent one of these outcomes. The law also expands labeling requirements for dietary supplements to include a domestic address or telephone number for reporting serious adverse events. Companies must submit reports of serious adverse events to the FDA no later than 15 business days after the report is received. Consumers and health care professionals also are encouraged to report both serious and nonserious dietary supplement related adverse events through the FDA MedWatch program (1-800-FDA-1088 or www. fda.gov/safety/medwatch). Dietary supplement alerts and safety information are available on the FDA Web site at DietarySupplements/Alerts/default. htm. Advising Patients About Dietary Supplement Use As few as one third of adults disclose their use of herbal and other dietary supplements to conventional health care providers, and only about half (54.9%) use these products in accordance with evidence-based indications (ranging from a high of 68.0% for echinacea to a low of 3.8% for ginseng). As the health care professional most likely to be accessible at the point of purchase, pharmacists are well positioned to talk with consumers about dietary supplements, provide evidence-based recommendations for the use of dietary supplements, and discourage the use of unsafe products and practices. Ashar and Rowland-Seymour recommend the following six-step framework for engaging patients in discussions about dietary supplement use: 1. Inquire about supplement use. 2. Evaluate the supplement. 3. Discuss regulatory issues surrounding dietary supplements. 4. Discuss the available safety and efficacy data. 5. Compare risk/benefit of use to available conventional therapies. 6. Monitor for adverse effects and therapeutic response. Key considerations for implementing this framework are described below. Set the Tone for a Productive Interaction Asking patients about their use of herbal products and other dietary supplements should be a routine part of pharmacist-patient interactions. Because it is more likely that patients will disclose this information openly if they feel comfortable, pharmacists must recognize the importance of respecting the patient s beliefs and values so that a trusting, nonjudgmental relationship can develop. Examples of questions that will assist in characterizing the patient s use of dietary supplements are listed in Table 1. Consider Possible Risks of Dietary Supplement Use Many patients consider dietary supplements herbal products in particular to be natural and therefore milder and safer than prescription and nonprescription medications. Unfortunately, the fact that herbal dietary supplements are derived from natural sources does not guarantee safety. Although adverse effects sometimes are linked to product contaminants, they more frequently result from the basic pharmacology of the supplement or its biologically active constituents. For example, the pyrrolizidine alkaloids present in comfrey have been associated with hepatotoxicity that may be rapidly progressive and fatal. Data from the 2002 National Health Interview Survey showed that more than 80% of respondents who used herbal dietary supplements also had used a nonprescription medication during the previous 12 months, and 72% had used a prescription medication. Patients generally are unaware of the potential for interactions between dietary supplements and conventional medications. These interactions may have either a pharmacodynamic or pharmacokinetic OTC Advisor: Popular Herbal and Dietary Supplements 5

8 Table 1. Assessing Dietary Supplement Use By Patients What are the patient s goals for using a dietary supplement? Is the product being used to treat a specific condition or symptom? Is the product being used for possible preventive purposes? What benefit or effect does the patient expect from the dietary supplement? Is the patient currently taking a nonprescription or prescription medication for the same condition or purpose? Is there a cultural context that needs to be understood? basis. Pharmacodynamic interactions are possible when a supplement augments or antagonizes the activity of a medication the patient is taking; for example, both St. John s wort and l-tryptophan increase the levels of circulating serotonin and have been linked to reports of serotonin syndrome in patients taking psychotropic medications. Pharmacokinetic interactions are caused by changes in the absorption, distribution, metabolism, or excretion of the supplement, the medication, or both, resulting in more pronounced or diminished pharmacologic activity. For example, St. John s wort induces multiple cytochrome P450 (CYP) isoenzymes and has been reported to induce the metabolism of drugs such as oral contraceptives, protease inhibitors, and cyclosporine. Consult Reliable Sources of Information The safety and efficacy of most dietary supplements sold in the United States have not been well established. Although the body of information is growing, the overwhelming majority of dietary supplements have not been studied using modern scientific techniques, and it remains unlikely that definitive evidence will be available anytime soon. There is limited government funding available to conduct high-quality clinical trials, so the pace of research is slow. There also are few incentives for manufacturers or scientists to conduct efficacy or safety studies. Companies cannot obtain patents on existing dietary ingredients and thus have little possibility of market exclusivity. Researchers seeking National Institutes of Health funding to assess the efficacy of a dietary supplement in treating or preventing a specific disease or condition would need to file an investigational new drug application. To do so, the researcher would need to obtain manufacturer support and detailed analytical information about the specific supplement, which the manufacturer may or may not be willing to provide. To help patients make informed choices about dietary supplement use, pharmacists need to be aware of and have access to reliable sources of product information. Examples of popular resources are described in this section. Office of Dietary Supplements The DSHEA authorized the establishment of the Office of Dietary Supplements (ODS) within the National Institutes of Health in The main purposes of the ODS are to: Explore more fully the potential role of dietary supplements as a significant part of the efforts of the United States to improve health care. Promote scientific study of the benefits of dietary supplements in maintaining health and preventing chronic disease and other healthrelated conditions. The ODS Web site includes a library of Dietary Supplement Fact Sheets that are suitable for distribution to patients (although not all of these sheets would be appropriate for patients with low literacy). The Web site ( also serves as a portal to the International Bibliographic Information on Dietary Supplements database, which provides access to bibliographic citations and abstracts from published, international, and scientific literature on dietary supplements. National Center for Complementary and Alternative Medicine The National Institutes of Health National Center for Complementary and Alternative Medicine (NCCAM) was created by Congress in The mission of NCCAM is to explore complementary and alternative healing practices in the context of rigorous science, train CAM researchers, and disseminate authoritative information to the public and professionals. Accordingly, the NCCAM Web site offers extensive information about dietary supplements for both consumers and health care practitioners, including a list of clinical trials. The Web site ( gov) also includes a link to CAM on PubMed, which automatically limits literature searches to the CAM subset of PubMed citations. Cochrane Reviews Cochrane Reviews are systematic reviews of research in health care and health policy, including research about dietary supplements. Each review provides detailed information about the trials that were included and excluded from analysis, summarizes the results of included studies, and offers the authors evidencebased conclusions. The Cochrane Library Web site ( library.com) offers free access to the abstracts and, where available, the plain language summaries of all Cochrane systematic reviews. Access to the full reports is available for a fee; some pharmacists may have access to the full reports through institutional subscriptions. ConsumerLab.com In addition to the Product Reviews described earlier, subscribers to the ConsumerLab.com Web site have access to an encyclopedia of natural and alternative treatments. Each entry contains a brief summary of what the herb or supplement is used for, the evidence supporting its use, the usual dosage, and safety issues. Both English and Spanish versions are available. Natural Medicines Comprehensive Database The Natural Medicines Comprehensive Database at database.com is a subscription service from the company that publishes Pharmacist s Letter and Prescriber s Letter. The database consists of more 6 American Pharmacists Association

9 than 1,100 detailed, evidence-based monographs on individual natural ingredients; each monograph provides ratings of the safety of the ingredient as well as its effectiveness for specific indications. In addition, possible interactions with other dietary supplements, drugs, foods, laboratory tests, and diseases and conditions are rated as major, moderate, or minor. Products that have been awarded the USP Dietary Supplement Verification Program certification mark are identified with this mark next to their listing in the database. The online monographs include links to a list of brand name products that contain the ingredient, as well as to patient handouts in English and Spanish. Downloads for personal digital assistant (PDA) and print options are available. A consumer version of the database is available at baseconsumer.com. Natural Standard Natural Standard is an international research collaboration that aggregates and synthesizes data on complementary and alternative therapies. The Natural Standard electronic database on foods, herbs, and supplements includes comprehensive, evidence-based monographs designed to facilitate clinical decision making. The quality of the available evidence supporting the efficacy of each therapy for a given indication is rated on a validated, five-point scale (A = strong evidence, B = good evidence, C = unclear or inconclusive evidence, D = fair negative evidence, F = strong negative evidence). Pharmacists can access the database at through an individual or institutional subscription (including abridged desktop and PDA options). A number of print products also are available. Weigh the Benefits and Risks of Dietary Supplement Use Once the pharmacist understands a patient s reasons for using (or wanting to use) a dietary supplement and has consulted a reliable source of information about the supplement, it is possible to provide the patient with an evidence-based recommendation (or explain when the available information is insufficient). A schema that considers both the efficacy and safety of a given therapy is presented in Figure 3. Very few dietary supplements have conclusive evidence supporting both safety and efficacy. Those that do generally can be recommended to patients, assuming that no risk of drug or disease state interactions exists. Similarly, few dietary supplements have conclusive evidence indicating a serious safety risk, complete lack of efficacy, or both. When such evidence does exist, pharmacists should actively discourage patients from using the product. Most dietary supplements fall into one of the remaining two categories: There is evidence supporting safety, but evidence regarding efficacy is inconclusive. There is evidence supporting efficacy, but evidence regarding safety is inconclusive. In either case, use of the desired product most likely is acceptable with appropriate patient counseling and monitoring. Following the framework outlined by Ashar and Rowland-Seymour, pharmacists should acquaint patients with the regulatory issues surrounding dietary supplements and summarize what is known about the efficacy and safety of the desired product. Whenever appropriate, pharmacists also might discuss the efficacy and safety data for related prescription and nonprescription treatment options to ensure that the patient is fully informed about all possible choices. As an example, a patient intent on purchasing a weight loss dietary supplement might instead elect to try a course of therapy with nonprescription orlistat. The FDA offers two publications that acquaint consumers with basic issues related to dietary supplement use. Tips for the Savvy Supplement User: Making Informed Decisions and Evaluating Information includes links to a number of other online resources; it is available at gov/food/dietarysupplements/con sumerinformation/ucm htm. Tips for Older Dietary Supplement Users is targeted to older adults, but it contains information that would be of value to any patient who is considering using dietary supplements. It is available at DietarySupplements/ConsumerInfor mation/ucm htm#botline. All patients who elect to use dietary supplements should be advised to inform all of their health care providers of the products they are taking. Assist Patients With Product Selection and Use If a patient decides to purchase a dietary supplement, the pharmacist Figure 3. Dietary Supplement Counseling Actions Based on Evidence of Safety and Efficacy Evidence supports both safety and efficacy Recommend Continue to monitor Evidence supports efficacy, but evidence regarding safety is inconclusive Provide caution Monitor closely Evidence supports safety, but evidence regarding efficacy is inconclusive Use more than likely acceptable Provide caution Monitor closely Evidence indicates serious safety risk, lack of efficacy, or both Actively discourage use OTC Advisor: Popular Herbal and Dietary Supplements 7

