30678 Federal Register / Vol

30678 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

DEPARTMENT OF HEALTH AND agency’s investigations and analyses of the United States (Refs. 1 through 3). HUMAN SERVICES these illnesses and injuries. FDA is also The ingredient sources of the ephedrine incorporating by reference its alkaloids include raw botanicals and Food and Drug Administration Laboratory Information Bulletin (LIB) extracts from botanical sources. Ma No. 4053, that FDA will use in huang, Ephedra, Chinese Ephedra, and 21 CFR Part 111 determining the level of ephedrine epitonin are several names used for [Docket No. 95N±0304] alkaloids in a dietary supplement. botanical products, primarily from DATES: Written comments by August 18, Ephedra sinica Stapf, E. equistestina RIN 0901±AA59 1997. The agency proposes that any Bunge, E. intermedia var. tibetica Stapf Dietary Supplements Containing final rule that may issue based on this and E. distachya L. (the Ephedras), that Ephedrine Alkaloids proposal become effective 180 days after are sources of ephedrine alkaloids. date of publication of the final rule. These alkaloids, ephedrine, AGENCY: Food and Drug Administration, ADDRESSES: Submit written requests for pseudoephedrine, norpseudoephedrine, HHS. single copies of the analytical method norephedrine, methylephedrine, ACTION: Proposed rule. LIB No. 4053 to the Director, Office of methylpseudoephedrine, and related Constituent Operations, Industry alkaloids, are naturally occurring SUMMARY: The Food and Drug Activities Staff (HFS–565), Food and chemical stimulants (Refs. 4 through 8). Administration (FDA) is proposing to Drug Administration, 200 C St. SW., rm. Although the proportions of the various make a finding, which will have the 5827, Washington, DC 20204. Send two ephedrine alkaloids in botanical species force and effect of law, that a dietary self-addressed adhesive labels to assist vary from one species to another, in supplement is adulterated if it contains that office in processing your requests. most species used commercially, 8 milligrams (mg) or more of ephedrine Submit written comments to the ephedrine is the most predominant alkaloids per serving, or if its labeling Dockets Management Branch (HFA– alkaloid. suggests or recommends conditions of 305), Food and Drug Administration, The ephedrine and related alkaloids use that would result in intake of 8 mg 12410 Parklawn Dr., rm. 1–23, are amphetamine-like compounds. They or more in a 6-hour period or a total Rockville, MD 20857. Requests and exhibit some common types of effects daily intake of 24 mg or more of comments should be identified with the but vary in the relative intensity of these ephedrine alkaloids; require that the docket number found in brackets in the effects (Table 1) (Refs. 5, 6, and 9 label of dietary supplements that heading of this document. A copy of the through 15). For example, ephedrine is contain ephedrine alkaloids state ‘‘Do analytical method LIB No. 4053, a cardiovascular system (CVS) and not use this product for more than 7 redacted adverse event reports (AER’s) days’’; prohibit the use of ephedrine associated with the use of dietary nervous system (NS) stimulant. alkaloids with ingredients, or with supplements containing ephedrine Pseudoephedrine has some CVS and NS ingredients that contain substances, that alkaloids as well as copies of any stimulatory effects but is less potent have a known stimulant effect (e.g., accompanying medical records, and than ephedrine. Norephedrine (also sources of caffeine or yohimbine), received comments are available for called phenylpropanolamine) is similar which may interact with ephedrine public examination in the Dockets to ephedrine in its NS stimulant effects alkaloids; prohibit labeling claims that Management Branch between 9 a.m. and but has fewer CVS stimulant effects than require long-term intake to achieve the 4 p.m., Monday through Friday. ephedrine (Refs. 12 and 16 through 18). Although norephedrine is often a minor purported effect (e.g., weight loss and FOR FURTHER INFORMATION CONTACT: ephedrine alkaloid constituent, in body building); require a statement in Margaret C. Binzer, Center for Food humans it can be produced from conjunction with claims that encourage Safety and Applied Nutrition (HFS– ingested ephedrine through normal short-term excessive intake to enhance 456), Food and Drug Administration, the purported effect (e.g., energy) that 200 C St. SW., Washington, DC 20204, metabolic processes (Refs. 9, 19, and ‘‘Taking more than the recommended 202–401–9859, FAX 202–260–8957, or 20). Thus, its presence in body tissues serving may result in heart attack, E-mail [email protected]. and fluids may be detected, and its stroke, seizure or death’’; and require physiological effects can occur, even if specific warning statements to appear SUPPLEMENTARY INFORMATION: norephedrine is not contained in on product labels. FDA is proposing I. Background meaningful amounts in the original these actions in response to serious supplement product. Data on the other illnesses and injuries, including A. Characteristics of Ephedrine ephedrine alkaloids and related multiple deaths, associated with the use Alkaloids alkaloids are limited, and thus their of dietary supplement products that Dietary supplements containing physiological and pharmacological contain ephedrine alkaloids and the ephedrine alkaloids are widely sold in effects are largely unknown (Ref. 15).