10 should help the patient choose a quality product. In general, patients should be counseled to purchase products that either (1) bear a certification mark from one of the voluntary programs discussed earlier or (2) meet their content claim as assessed by ConsumerLab.com. Pharmacists may feel most comfortable recommending products from large companies with known reputations, or from companies that also manufacture prescription or nonprescription medications. Once a quality product has been selected, patients should continue to purchase and use the same brand and formulation. This approach increases the likelihood of a consistent active ingredient, dose, and response. Patients who have not had positive results with a specific dietary supplement product might consider a trial with a different brand before concluding that the supplement is ineffective. Additional recommendations for product counseling are presented in Table 2. Monitor for Adverse Effects and Therapeutic Response Patients should be advised to monitor for short-term adverse events for at least 2 weeks after initiating a new dietary supplement and to continue monitoring for longer-term adverse events while using the product. Educating patients about anticipated adverse effects will enable them to recognize a problem and discontinue product use early enough to minimize harm. Patients also should be educated about the likely window for therapeutic response. For some chronic conditions, dietary supplements may not produce noticeable effects for 30 days or longer. Patients who are unaware of the anticipated response time frame may discontinue product use prematurely. Considerations for Special Groups A number of special populations provide unique challenges when counseling patients about dietary supplements. The lack of data on safety and efficacy in these populations underscores the need for comprehensive assessment of the patient s health status and knowledgeable counseling on dietary supplement use. Older Adults Older adults are more likely than younger patients to have multiple chronic diseases and to be taking multiple prescription and nonprescription medications. Older adults also are likely to have age- and disease-related changes in physiologic function (e.g., decreased renal function). Thus, the potential for drug interactions, age-related functional declines, and concomitant disease must be considered when counseling older adults about the use of dietary supplements. Children Body and organ functions are in a continuous state of development in children. Especially in children younger than 2 years of age, renal function is less developed, and the central nervous system may be uniquely sensitive to many substances. In addition, the pharmacokinetic properties of dietary supplements may be different in children and may undergo rapid change as children grow and mature. It may be difficult or impossible to determine an appropriate pediatric dose of a dietary supplement. Table 2. General Recommendations for Advising Consumers About Dietary Supplements Appropriate Use Read all labels carefully; never take more than the recommended amount. Never share dietary supplements with others. Do not select a product that lacks dosing recommendations on the label. Avoid products that do not carry a lot number or expiration date. Discard products 1 year from the date of purchase if no other expiration date is present. Select products that list the manufacturer s name, address, and telephone number. Store products in a dry environment out of direct sunlight and humidity, and away from young children and pets. Special Groups Always seek the advice of a pediatrician before using dietary supplements in children. Avoid dietary supplements if you are pregnant or nursing, or trying to become pregnant. Speak to your health care professional if you are trying to treat a life-threatening condition, such as cancer or human immunodeficiency virus infection. Adverse Effects The term natural does not mean safe; be diligent and report any unusual experiences to your physician and pharmacist. If you are allergic to plants, weeds, and/or pollen, ask your health care provider about dietary supplements before using these products. Interactions If you are taking a prescription medicine, do not take a dietary supplement for the same condition. When possible, avoid taking multi-ingredient preparations; select single-ingredient products that list the strength per dose. Do not take these products with alcohol until you know it is safe to do so, or you are familiar with the effects. Check with your health care provider if you are taking blood thinning drugs; some dietary supplements may interact with the drugs. Always inform your health care provider of the products you are taking; keep a list if necessary or bring them with you to your appointment. Expectations Never use these products in place of proper rest and nutrition; eat a balanced diet. Do not expect a cure or unrealistic results; these agents are not cure-alls. If it sounds too good to be true, it probably is; use discretion when evaluating claims. Keep a diary to track dietary supplement effectiveness and side effects. 8 American Pharmacists Association

11 Pregnant Women Little information exists about the safety of dietary supplement use during pregnancy. This is of particular concern because as many as 395,000 births in the United States each year involve antenatal exposure to at least one herbal supplement. Of the 4,239 women included in the National Birth Defects Prevention Study, 462 (10.9%) reported use of an herbal product during the 3 months before or during pregnancy. Among pregnant women, herbal use was highest (6.9%) during the first trimester a critical period of fetal organ development. Patients Undergoing Surgical Procedures Several different dietary supplements may increase the risk of bleeding before or after surgery; some have the potential to affect the metabolism of anesthetic agents. It is prudent for patients to discontinue use of all dietary supplements at least 2 weeks before any scheduled surgical procedure. Because some institutions may have more stringent policies, patients should check with all health care providers involved in the surgery regarding specific guidelines for discontinuation of dietary supplements. Patients With Renal Disease Many Americans have chronic renal insufficiency or failure attributable to systemic diseases such as diabetes. Their renal systems may be unable to eliminate dietary supplements appropriately, potentially resulting in supratherapeutic concentrations. In addition, herbs that possess antiplatelet properties might increase the risk of bleeding in adults with chronic renal insufficiency. Summaries of Selected Dietary Supplements Literally thousands of different dietary supplements are available on the market today. This section provides an overview of selected nonvitamin, nonmineral supplements that are used widely in the United States. Because this monograph covers only a small subset of dietary supplements and their uses, pharmacists are encouraged to consult any of the more comprehensive resources discussed earlier to obtain additional information about the products discussed here or to learn about other products that their patients use. Black Cohosh Black cohosh (Actaea racemosa or Cimicifuga racemosa) is a perennial plant and a member of the buttercup family native to North America. Black cohosh should not be confused with blue cohosh (Caulophyllum thalictroides), a different herb with chemicals that may damage the heart and increase blood pressure. Preparations of black cohosh are made from the roots and rhizomes (underground stems) of the plant. The mechanism of action of black cohosh remains unclear. Although it is possible that black cohosh exhibits estrogenic activity, the evidence is contradictory and the issue remains controversial; it has shown no effect on vaginal epithelium, endometrium, or hormone concentrations. Black cohosh is used most commonly to treat symptoms of menopause. The usual dosage is 40 to 80 mg daily (as a standardized extract) in one or two doses. Black cohosh also is used in the treatment of premenstrual syndrome and dysmenorrhea. There is some evidence to support its use for joint pain in rheumatoid arthritis or osteoarthritis. A 2005 review of five published studies on the effectiveness of black cohosh for the relief of menopausal symptoms (including hot flashes, profuse sweating, insomnia, and anxiety) concluded the herb was a safe and effective alternative to estrogen replacement therapy, although the author acknowledged limitations in the clinical studies reviewed. In a 2010 meta-analysis that included nine randomized, placebo-controlled trials, six of the trials were found to demonstrate a significant improvement in menopausal symptoms in the black cohosh group compared with the placebo group; aggregate data from seven of the trials indicated that black cohosh improved symptoms overall by 26% (95% confidence interval, 11% 40%). However, the trials were significantly heterogeneous, and the Standardization of Herbal Dietary Supplements Herbs contain many active and inactive constituents. The process known as standardization involves identifying specific chemicals or markers that are thought to possess therapeutic activity, isolating them, and then formulating them into a final and consistent product. Standardization can occur only if the chemical markers that contribute to the pharmacologic effect of a plantbased dietary supplement have been identified. For example, a Ginkgo biloba product may indicate that it is standardized to contain 6% terpene lactones and 24% flavonoid glycosides, whereas an echinacea product may not list any standardized markers. In some cases, the identified active chemical markers change over time as new pharmacologic research is performed. This happened with St. John s wort; the active antidepressant marker was initially thought to be hypericin but is now thought to be hyperforin. St. John s wort products may list one or both of these standardizations on the package label. trial with the longest follow-up and the highest dose of black cohosh (160 mg) a 1-year randomized, doubleblind, placebo-controlled trial (n = 351) funded by NCCAM did not demonstrate significant improvement in the black cohosh group compared with the placebo group. The use of black cohosh for up to 6 months generally is considered to be safe. Common adverse effects include gastrointestinal complaints, headache, rash, and occasional weight gain. In a review of more than 2,800 patients using black cohosh, the incidence of reported adverse events was only 5.4%, and most events were minor. Hepatitis and liver failure have been reported in patients taking black cohosh, but the causal association is unclear. Until more data are available, pharmacists should advise patients to inform their primary care provider of any symptoms such as abdominal discomfort, dark urine, or jaundice that may indicate liver disease. The use of black cohosh by women who have had breast cancer appears to be safe but remains controversial. In a 2007 study, 1,102 breast cancer survivors taking black OTC Advisor: Popular Herbal and Dietary Supplements 9

12 cohosh were followed over an average of 3.6 years; the study concluded that black cohosh was not associated with an increased risk of recurrence. However, it may be best for women with a history of breast cancer to avoid black cohosh until its effects on breast tissue are better understood. Because of potential hormonal effects, the use of black cohosh during pregnancy and breastfeeding should be avoided. Information about black cohosh, including drug interactions, is summarized in Table 3. Coenzyme Q 10 Coenzyme Q 10 (CoQ 10 ) is found in every cell of the human body, primarily in the mitochondria. It is a cofactor in many functions associated with energy production; it is the ratelimiting cofactor in the formation of mitochondrial adenosine triphosphate (ATP). CoQ 10 stabilizes membranes and may have vasodilatory and inotropic effects. One CoQ 10 preparation has FDA orphan drug status for the treatment of Huntington s disease. As a dietary supplement, CoQ 10 is used as a treatment for several cardiovascular conditions, especially heart failure, cardiomyopathy, and hypertension. It also is used as a general antioxidant. Some patients have a documented CoQ 10 deficiency and take supplements to correct that deficiency. Evidence for most uses of CoQ 10 is contradictory or preliminary. Recent studies in patients with heart failure have demonstrated both positive and negative results in outcomes such as overall symptoms, ejection fraction, and oxygen consumption. Nonetheless, the use of CoQ 10 as an adjunctive therapy is considered to be acceptable because of its favorable adverse effect profile. Nausea, gastrointestinal distress, anorexia, headache, irritability, and dizziness have occurred in less than 1% of patients. CoQ 10 is manufactured using a beet and sugarcane fermentation process. The chemically reduced form is called ubiquinone. The usual dosage of CoQ 10 is 100 to 200 mg daily; doses greater than 100 mg generally are administered as divided doses. Information about CoQ 10, including drug interactions, is summarized in Table 4. Echinacea Echinacea, or purple coneflower, is a member of the Asteraceae family. Nine Echinacea species are indigenous to North America; the species used most frequently in clinical trials are Echinacea purpurea, Echinacea angustifolia, and Echinacea pallida. The roots, leaves, and flowers all are considered to be medicinally active. Echinacea preparations typically are not standardized to a single active constituent. Products may contain more than one Echinacea species and more than one part of the plant; it is not clear which single species or combination may be most effective. Because products differ appreciably in composition, each product has its own dose and dosing regimen. Echinacea is used primarily as an immune stimulant to prevent and treat the common cold and other respiratory infections. Components that target the nonspecific cellular immune system have been identified and include alkylamides, caffeic acid derivatives (e.g., chicoric acid, Table 3. Black Cohosh at a Glance Most Common Uses Menopausal symptoms Usual Dosages 40 to 80 mg daily in one or two doses chlorogenic acid, cynarin), glycoproteins, isobutylamides, polyenes, and polysaccharides. Although the specific mechanism of action of echinacea preparations remains unclear, its effects include increasing cytokine secretion, lymphocyte activity, and phagocytosis. Antiviral, antifungal, and anti-inflammatory activity also have been observed. The evidence supporting the ability of echinacea to prevent or treat the common cold is inconclusive. A 2006 Cochrane review analyzed 16 randomized, controlled trials that compared echinacea with a placebo, no treatment, or another treatment for the prevention or treatment of the common cold a total of 22 comparisons. None of the three comparisons in the prevention trials showed an effect over placebo; in the treatment trials, a significant effect for echinacea over placebo was reported in nine comparisons, a trend in one, and no difference in six. Conversely, a 2007 meta-analysis of 14 trials encompassing more than 2,900 participants found that echinacea decreased the odds of developing the common cold by 58% and the duration of a cold by 1.4 days. Adverse Effects Generally safe at recommended doses for use up to 6 months Adverse effects may include occasional, mild gastrointestinal complaints; headache; rash; weight gain High doses may cause headache, dizziness, perspiration, visual disturbances Controversial hepatic effects; approximately 30 case reports of acute hepatitis Selected Drug Interactions Possible interaction with medications metabolized by CYP2D6, such as tricyclic antidepressants, β-blockers, and antipsychotics; use cautiously or avoid Possible additive estrogenic activity with hormone therapy or oral contraceptives Possible interaction with tamoxifen, raloxifene May increase toxicity of doxorubicin and docetaxel May decrease effectiveness of cisplatin Avoid concurrent use with hepatotoxic medications Cautions Avoid use during pregnancy and breastfeeding because of possible hormonal effects Use in high-risk populations (e.g., women with a history of breast cancer) should be supervised by a health care professional 10 American Pharmacists Association

13 Echinacea appears to work best when treatment is started at the first sign of cold symptoms and continued for 5 to 7 days. The existing evidence does not support chronic use of echinacea to prevent or reduce the frequency of respiratory infections. Echinacea products generally are well tolerated. Adverse effects may include mild gastrointestinal discomfort, tingling sensation of the tongue, and headache. Patients with allergies to plants in the Asteraceae or Compositae family including ragweed, chrysanthemums, marigolds, and daisies are more likely to have an allergic reaction to echinacea and should avoid using these products. Echinacea products also are best avoided by patients with a history of asthma, atopy, or allergic rhinitis. Information about echinacea, including drug interactions, is summarized in Table 5. Evening Primrose Oil Evening primrose (Oenothera biennis) is a member of the primrose family Onagraceae. The oil from evening primrose seeds consists of at least 85% to 92% unsaturated fatty acids. The essential omega-6 fatty acids cis-linoleic acid and cis-gamma-linolenic acid (GLA) are the primary components; GLA is believed to be the active constituent. The seed oil also contains smaller amounts of oleic, palmitic, and stearic acids. Evening primrose oil has been used for a wide range of symptoms and conditions, including mastalgia, premenstrual syndrome, menopausal symptoms, preeclampsia, diabetic neuropathy, chronic fatigue syndrome, and atopic dermatitis. Highquality evidence for most of these uses is lacking, and much of the evidence that does exist is inconsistent or inconclusive. A systematic review of 11 randomized, controlled trials of evening primrose oil in the treatment of premenstrual syndrome found no conclusive evidence for efficacy. In a meta-analysis of English language trials on mastalgia, evening primrose oil was no better for pain relief than placebo. Several studies support the use of evening primrose for the treatment of atopic dermatitis, but additional data from large, well-designed trials is needed. Evening primrose oil generally is well tolerated. Adverse effects may include headache, nausea, diarrhea, and abdominal pain. Because there have been several reports of seizures in people using evening primrose oil, these products are best avoided in patients with a history of seizure Table 4. Coenzyme Q 10 at a Glance Most Common Uses Cardiomyopathy Coenzyme Q 10 deficiency General antioxidant effects Heart failure Hypertension disorders, as well as patients being treated with medications that may lower the seizure threshold (e.g., phenothiazines). The usual dosage of evening primrose oil depends on the condition being treated. For example, dosages of 4 to 8 g daily in divided doses have been used for atopic dermatitis; dos- Usual Dosages 100 to 200 mg daily; doses greater than 100 mg should be administered as divided doses Adverse Effects Generally well tolerated Nausea, gastrointestinal distress, anorexia, headache, irritability, dizziness have been reported by less than 1% of patients Selected Drug Interactions Possible vitamin K like procoagulant effects if taken with warfarin; monitor international normalized ratio Cautions Safety during pregnancy and breastfeeding has not been determined Table 5. Echinacea at a Glance Most Common Uses Prevention of common cold Treatment of common cold (reduction in duration, severity of symptoms) Usual Dosages Echinacea preparations are not standardized to one active constituent; each product has its own dosing regimen Adverse Effects Generally well tolerated Adverse effects may include mild gastrointestinal discomfort, tingling sensation of the tongue, headache Selected Drug Interactions Possible interactions with immunosuppressant agents (e.g., azathioprine, cyclosporine), although none documented Potential CYP3A4 inhibitor (in vitro data only) Cautions Avoid use in patients with: Allergies to plants in the Asteraceae family A history of asthma, atopy, or allergic rhinitis OTC Advisor: Popular Herbal and Dietary Supplements 11