TABLE 1.ÐPATTERNS OF SIGNS AND SYMPTOMS ASSOCIATED WITH DIETARY SUPPLEMENTS CONTAINING EPHEDRINE ALKALOIDS

Organ/system involved Clinical significance Signs and symptoms

Cardiovascular system ...... Serious ...... Dysrhythmias, severe hypertension, cardiac arrest, angina, myocardial infarction, and stroke 1 Less clinically significant .... Tachycardia, mild hypertension, palpitations. Nervous system ...... Serious ...... Psychosis, suicidal, altered or loss of consciousness (including disorientation or confusion), and seizures. Less clinically significant .... Anxiety, nervousness, tremor, hyperactivity, insomnia, altered behavior, memory changes. Gastrointestinal (GI) ...... Serious ...... Altered serum enzymes, hepatitis. Less clinically significant .... GI distress (nausea, vomiting, diarrhea, constipation). Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30679

TABLE 1.ÐPATTERNS OF SIGNS AND SYMPTOMS ASSOCIATED WITH DIETARY SUPPLEMENTS CONTAINING EPHEDRINE ALKALOIDSÐContinued

Organ/system involved Clinical significance Signs and symptoms

Dermatologic ...... Serious ...... Exfoliative dermatitis. Less clinically significant .... Nonspecific rashes. General manifestations ...... Numbness, tingling, dizziness, fatigue, lethargy, weakness. 1 For the purposes of this document, strokes (i.e., cerebrovascular accidents) are considered to be related to the cardiovascular system, because predisposing or inciting factors include hypertension, dysrhythmias and ischemia, although it is recognized that the consequences affect the central nervous system.

B. The Availability of Ephedrine 25). Results of the analyses show that The AER’s associated with the Alkaloids these products, taking into account the ephedrine alkaloid-containing products To determine the types of ephedrine labeled recommended serving included consistent patterns of signs alkaloid-containing dietary supplements instructions, are likely to provide and symptoms among both otherwise available in the marketplace, the agency intakes of ephedrine alkaloids that range healthy individuals and those with has collected over 125 dietary from below the detectible limits of underlying diseases or conditions. supplement products labeled as FDA’s analytical method to 110 mg per These signs and symptoms included containing a known source of ephedrine serving (i.e., per single use) (Refs. 1, 2, rapid and irregular heart rhythms, alkaloids during the past 2 years (Refs. 21, 25, and 26). Most of the products, increased blood pressure, chest pain, 1 and 2). These products show that regardless of their promoted use, had anxiety, nervousness, tremor, ephedrine alkaloid-containing-dietary ephedrine alkaloid levels at or above 10 hyperactivity, and insomnia (i.e., supplements are marketed in a variety mg per serving. inability or difficulty in sleeping) and of forms, including capsules, tablets, Many of the dietary supplement were associated with clinically powders, and liquids. The source of the products that FDA collected were significant conditions, including heart ephedrine alkaloids in these promoted for uses such as weight loss, attack, stroke, psychoses, seizure, and, supplements vary from the raw body building, increased energy, in a few cases, death. Many of these botanical to powdered plant material increased mental concentration, signs and symptoms occurred in young and concentrated extracts; however, increased sexual sensations, or euphoria adults who generally would not have most of the products contain or as alternatives to illicit street drugs been expected to be at high risk for such concentrated extracts. Although FDA is (Refs. 1, 2, and 25). The majority of the conditions (e.g., heart attack and stroke). aware that some companies have products collected also bore warning Many adverse events were reported to changed their labeling and formulation statements on their labels (Refs. 1, 2, occur with the first use or within the since the market review, this review of and 27). The warning statements varied first 2 weeks of use. Although the the marketplace reflects the general from general precautions, suggesting majority occurred in women, men also contours of products currently sold in that the consumer check with a health reported experiencing adverse events. the United States. care professional before beginning any The nature and patterns of these Ephedrine alkaloids are present in diet or exercise program, to more AER’s are consistent with the known some products as a single ingredient, specific warning statements. The more physiological and pharmacological but more commonly, they are combined specific warning statements contained effects of ephedrine alkaloids as with other ingredients, including several elements, including cautions described in: (1) Pharmacology texts for vitamins, minerals, amino acids, and that the consumer not use the product single ephedrine alkaloid products, (2) other botanicals (Refs. 1, 2, and 21). if they have certain diseases or health case reports of adverse effects from the Most of the dietary supplements that conditions or are using certain drugs, scientific literature related to the contain an ingredient source of the and to stop the use of the product if they pharmaceutical use of ephedrine ephedrine alkaloids also contain develop certain symptoms (Refs. 1, 2, alkaloids, (3) adverse events reported in between 6 and 20 other ingredients. Some of these other ingredients have 25, and 27). controlled clinical trials using known or suspected physiological and ephedrine in the treatment of obesity, C. Adverse Events Associated With and (4) known safety concerns with pharmacological activities that have the Ephedrine Alkaloids potential for interacting with the traditional medical uses of botanicals ephedrine alkaloids so as to increase Since 1993, FDA has received more that contain ephedrine alkaloids. As a their effects. For example, the majority than 800 reports of illnesses and injuries result, FDA focused its investigation on of dietary supplements containing (AER’s) associated with the use of more ephedrine alkaloids as a likely factor in ephedrine alkaloids also contain a than 100 different dietary supplement the rapidly increasing number of serious source of xanthine alkaloids (e.g., products that contained, or were AER’s associated with the use of dietary caffeine), another stimulant substance suspected to contain, ephedrine supplement products. that is known to increase the effects of alkaloids. These adverse events tended D. Review Activities ephedrine alkaloids (Refs. 7, 16, 22, and to involve CVS effects and NS effects. 23). FDA evaluated the AER’s showing CVS The growing number and consistency Because product labels do not usually and NS effects and found that the single of reports of serious adverse events provide information on product most common element was that the associated with a wide variety of composition (Ref. 24), and there are no products contained, or were thought to ephedrine alkaloid-containing dietary data bases containing such data, FDA contain, a source of ephedrine alkaloids. supplements, and the virtual absence of laboratories analyzed the products Approximately 50 to 60 percent of the publicly available safety data on these collected to quantify the levels of AER’s associated with use of dietary supplements, prompted FDA to convene ephedrine alkaloids (Refs. 1, 2, 21, and supplements were for such products. an ad hoc Working Group of its Food 30680 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