14 ages of 3 g daily in divided doses have been used for mastalgia. Information about evening primrose oil, including drug interactions, is summarized in Table 6. Fish Oil Fish oil oil obtained from fish that store lipid in their flesh or liver (e.g., cod liver) is a rich source of the essential omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). As essential fatty acids, DHA and EPA cannot be manufactured in the body; preformed DHA and EPA must be obtained from exogenous sources. The American Heart Association emphasizes obtaining omega-3 fatty acids from dietary sources; the general recommendation is to consume at least two servings of a variety of oily fish (salmon, tuna, mackerel, herring, and trout) per week. Because the requisite amount of fish intake may be difficult for many people to achieve and sustain over the long term, fish oil may be consumed to help ensure an adequate intake of DHA and EPA. Fish oil also is used for cardiovascular benefits (including treatment of hypertriglyceridemia and hypertension) or to improve a variety of inflammatory conditions (e.g., rheumatoid arthritis). In contrast to many other dietary supplements, there is a strong body of evidence to support the use of fish oil. In epidemiological and clinical trials, consumption of omega-3 fatty acids from fish or fish oil supplements has been shown to reduce both the incidence of cardiovascular disease and the rates of all-cause mortality, cardiac and sudden death, and possibly stroke. The evidence for the benefits of fish oil is stronger in secondary prevention than in primary prevention. Fish oil supplements also have been shown to reduce serum triglyceride concentrations by 20% to 40%, with little or no effect on total cholesterol and low-density lipoprotein cholesterol concentrations. Multiple small clinical trials have reported small reductions in blood pressure with intake of omega-3 fatty acids; however, because the results are considered to be inconclusive, any hypertensive effect should be considered a beneficial side effect of using fish oil supplements rather than a primary reason for taking them. Clinical trials that investigated the use of fish oil for rheumatoid arthritis have demonstrated beneficial anti-inflammatory effects, with reductions in pain and swelling, increased range of motion, and the ability to reduce doses of prescription medications. Fish oil supplements are available primarily in capsule and liquid formulations, although novel dosage forms (e.g., soft chews, squeeze packets) are being introduced. DHA and EPA account for approximately 30% of the fatty acids in a typical fish oil preparation, with a standard 1 g capsule providing about 300 mg of DHA plus EPA. More concentrated versions are available. The labeled strength may reflect only the DHA plus EPA content, or it may reflect the total fish oil content (including omega-3 fatty acids other than DHA and EPA); consumers should be cautioned to check the Supplement Facts label carefully to ensure that they are getting the desired amount of DHA plus EPA. The primary adverse effect associated with fish oil supplements is gastrointestinal upset, especially belching with a fishy aftertaste. Belching generally can be lessened by using enteric-coated products and consuming doses with meals; storing capsule formulations in the freezer also may help. (Liquid formulations of fish oil always should be stored in the refrigerator.) Very high intake of omega-3 fatty acids (e.g., more than 3 g of DHA plus EPA) may increase the risk of bleeding, but there is little evidence of significant bleeding risk at lower doses. There is a potential, albeit unlikely, risk of increases in blood glucose levels. Safety concerns that apply to the consumption of oily fish do not apply to fish oil supplements, which are essentially mercury free. Recommendations for daily intake of DHA plus EPA for general good health range from 200 mg to 2 g. A dose of 1 g per day is recommended for secondary prevention of cardiovascular disease; doses of 2 to 4 g per day are recommended for triglyceride lowering. Doses of 2.5 g or more have been used in rheumatoid arthritis studies. Patients with coronary heart disease, elevated triglycerides, or rheumatoid arthritis should consume supplemental fish oil only in consultation with their physician. A prescription product (e.g., Lovaza, which contains omega-3-acid ethyl esters) may be more appropriate for some patients with hypertriglyceridemia. Table 6. Evening Primrose Oil at a Glance Most Common Uses Atopic dermatitis (eczema) Chronic fatigue syndrome Diabetic neuropathy Mastalgia Menopausal symptoms Preeclampsia Premenstrual syndrome Usual Dosages Depends on condition being treated; up to 8 g daily in divided doses Adverse Effects Generally well tolerated Adverse effects may include headache, nausea, diarrhea, abdominal pain Selected Drug Interactions Possible additive effects if taken with other platelet-active drugs (e.g., warfarin) or supplements Seizures possible if taken with phenothiazines Potential additive effects to antihypertensive agents Cautions May lower the seizure threshold in patients who have seizure disorders 12 American Pharmacists Association

15 Information about fish oil, including drug interactions, is summarized in Table 7. Garlic Garlic dietary supplements are derived from dried or fresh bulbs of garlic (Allium sativum) the same plant that is used for cooking. Garlic bulbs contain alliin, an odorless, sulfoxide amino acid derivative. Crushing a bulb of garlic releases the enzyme allinase, which converts alliin to allicin. Allicin is the main component of garlic s pungent, volatile oil. Garlic possesses hypolipidemic, hypotensive, antiplatelet, and antiinfective properties and may have antioxidant activity. Most research examining the effects of garlic has been conducted using tablets or capsules containing dehydrated, powdered garlic standardized to an allicin content of 1% to 1.6%, providing 3 to 5 mg of allicin per day. The World Health Organization recommends a dosage of 2 to 5 mg of allicin per day (the equivalent of 2 5 g fresh garlic, g dried garlic powder, 2 5 mg oil, or 300 1,000 mg extract). Although allicin is used as the primary standardization marker, other sulfurcontaining substances in garlic also may exert pharmacologic activity. Numerous studies of the hypocholesterolemic effects of garlic have yielded conflicting results. Positive findings generally have been modest, with the most rigorous studies showing reductions in total cholesterol of approximately 5% over the short term (similar to the reductions attainable with dietary changes alone). However, a recent parallel-design, placebo-controlled trial of three garlic preparations (i.e., fresh garlic, dried powdered garlic tablets, and aged garlic extract tablets) in adults with moderate hypercholesterolemia found no statistically or clinically significant effects on total cholesterol, lowdensity lipoprotein cholesterol, or other plasma lipid concentrations. Garlic also has been used to treat hypertension and type 2 diabetes. The clinical evidence for these uses is considered to be preliminary. Regular consumption of large amounts of raw or cooked (dietary) garlic may help to reduce the risk of developing several types of cancer, including gastric and colorectal cancer. No clinical trials have been performed using garlic supplements. Garlic supplements generally are well tolerated. Bad breath and body odor are the most common adverse effects; enteric-coated products may help to prevent or lessen bad breath. (So-called odorless products may contain insufficient amounts of allicin.) Other common gastrointestinal effects include nausea, vomiting, and heartburn, all of which are more likely at higher doses. Some patients may experience allergic reactions to garlic. Because garlic has antiplatelet and antithrombotic effects, bleeding is a potentially serious adverse effect of garlic use. Information about garlic, including drug interactions, is summarized in Table 8. Ginkgo Ginkgo dietary supplements are produced from the leaves of the Ginkgo biloba tree. The standardized, concentrated (50:1) leaf extract contains diterpene lactones such as ginkgolides (A, B, C, and M) and the sesquiterpene bilobalide, as well as bioflavonoids and flavone glycosides. Table 7. Fish Oil at a Glance Most Common Uses Dietary supplementation of essential omega-3 fatty acids Cardiovascular health Secondary prevention of coronary heart disease Treatment of hypertriglyceridemia Inflammatory conditions (e.g., rheumatoid arthritis) These compounds exhibit a complex pharmacologic profile that includes neuroprotective, antioxidant, and free radical scavenger effects. Ginkgolide B is a potent platelet-activating factor antagonist. Ginkgo is used commonly to treat dementia and to enhance memory. Data from a well-controlled, prospective study suggest that a patient s baseline cognitive state may influence the clinical response to ginkgo; patients with mild to moderate dementia showed actual improvement, whereas those with more severe disease showed stabilization or a diminished rate of deterioration. Another randomized, double-blind, placebo-controlled study comparing the efficacy of ginkgo with that of donepezil for the treatment of Alzheimer s dementia found they were equally effective. In contrast, a Cochrane review of randomized, placebo-controlled, double-blind trials examining the effects of ginkgo in patients with cognitive impairment and dementia (of any severity) concluded that the evidence for ginkgo s benefit was inconsistent and unconvincing. The authors noted that early trials used small populations and less rigorous methodology. Conflicting data continue to ap- Usual Dosages General good health: 200 mg to 2 g DHA + EPA daily Secondary prevention of cardiovascular disease: 1 g DHA + EPA daily Hypertriglyceridemia: 2 to 4 g DHA + EPA daily Rheumatoid arthritis: 2.5 g or more DHA + EPA daily Adverse Effects Generally well tolerated Adverse effects may include gastrointestinal upset, especially belching with a fishy aftertaste ( fish burps ) Selected Drug Interactions Possible additive effects if taken with anticoagulant and antiplatelet therapy Cautions Increased risk of bleeding with very high intake (e.g., more than 3 g of DHA plus EPA) DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid (EPA). OTC Advisor: Popular Herbal and Dietary Supplements 13

16 pear in the literature. One randomized, double-blind, placebo-controlled trial used a special standardized extract (EGb 761) to assess the effects of ginkgo in 400 patients 50 years of age or older with Alzheimer s disease or vascular dementia. EGb 761 proved to be superior to placebo on all outcome measures. A second randomized, double-blind, placebocontrolled clinical trial assessed cognitive function and quality of life in 90 healthy, cognitively intact persons 64 years of age or older. In this study, ginkgo was not superior to placebo. In the recently concluded Ginkgo Evaluation of Memory (GEM) Study, ginkgo 120 mg twice daily was no more effective than placebo in reducing the overall incidence rate of dementia, reducing the incidence of Alzheimer s disease, or preventing cognitive decline in more than 3,000 older adults with either normal cognition or mild cognitive impairment. There is strong evidence supporting the use of ginkgo for the treatment of intermittent claudication. Numerous studies suggest that ginkgo supplements cause small improvements in leg pain that occurs with exercise or at rest. However, ginkgo may not be as helpful as either exercise therapy or prescription medications. Ginkgo supplements generally are well tolerated. Mild gastrointestinal effects, headache, dizziness, and allergic skin reactions all have been reported. There may be a risk of seizure, particularly in patients with a seizure disorder. Although most reports of seizures have involved eating ginkgo seeds (as opposed to consuming the ginkgo leaf extract that is used in most products), the use of ginkgo is best avoided in patients with a history of seizures and patients who take medications that may lower the seizure threshold. Ginkgo use has been associated with bleeding, with case reports ranging from nose bleeds to life-threatening bleeds. Although standardized ginkgo is unlikely to cause bleeding, patients who take other platelet-active medications or dietary supplements (e.g., warfarin, garlic) should use ginkgo with caution. Use of ginkgo is not recommended during pregnancy and breastfeeding because of the lack of information about possible effects. The usual daily dosage of ginkgo is 80 to 240 mg of a 50:1 standardized leaf extract administered in two or three divided doses. Ginkgo preparations should be standardized to 24% ginkgo flavones glycosides and 6% terpenoids. Table 8. Garlic at a Glance Most Common Uses High cholesterol levels Hypertension Type 2 diabetes Table 9. Ginkgo at a Glance Most Common Uses Dementia Intermittent claudication Memory enhancement Information about ginkgo, including drug interactions, is summarized in Table 9. Ginseng The term ginseng applies to several species of the genus Panax. The two species used most commonly in dietary supplements are Panax ginseng (referred to as Asian ginseng, usually from Korea or China) Usual Dosages 0.4 to 1.2 g dried garlic powder daily (equivalent to 2 to 5 mg allicin per day) Adverse Effects Bad breath and body odor are common and expected Gastrointestinal adverse effects (nausea, vomiting, heartburn) more common at higher dosages Allergic reactions possible Selected Drug Interactions Warfarin: increased international normalized ratio in case reports Saquinavir: up to 50% decrease in serum levels, with possible reduction in efficacy Decreased effectiveness of oral contraceptives Possible alterations in serum levels of drugs metabolized through CYP3A4 and CYP2D6 Cautions May cause bleeding (including bleeding after surgery and spontaneous bleeding) Usual Dosages 80 to 240 mg of a 50:1 standardized leaf extract administered in two or three divided doses Adverse Effects Generally well tolerated Adverse effects may include mild gastrointestinal complaints, headache, dizziness, allergic skin reactions Selected Drug Interactions Platelet-active drugs: possible additive effect Trazodone: case report of coma in patient taking low-dose trazodone Avoid concurrent use in patients taking medications that may lower seizure threshold Potential additive effects with antihypertensive agents Cautions Avoid use in patients with a history of seizures Avoid using during pregnancy and breastfeeding 14 American Pharmacists Association

17 and Panax quinquefolia (referred to as American ginseng). The roots and rhizomes of Panax species are considered to be medicinally active. Ginseng is considered to be an adaptogen a substance that increases resistance to physical, chemical, and biological stress and has a normalizing effect on the body. The constituents believed to be responsible for adaptogen activity are ginsenosides, which are triterpenoid saponins. At least 30 ginsenosides have been identified; Asian and American ginseng contain different types and ratios of ginsenosides, which accounts in part for different physiologic effects. Additional constituents include carbohydrates, B vitamins, and flavonoids. The plant sometimes referred to as Siberian ginseng (Eleutherococcus senticosus) is distinct from true ginseng (Panax species) and is more accurately referred to as eleuthero. Although Siberian ginseng may be included in commercially available ginseng preparations, it does not contain ginsenosides and therefore does not offer benefits similar to Panax species. Asian ginseng is the best studied of the various Panax species. It has been investigated in a wide variety of conditions, often in combination with other botanicals; additional or higherquality studies are needed before clear conclusions can be reached for most uses. Currently, Asian ginseng is used primarily to enhance immune function and mental performance, to improve cardiovascular health and physical endurance, and to treat mental and physical stress. American ginseng is recommended most frequently to reduce postprandial glucose elevations and to reduce the severity of cold and upper respiratory infection symptoms. American ginseng contains more nonsaponin components (e.g., quinquefolans A, B, and C) than other Panax species do; there is speculation that these nonsaponin components, or different ginsenosides present in American ginseng, are responsible for hypoglycemic effects. Ginseng preparations generally are well tolerated. Possible adverse effects include insomnia, headache, blood pressure changes, anorexia, rash, mastalgia, and menstrual abnormalities. Large doses may cause gastric upset and central nervous system stimulation. Ginseng should be used with caution in patients with acute illness, cardiovascular disease, or diabetes. Because ginseng may have estrogen-like effects, its use generally should be avoided in patients with hormone-sensitive conditions (e.g., breast cancer, endometriosis). Ginseng has been used traditionally in pregnant and breastfeeding women. However, its use is not recommended because safety in humans has not been clearly established. Most studies of Asian ginseng have used dosages between 100 and 400 mg per day of extracts standardized to 4% ginsenosides. Some studies have used powdered root in doses of 0.5 to 9 g. Trials of American ginseng that demonstrated positive results in reducing postprandial glucose Table 10. Ginseng at a Glance Most Common Uses Immune system enhancement Improved mental and physical performance Increased sense of well-being and stamina Type 2 diabetes/glucose intolerance concentrations used doses of 1 to 3 g, 30 minutes before meals. Long-term dosing generally should not exceed 1 g of dry root per day. Some practitioners recommend discontinuing use of ginseng for 1 to 2 weeks after using it continuously for 2 to 3 weeks. Information about ginseng, including drug interactions, is summarized in Table 10. Kava Kava is derived from the roots and rhizomes of Piper methysticum, a member of the black pepper family. The pharmacologically active constituents are fat-soluble lactones referred to as kavalactones and kavapyrones. The mechanism of action includes interacting with dopaminergic transmission, inhibiting central monoamine oxidase-b, and modulating gammaaminobutyric acid-b receptors. Kava also may inhibit uptake of noradrenaline and have antithrombotic activity. Kava is used widely by Pacific Islanders as a social and ceremonial Usual Dosages Asian ginseng: 100 to 400 mg per day of extracts standardized to 4% ginsenosides American ginseng: 1 to 3 g, 30 minutes before meals Adverse Effects Generally well tolerated Adverse effects may include insomnia, headache, blood pressure changes, anorexia, rash, mastalgia, menstrual abnormalities Large doses may cause gastric upset and central nervous system stimulation Selected Drug Interactions Glucose-lowering medications: possible lowered blood glucose levels in type 2 diabetes Phenelzine: possible headache, tremor, and mania in case report Unpredictable effect on concurrent anticoagulant and antiplatelet therapy Possible interference with antipsychotics and immunosuppressants Possible inhibition of CYP2D6 (not clinically significant) Cautions Use with caution in patients with acute illness, cardiovascular disease, or diabetes Avoid use in patients with hormone sensitive conditions (e.g., breast cancer, endometriosis) because of possible estrogen-like effects Avoid use during pregnancy and breastfeeding Some practitioners recommend discontinuing use of ginseng for 1 to 2 weeks after using it continuously for 2 to 3 weeks OTC Advisor: Popular Herbal and Dietary Supplements 15

18 tranquilizing beverage. As a dietary supplement, kava is used most commonly to treat mild anxiety and sleep disturbances. A number of small studies have shown kava to be superior to placebo for the short-term treatment of anxiety; efficacy similar to benzodiazepines and buspirone has been reported. Until recently, kava was generally thought to be safe, with dizziness and drowsiness the most common adverse effects. But as of 2004, at least 78 cases of hepatotoxicity have been associated with kava ingestion; 4 are probably linked to kava and 23 are potentially linked. Some of these cases involved coadministration with other products with known hepatotoxic potential or consumption of large quantities of alcohol. In other cases, hepatotoxicity occurred in previously healthy patients who were taking no other medications and consuming minimal amounts of alcohol. In one case, symptoms of hepatitis resolved spontaneously after the patient stopped taking kava, then returned after rechallenge with kava. As a result of these reports, the safety of kava is controversial. Many natural medicine experts continue to believe that kava is safe at recommended doses. Conversely, several European nations have restricted the sale of kava products. Until the potential for hepatotoxicity with kava is characterized completely, pharmacists should discourage patients from using kava. Patients who insist on using kava should do so only with the knowledge and supervision of a health care provider; patients who have liver problems, take medications with known liver toxicity, or consume alcohol regularly should not use kava. Typical dosages of kava preparations range from 50 to 280 mg of kavalactones per day administered at bedtime. Many clinical trials used extracts standardized to 70% kavalactone content at a dosage of 100 mg two to three times daily. Because the kavalactone content of products varies, different dosages will be necessary for various products. Information about kava, including drug interactions, is summarized in Table 11. Melatonin Melatonin is an endogenous hormone synthesized from tryptophan via a serotonin pathway. It is produced in the brain by the pineal gland. Although its exact role has not been characterized fully, melatonin is known to play a critical role in regulating sleep and circadian rhythms. Melatonin release is induced by darkness and suppressed by light via a multisynaptic pathway that links the pineal gland and the retina. Melatonin has FDA orphan drug status for the treatment of sleep disorders in blind patients. As a dietary supplement, synthetic melatonin products are used primarily as a sleep aid and for the prevention and treatment of jet lag. When taken in doses of 0.3 to 5 mg, 30 minutes before bedtime, melatonin may make a patient s attempt to sleep more successful; it does not generally cause a feeling of drowsiness. The effects of melatonin on jet lag may result from more rapid adjustment of circadian rhythm after changing time zones. The recommended dosing regimen for jet lag is 2 to 5 mg on the day of arrival at the destination (between Table 11. Kava at a Glance Most Common Uses Anxiety Sleep disturbances Usual Dosages 50 to 280 mg of kavalactones per day administered at bedtime 5:00 pm and 10:00 pm local time), followed by 2 to 5 mg at bedtime for the next 2 to 5 days. Evidence for the efficacy of melatonin in the treatment of insomnia is not definitive. A number of studies have demonstrated clinical benefits, such as increases in rapid eye movement sleep, slightly faster sleep onset, increased duration of sleep, decreased daytime somnolence, and more normal patterns of time in sleep stages in healthy patients with insomnia and in women with asthma. A meta-analysis of 17 trials (n = 284) conducted primarily in healthy subjects and patients with insomnia supports the claim that melatonin has small but clinically significant benefits. Patients whose natural sleep patterns are disrupted for physical reasons (e.g., ill health) may derive the greatest benefit. There is some evidence that melatonin may be effective in healthy children 6 to 12 years of age with chronic sleep-onset insomnia. (Children should take melatonin only under the advice and supervision of a primary care provider.) The clinical evidence for the use of melatonin in preventing and treat- Adverse Effects May cause serious hepatotoxicity; use of kava is best avoided until more information is available Adverse effects may include dizziness and drowsiness Selected Drug Interactions Do not use concurrently with medications or other dietary supplements that may damage liver Levodopa: reduced efficacy of levodopa Possible increased sedative effect with alcohol and other central nervous system depressants Possible additive effects with other platelet-active medications or dietary supplements Possible additive effects with monoamine oxidase inhibitors Preliminary evidence suggests kava may inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A4 (significance unknown) Cautions Patients with liver problems and patients who consume alcohol regularly should not use kava Avoid use during pregnancy and breastfeeding 16 American Pharmacists Association

19 ing jet lag is more consistent than the evidence for insomnia. A Cochrane review concluded that melatonin can decrease jet lag in people crossing five or more time zones and has greater benefit for eastward travel than westward travel. Of note, melatonin does not appear to be effective for treatment of circadian rhythm disruption caused by shift work. Melatonin generally is well tolerated. Possible (albeit rare) adverse effects include nausea and vomiting, headache, tachycardia, irritability, dysthymia and worsening of depressive symptoms, and morning hangover effect. Long-term administration is appropriate only under the direct supervision of a primary care provider. Use of melatonin is not recommended during pregnancy and breastfeeding because of possible hormonal effects on the fetus. Information about melatonin, including drug interactions, is summarized in Table 12. Table 12. Melatonin at a Glance Most Common Uses Insomnia Prevention and treatment of jet lag Treatment of circadian rhythm disorders in blind patients a Phytoestrogens (Red Clover and Soy) A number of different plants including red clover (Trifolium pratense L.) and soy (Glycine max [L.] Merrill) contain compounds that are believed to have estrogen-like effects in the body. These compounds often are referred to as phytoestrogens. Phytoestrogens in soy include isoflavones such as genistein, daidzein, and glycitein. Phytoestrogens in red clover may include biochanin, genistein, daidzein, and formononetin. All of these compounds have multiple complex effects that also may encompass antiestrogenic, antioxidant, and anticancer activity. Dietary supplements containing red clover or soy are used primarily for managing vasomotor symptoms associated with menopause. The evidence supporting the use of supplements for this purpose is inconclusive. Studies involving soy have been limited by poor design, small sample size, or short duration; additionally, many studies have focused on dietary sources of soy rather than supplements. The ongoing Soy Phytoestrogens As Replacement Estrogen (SPARE) study is examining the efficacy of a purified soy isoflavone supplement (administered in tablet form) in preventing menopausal symptoms and spinal bone loss in the initial years of menopause. In a recent Cochrane review of 30 trials that investigated the use of phytoestrogens for vasomotor menopausal symptoms, only five trials were suitable for meta-analysis, and all used red clover extract. There was no significant difference in those trials in the frequency of hot flushes between red clover and placebo. Both soy and red clover are well tolerated. Possible adverse effects include gastrointestinal complaints, headaches, and allergic reactions. The long-term safety of phytoestrogens is not established, especially with respect of estrogen-dependent cancers and thromboembolic disease. Because the safety of phytoestrogen supplements in women with estrogen receptor positive breast cancer is unknown, these supplements should be avoided. Coumestans in red clover may increase the risk of bleeding, especially if warfarin and similar drugs are taken concomitantly. A recommended dose of phytoestrogens has not been established. Clinical studies of soy have examined 40 to 120 mg of soy isoflavones taken daily for up to 6 months. Clinical studies of red clover have used widely varying doses. Information about red clover and soy, including drug interactions, is summarized in Table 13. Probiotics Probiotics are nonpathogenic, living microorganisms that have a beneficial effect on the host when consumed in adequate amounts. Most probiotics are lactic acid producing bacteria, especially strains of Bifidobacterium or Lactobacillus species; the yeast Saccharomyces boulardii also is used widely. These microorganisms do not permanently colonize Usual Dosages Insomnia: 0.3 to 5 mg, 30 minutes before bedtime Jet lag: 2 to 5 mg in the evening on the day of arrival at the destination (between 5:00 pm and 10:00 pm local time), followed by 2 to 5 mg at bedtime for the next 2 to 5 days Adverse Effects Generally very well tolerated Adverse effects may include nausea and vomiting, headache, tachycardia, irritability, dysthymia and worsening of depressive symptoms, morning hangover effect Selected Drug Interactions Nifedipine: reduced delivery via the gastrointestinal therapeutic system (i.e., Procardia XL) Fluvoxamine, monoamine oxidase inhibitors, tricyclic depressants all may increase melatonin levels Benzodiazepines and sodium valproate may decrease nighttime melatonin levels Verapamil may decrease melatonin levels Caffeine, oral contraceptives have variable effects on melatonin levels Possible interaction with immunosuppressant drugs as a result of immunostimulating properties Cautions Avoid use during pregnancy and breastfeeding Long-term use and use in children should be supervised by a primary care provider a Approved by the U.S. Food and Drug Administration as an orphan drug for this indication. OTC Advisor: Popular Herbal and Dietary Supplements 17

20 the gastrointestinal tract beyond early infancy, so they must be consumed regularly to maintain their presence in the colon. When a sufficient number of these organisms are present, they appear to reduce colonization by pathogenic bacteria. The normalization of gut flora decreases inflammatory responses, but probiotics also have some immunomodulating activity. Macrophage and lymphocyte activity are both affected, as are various cytokines, such as increased interferon-alfa and immunoglobulin and decreased tumor necrosis factor. Probiotics also stabilize the intestinal barrier function by reducing intestinal permeability. Probiotics differ from prebiotics, which are nondigestible food components that stimulate the growth or activity of the beneficial microorganisms already in the colon. Inulin-type fructans, including their partial hydrolysis product fructose oligosaccharides, are the most common prebiotics; they are found in many edible plants (e.g., asparagus, bananas, chicory, Jerusalem artichoke, leek, onion, soy, wheat) and may be added to other foods as a source of fiber. Products that contain both probiotics and prebiotics are known as synbiotics. The proposed health benefits of probiotics have undergone increasingly rigorous scientific evaluation in recent years, to the point that there are well-established benefits in a growing number of conditions (primarily gastrointestinal conditions such as constipation, diarrhea, inflammatory bowel disease, and irritable bowel syndrome). Probiotics also show promise for the prevention and treatment of atopic dermatitis in children, as well as for the treatment of allergic disorders in adults. It is important to note that the effects of probiotics are specific to individual strains. Effects also may vary in healthy patients versus those with a disease, in different disease states, and in different age groups. Thus, the results of clinical trials that use a certain probiotic strain in a certain population should not be generalized to other strains or other populations. Pharmacists should consult published studies, as well as emerging meta-analyses, to determine the particular strains and doses used. Caution is urged when considering individual studies; many have inadequate specification of the microorganisms, variable preparations, small patient populations, and imprecise endpoints. Probiotics generally are well tolerated. Gastrointestinal effects such as gas and bloating are common and subside as therapy continues. There are a few reports of fungemia caused by S. boulardii and bacteremia and endocarditis caused by lactobacilli. Although all of these cases had complicating factors, it is prudent for patients who are immunocompromised to avoid the use of probiotic preparations. Probiotics are available in foods and as dietary supplements. The major food source of probiotic bacteria is dairy foods. Most major brands of yogurt contain probiotic bacteria, although viable cultures are not required for yogurt in the United States and labels do not list the number of viable probiotic organisms. The Live & Active Cultures seal of the National Yogurt Association is allowed on products containing 10 8 viable organisms per gram at the time of manufacture. Unfortunately, the value of the seal is limited because starter cultures for acid production are not distinguished from probiotic bacteria. Liquid yogurt drinks (kefir) and cultured fluid milk, such as sweet acidophilus milk and buttermilk, can contain variable amounts of viable organisms; however, most provide adequate amounts (10 8 viable organisms per gram), usually in the form of Lactobacilllus acidophilus and Bifidobacterium species. A few brands of cottage cheese contain active cultures, but most do not. Other foods containing probiotics include brined olives, kimchi (Korean form of fermented cabbage), miso, sauerkraut, tempeh, and some juices and soy beverages. Various probiotic supplements are available, containing one or multiple species; some examples are provided in Table 14. Because probiotic microorganisms should be live, the quality of probiotic products is essential. Ideally, products should list the genus, species, and strain of the probiotics they contain. They also should clearly state the number of colony-forming units (i.e., live microbes) provided in each serving. Table 13. Phytoestrogens (Red Clover and Soy) at a Glance Most Common Uses Menopausal symptoms Usual Dosages Varies according to intended therapeutic use, specific product composition Clinical studies of red clover have employed a wide range of doses Clinical studies of soy have examined 40 to 120 mg of soy isoflavones taken daily for up to 6 months Adverse Effects Generally well tolerated Adverse effects may include gastrointestinal complaints, headache, allergic reactions Selected Drug Interactions Possible increased risk of bleeding in patients taking warfarin with red clover products Genistein (an isoflavone found in red clover and soy products) may counteract the beneficial effect of tamoxifen in slowing breast cancer growth Daidzein (an isoflavone found in red clover and soy products) may inhibit the activity of CYP1A2 Cautions Women with estrogen receptor positive breast cancer should not use supplements containing phytoestrogens Avoid use during pregnancy and breastfeeding because of possible hormonal effects Long-term safety of phytoestrogens has not been established 18 American Pharmacists Association

21 The optimum dose for a given probiotic is not known. Usual doses of S. boulardii are 250 to 500 mg two to four times daily. Doses of Lactobacillus and Bifidobacteria vary by product, with most recommended dosages ranging from 1 billion to 10 billion colony-forming units per day. St. John s Wort St. John s wort is derived from the flowers and leaves of Hypericum perforatum, a perennial plant that grows wild throughout Europe, Asia, North America, and South America. Potentially biologically active constituents include hyperforin, hypericin, flavonoids, tannins, volatile oils, and phenols. St. John s wort may modulate serotonin, dopamine, and norepinephrine; it also may act as an antagonist at various neuroreceptors. St. John s wort is used most commonly for the treatment of mild to Case 1. Drug-Dietary Supplement Interactions HW, a 36-year-old woman, visits her primary care provider with a chief complaint of anxiety. The primary care provider decides to initiate therapy with buspirone 7.5 mg twice daily. The prescribing information states that buspirone is metabolized primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). The patient reports current use of garlic, ginseng, and St. John s wort. Which of these products would be least likely to interfere with buspirone therapy? a. Garlic. b. Ginseng. c. St. John s wort. Case study responses appear on page 26. moderate depression. It also sometimes is used to treat pain, anxiety, obsessive-compulsive disorder, and premenstrual syndrome. A growing body of evidence supports the efficacy of St. John s wort for mild to moderate depression. Some short-term studies (12 weeks or less) have found the benefits of St. John s wort to be comparable to those of standard antidepressants (e.g., fluoxetine, sertraline, citalopram). However, because St. John s wort has the potential to interact with Table 14. Examples of Probiotic Supplements Product Name (Manufacturer) Contents (Trade Name) Amount AccuFlora (Northwest Natural Products Inc.) Bifidobacterium bifidum Lactobacillus acidophilus Lactobacillus rhamnosus Lactobacillus salivarius Streptococcus thermophilus 500 million CFU per capsule Align (Procter & Gamble) Bifidobacterium infantis (Bifantis) 1 billion CFU per capsule Culturelle (Amerifit Brands Inc.) Lactobacillus rhamnosus GG (LGG) 10 billion CFU per capsule Florastor (Biocodex Inc.) Saccharomyces boulardii lyophilized 5 billion CFU per capsule Pearls IC (Enzymatic Therapy) Bifidobacterium breve 1 billion CFU per capsule Bifidobacterium bifidum Bifidobacterium lactis Bifidobacterium longum Lactobacillus acidophilus Lactobacillus rhamnosus Sustenex (Ganeden Biotech Inc.) Bacillus coagulans GBI-30, 6086 (GanedenBC 30 ) 2 billion CFU per capsule VSL#3 (VSL Pharmaceuticals Inc.) Bifidobacterium breve Bifidobacterium infantis Bifidobacterium longum Lactobacillus acidophilus Lactobacillus bulgaricus Lactobacillus paracasei Lactobacillus plantarum Streptococcus thermophilus 225 billion CFU per 2 capsules 450 billion CFU per packet a a Powder in individual packet should be mixed with at least 4 ounces of cold water and consumed immediately. CFU = colony-forming units. OTC Advisor: Popular Herbal and Dietary Supplements 19

22 a large number of drugs, it is not an appropriate choice for many patients. An analysis of randomized trials found rates of adverse effects in patients taking St. John s wort similar to those in patients taking placebo, much lower than those in patients taking older antidepressants, and slightly lower than those in patients taking selective serotonin receptor inhibitors. Paresthesias, headache, nausea, dry mouth, agitation, and skin reactions have been reported most commonly. The use of St. John s wort should be avoided in patients with bipolar disorder and schizophrenia. Photosensitivity reactions have been reported, although there also is evidence indicating no effect. Until these results are sorted out, people who take St. John s wort should limit their exposure to sun and apply sunscreen. Abrupt discontinuation of St. John s wort after chronic use may result in withdrawal symptoms similar to those seen when withdrawing conventional antidepressants. Use of St. John s wort is not recommended during pregnancy and breastfeeding because of the lack of information about possible effects. Unlike many herb-drug interactions discussed in this monograph, interactions with St. John s wort are well documented and clinically significant. St. John s wort contains many compounds that influence activities of major human drug-metabolizing enzymes, resulting in multiple pharmacokinetic interactions. The specific enzymes, the degree of influence of hypericin versus hyperforin, and in vitro analysis versus clinical outcomes are still being studied. St. John s wort is a potent inducer of CYP3A4, resulting in significantly lower concentrations of drugs metabolized through this pathway, including amitriptyline, benzodiazepines, methadone, oral contraceptives, protease inhibitors, simvastatin, and warfarin. St. John s wort induces CYP1A2 and CYP2C9 to a lesser extent and may induce P-glycoprotein transport proteins, resulting in lower serum concentrations of drugs such as digoxin and fexofenadine. Many drug interactions are based on extrapolating across drug class or metabolic pathway. Patients taking other serotonergic drugs or natural products should avoid the use of St. John s wort because it may induce serotonin syndrome. The recommended dosage of St. John s wort for adults with mild to moderate depression is 300 to 900 mg (standardized at 0.3% hypericin or 5% hyperforin) three times daily with meals. Because the content of hypericin and hyperforin varies in commercial preparations, products may not be interchangeable. As with conventional antidepressants, the therapeutic effects of St. John s wort may not be evident for 3 to 4 weeks. Information about St. John s wort is summarized in Table 15. Saw Palmetto Saw palmetto (Serenoa repens) is a dwarf palm tree native to the southeast coastal region of the United States. The lipophilic extracts from the ripened fruit contain saturated and unsaturated fatty acids and plant sterols, which are believed to be the source of the biologically active components. Saw palmetto inhibits 5-alpha-reductase and cytosolic androgen receptor binding. It has local antiestrogenic and anti-inflammatory effects on the prostate. Saw palmetto is used primarily to treat urinary symptoms associated with benign prostatic hyperplasia. Table 15. St. John s Wort at a Glance Most Common Uses Treatment of mild to moderate depression It does not alter prostate volume or prostate-specific antigen levels. Men who have prostate symptoms should consult with a primary care provider before self-treating with saw palmetto to rule out prostate cancer. A number of clinical trials have reported that saw palmetto improves symptoms of benign prostatic hyperplasia, including nocturia, urinary flow, and overall quality of life. In some studies, the efficacy of saw palmetto was similar to that of finasteride. However, an updated Cochrane review that incorporated data from nine recent trials involving 2,053 additional men concluded that saw palmetto is no more effective than placebo. Saw palmetto generally is well tolerated. Gastrointestinal complaints are the most commonly reported adverse effects; stomach upset may be reduced by taking doses with food. There has been one case report of a man who had intraoperative hemorrhage during surgery; although causality has not been established, saw palmetto should be used with caution in patients taking any medication or dietary supplement that might prolong bleeding. Patients who already take androgenic medications should avoid using saw palmetto. Saw palmetto is included in some Usual Dosages 300 to 900 mg (standardized at 0.3% hypericin or 5% hyperforin) three times daily with meals Adverse Effects Generally well tolerated Adverse effects include paresthesias, headache, nausea, dry mouth, agitation, skin reactions Photosensitivity possible; advise patients to avoid sun exposure and use sunscreen Selected Drug Interactions Potent inducer of CYP3A4 and mild inducer of CYP1A2 and CYP2C9; use caution when medications metabolized by these enzymes are administered concurrently Possible increased risk of serotonin syndrome if taken with serotonergic medications Cautions Abrupt discontinuation after chronic use may precipitate withdrawal symptoms Avoid use in patients with bipolar disorder and schizophrenia Avoid use during pregnancy or breastfeeding 20 American Pharmacists Association

23 products intended for use by women. Because saw palmetto inhibits 5-alpha-reductase, its use is contraindicated during pregnancy and breastfeeding. The usual dosage of saw palmetto is 160 mg twice daily or 320 mg once daily. Products should contain 80% to 95% standardized fatty acids. Information about saw palmetto, including drug interactions, is summarized in Table 16. Summary Herbal products and other dietary supplements are used widely in the United States. Many consumers are unaware of important differences between the way medications and dietary supplements are regulated; as a result, they may take unintended risks with products that seem natural and benign. Pharmacists can help to ensure safe and effective use of these popular therapies by engaging patients in discussions about dietary supplements and providing evidence-based recommendations. Table 16. Saw Palmetto at a Glance Most Common Uses Treatment of urinary symptoms associated with benign prostatic hyperplasia Usual Dosages 160 mg twice daily or 320 mg once daily; products should contain 80% to 95% standardized fatty acids Adverse Effects Generally well tolerated Gastrointestinal complaints most common Selected Drug Interactions Potential interaction with hormonal or antihormonal therapies Possible additive effects when used with antiplatelet or anticoagulant agents Cautions Men who have prostate symptoms should consult with a primary care provider to rule out prostate cancer Use contraindicated during pregnancy and breastfeeding Case 2. Saw Palmetto LA, a 65-year-old man, was diagnosed recently with benign prostatic hyperplasia. He is interested in using an herbal product to help alleviate his symptoms (increased frequency of urination, nocturia, and reduced urinary flow). LA is aware of some prescription medications for benign prostatic hyperplasia, but really would prefer something natural so that he doesn t have to worry about side effects. His friend recommended that he check out saw palmetto. LA asks your opinion about using saw palmetto instead of a prescription medication. A review of LA s medication history shows current use of metoprolol 50 mg twice daily, hydrochlorothiazide 25 mg daily, simvastatin 40 mg at bedtime, and aspirin 81 mg daily. He reports having suffered a mild heart attack 2 years previously. Based on his medical history and profile, is the patient an appropriate candidate for a trial of therapy with saw palmetto? a. Yes. b. No. If the patient were to begin using saw palmetto, which of the following points should be conveyed when educating him about proper use of the selected product? a. He should take each dose with food or milk if stomach upset occurs. b. He should discontinue use of the product immediately if symptoms of jaundice, such as dark urine or yellowing of the eyes, occur. c. He should discontinue use of the product immediately if he detects an increase in blood pressure. d. All of the above. Case study responses appear on page 26. OTC Advisor: Popular Herbal and Dietary Supplements 21

24 References The following chapters in the Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care served as the primary sources of information for this monograph. McQueen CE, Orr KK. Natural products. In: Berardi RR, Ferreri SP, Hume AL, et al., eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. 16th ed. Washington, DC: American Pharmacists Association; 2009: Rollins CJ. Functional and meal replacement foods. In: Berardi RR, Ferreri SP, Hume AL, et al., eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self- Care. 16th ed. Washington, DC: American Pharmacists Association; 2009: Tsourounis C, Dennehy C. Introduction to dietary supplements. In: Berardi RR, Ferreri SP, Hume AL, et al., eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. 16th ed. Washington, DC: American Pharmacists Association; 2009: Additional primary sources of information for this monograph are listed below. 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Clin Cardiol. 2004;27: Ho MJ, Bellusci A, Wright JM. Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Syst Rev. 2009;(4):CD Khatta M, Alexander BS, Krichten CM, et al. The effect of coenzyme Q10 in patients with congestive heart failure. Ann Intern Med. 2000;132: Weant KA, Smith KM. The role of coenzyme Q10 in heart failure. Ann Pharmacother. 2005;39: Echinacea Linde K, Barrett B, Wolkart K, et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2006;(2):CD Shah SA, Sander S, White CM, et al. Evaluation of echinacea for the prevention and treatment of the common cold: a metaanalysis. Lancet Infect Dis. 2007;7: Turner RB, Bauer R, Woelkart K, et al. An evaluation of Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med. 2005;353: Evening Primrose Oil Budeiri D, Li Wan Po A, Dornan JC. Is evening primrose oil of value in the treatment of premenstrual syndrome? 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Circulation. 2002;106: McKenney JM, Sica D. Role of prescription omega-3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy. 2007;27: Wang C, Harris WS, Chung M, et al. n 3 Fatty acids from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006;84:5 17. Garlic Gardner CD, Lawson LD, Block E, et al. Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: a randomized clinical trial. Arch Intern Med. 2007;167: Garlic: Effects on Cardiovascular Risks and Disease, Protective Effects Against Cancer, and Clinical Adverse Effects. Summary, Evidence Report/Technology Assessment: Number 20. Rockville, MD: Agency for Healthcare Research and Quality; October AHRQ publication 01-E022. Available at: epcsums/garlicsum.htm. 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26 Ginkgo Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2007;(2):CD DeKosky ST, Williamson JD, Fitzpatrick AL, et al.; Ginkgo Evaluation of Memory (GEM) Study Investigators. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300: Hilton M, Stuart E. Ginkgo biloba for tinnitus. Cochrane Database Syst Rev. 2004;(2):CD Jacoby D, Mohler ER 3rd. Drug treatment of intermittent claudication. Drugs. 2004; 64: Le Bars PL, Velasco FM, Ferguson JM, et al. Influence of the severity of cognitive impairment on the effect of the Ginkgo biloba extract EGb 761 in Alzheimer s disease. Neuropsychobiology. 2002;45: Mazza M, Capuano A, Bria P, et al. Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer s dementia in a randomized placebo-controlled double-blind study. Eur J Neurol. 2006;13: Napryeyenko O, Borzenko I. Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trial. Arzneimittelforschung. 2007;57:4 11. Snitz BE, O Meara ES, Carlson MC, et al.; Ginkgo Evaluation of Memory (GEM) Study Investigators. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA. 2009;302: Ginseng Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf. 2002;25: Kiefer D, Pantuso T. Panax ginseng. Am Fam Physician. 2003;68: Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng. A systematic review of randomised clinical trials. Eur J Clin Pharmacol. 1999; 55: Kava Centers for Disease Control and Prevention. Hepatic toxicity possibly associated with kava-containing products United States, Germany, and Switzerland, MMWR Morb Mortal Wkly Rep. 2002; 51: Clouatre DL. Kava kava: examining new reports of toxicity. Toxicol Lett. 2004;150: Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev. 2003;(1):CD Melatonin Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev. 2005;9: Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD Phytoestrogens Lethaby AE, Brown J, Marjoribanks J, et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007;(4):CD Levis S, Strickman-Stein N, Doerge DR, et al. Design and baseline characteristics of the Soy Phytoestrogens As Replacement Estrogen (SPARE) study: a clinical trial of the effects of soy isoflavones in menopausal women. Contemp Clin Trials. March 15, [Epub ahead of print] Low Dog T. Menopause: a review of botanical dietary supplements. Am J Med. 2005;118(suppl 12B): Probiotics Boyle RJ, Robins-Browne RM, Tang MLK. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006;83: Floch MH, Madsen KK, Jenkins DJA, et al. Recommendations for probiotic use. J Clin Gastroenterol. 2006;40: Huffnagle GB, Wernick S. The Probiotics Revolution. New York, NY: Bantam Books; International Scientific Association for Probiotics and Prebiotics. Probiotics: A Consumer Guide for Making Smart Choices. March 11, Available at: Accessed April 3, Walker R, Buckley M. Probiotic Microbes: The Scientific Basis. Report of an American Society for Microbiology colloquium; November 5 7, 2005; Baltimore, MD. Available at: index.php?option=com_content&view= article&id=233:probiotic-microbes-thescientific-basis-june-2006&catid=40:browseall&itemid=79. Accessed April 6, Williams NT. Probiotics. Am J Health Syst Pharm. 2010;67: St. John s Wort Knuppel L, Linde K. Adverse effects of St. John s wort: a systematic review. J Clin Psychiatry. 2004;65: Linde K, Berner MM, Kriston L, et al. St. John s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33: Epub November 12, Saw Palmetto Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med. 2006;354: Tacklind J, MacDonald R, Rutks I, et al. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2009;(2):CD Willetts KE, Clements MS, Champion S, et al. Serenoa repens extract for benign prostate hyperplasia: a randomized controlled trial. BJU Int. 2003;92: American Pharmacists Association

27 Case Study Responses Case 1. Drug-Dietary Supplement Interactions The patient reports current use of garlic, ginseng, and St. John s wort. Which of these products would be least likely to interfere with buspirone therapy? a. Garlic. Incorrect. Garlic may induce CYP3A4 and thus could increase the rate of buspirone metabolism. b. Ginseng. Correct. Ginseng is not known to interact with buspirone. c. St. John s wort. Incorrect. St. John s wort is a potent inducer of CYP3A4 and thus would be likely to increase the rate of buspirone metabolism. Case 2. Saw Palmetto Based on his medical history and profile, is the patient an appropriate candidate for a trial of therapy with saw palmetto? a. Yes. Correct. The patient has no obvious contraindications to the use of saw palmetto. b. No. Incorrect. The patient has no obvious contraindications to the use of saw palmetto. If the patient were to begin using saw palmetto, which of the following points should be conveyed when educating him about proper use of the selected product? a. He should take each dose with food or milk if stomach upset occurs. Correct. Gastrointestinal complaints, including stomach upset, are the most common adverse effects of saw palmetto and can be minimized by taking doses with food. b. He should discontinue use of the product immediately if symptoms of jaundice, such as dark urine or yellowing of the eyes, occur. Incorrect. Saw palmetto is not associated with hepatotoxicity. c. He should discontinue use of the product immediately if he detects an increase in blood pressure. Incorrect. Saw palmetto is not known to increase blood pressure. d. All of the above. Incorrect. OTC Advisor: Popular Herbal and Dietary Supplements 25

28 CPE Exam Instructions: The assessment questions printed below allow you to preview the online CPE exam. Please review all of your answers to be sure you have marked the proper letter on the online CPE exam. There is only one correct answer to each question. 1. Under the Dietary Supplement Health and Education Act of 1994, dietary supplements are regulated as: a. Food. b. Medical devices. c. Nonprescription medications. d. Prescription medications. 2. The Dietary Supplement Health and Education Act states that the FDA: a. Must evaluate the safety of dietary supplements prior to marketing. b. Must regularly inspect manufacturing facilities of dietary supplements to ensure compliance with Good Manufacturing Practices. c. Can remove a dietary supplement from the market only after the product has been proven to be unsafe. d. All of the above. 3. Of the following quality assurance programs for dietary supplements, which certifies a company s manufacturing practices rather than specific dietary supplements? a. ConsumerLab.com Approved Quality Product Seal. b. Natural Products Association GMP Certification Program. c. NSF International Dietary Supplements Certification Program. d. USP Dietary Supplement Verification Program. 4. The Current Good Manufacturing Practices final rule for dietary supplements should help to do all of the following except: a. Ensure that products are not contaminated with harmful substances. b. Ensure that products contain the stated amount of an ingredient. c. Ensure that the active ingredients in products are safe and effective. d. Reduce the number of misbranded products. 5. Which of the following claims is not permitted on a dietary supplement label? a. Efficacy for treating a specific disease. b. Nutrient content of the product. c. The relationship between a dietary ingredient and a disease or health-related condition. d. Structure/function claims related to health maintenance. 6. Which of the following pieces of legislation requires manufacturers of dietary supplements to report serious adverse events to the FDA? a. Dietary Supplement Health and Education Act. b. Dietary Supplement and Nonprescription Drug Consumer Protection Act. c. Federal Food, Drug, and Cosmetic Act. d. Adverse event report is not mandatory for dietary supplements. 7. Which of the following dietary supplements has orphan drug status for the treatment of Huntington s disease? a. Coenzyme Q 10. b. Echinacea. c. Garlic. d. Ginkgo. 8. Which of the following dietary supplements is identified in this monograph as being well documented for having the potential to interact with a large number of drugs, thereby rendering it an inappropriate choice for many patients? a. Evening primrose oil. b. Garlic. c. Kava. d. St. John s wort. 9. Which of the following statements about homeopathy and homeopathic medications is true? a. A guiding principle of homeopathy states that substances become more potent as they become more dilute. b. All homeopathic medications are available on a nonprescription basis. c. Homeopathic medications are subject to the provisions of the Dietary Supplement Health and Education Act. d. All of the above. 10. Black cohosh is used most commonly to treat which of the following conditions? a. Heart failure. b. Insomnia. c. Mastalgia. d. Menopausal symptoms. 26 American Pharmacists Association