Advisory Committee (the Working 2. The Food Advisory Committee should take action to address the Group) (Refs. 27 through 29). Meeting rapidly evolving and serious public health concerns associated with the use 1. The Food Advisory Committee In the 6 months that followed the of ephedrine alkaloid-containing dietary Working Group Meeting on Dietary Working Group meeting, the number of supplements (Ref. 25). The Food Supplements Containing Ephedrine reports of adverse events associated Advisory Committee could not, Alkaloids with the use of dietary supplements thought to contain ephedrine alkaloids however, come to consensus on a On October 11 and 12, 1995, the doubled. In addition, FDA received specific approach to the public health Working Group, which consisted of information on two deaths of young concerns. Over half of the Food medical and other scientific experts adult males in which the medical Advisory Committee members stated from outside FDA as well as industry examiners specifically attributed the that, based on the available data, no safe and consumer representatives, cause of death to use of ephedrine level of ephedrine alkaloids could be considered the potential public health alkaloid-containing dietary supplements identified for use in dietary problems associated with the use of (see medical examiners’ reports in supplements (Ref. 25). Many of these dietary supplements and other food Adverse Reaction Monitoring System members expressed concern that many products containing ephedrine (ARMS) No. 10862 and 11134). FDA individuals who would be at risk if they alkaloids. analyzed samples of products that were to use products were unaware of The Working Group reviewed the consumers claimed that they had that risk because many of the conditions evidence on the occurrence of adverse consumed and suffered an adverse event that increase the risk of adverse events events associated with the use of and found that the ephedrine alkaloid may not be self-evident (Ref. 25). ephedrine alkaloids. This evidence levels in many of these products were Consequently, they recommended included the known pharmacology of below the 25-mg limit suggested by removing dietary supplements ephedrine alkaloids, numerous case certain members of the Working Group. containing ephedrine alkaloids from the reports published in the scientific In light of the rapidly increasing market (Ref. 25). Other members of the literature, and published findings from numbers of adverse events as well as of Food Advisory Committee suggested clinical studies investigating the use of the new analytical information on AER- that the agency establish conditions of ephedrine in the treatment of obesity related intakes of ephedrine alkaloids, use that would reduce the risk of (Ref. 30). The evidence also included FDA recognized that a determination on adverse events, including establishing over 325 AER’s that had been received how to deal with dietary supplements ‘‘reasonably’’ safe per serving and daily by FDA that were associated with the that contained these substances could use levels for both ephedrine alkaloids consumption of dietary supplements not be further delayed. Thus, FDA and ephedrine as well as other known to contain, or suspected of convened its Food Advisory Committee requirements (Ref. 25). containing, ephedrine alkaloids (Refs. in conjunction with the Working Group II. FDA’s Response 29 and 31). The Working Group also to review and provide final considered public comments made recommendations on what to do with Following the August 1996 meeting of during the meeting (Ref. 27). ephedrine alkaloid-containing dietary the Food Advisory Committee, the Following their review of this supplements. agency completed its review of the evidence, the members of the Working The Food Advisory Committee met on majority of the AER’s associated with Group agreed that the use of certain August 27 and 28, 1996. The meeting these products and reviewed the dietary supplements containing included all members from the Working discussions and the recommendations ephedrine alkaloids may cause Group who were available to attend the of the Food Advisory Committee, the consumers to experience serious meeting, as well as additional experts to scientific literature, the views expressed adverse events. On this basis, the replace those experts unable to attend or in public comments, and other data. Working Group recommended that FDA: to fill out the range of expertise needed Based on this information, the agency (1) Establish single serving and daily to appropriately evaluate the subject. has tentatively concluded that use of total use limits for ephedrine and total FDA asked the Food Advisory ephedrine alkaloids raises important ephedrine alkaloids; (2) require warning Committee to consider the safety of public health concerns, that the risks or cautionary statements on the labels of using dietary supplements containing these substances create are potentially these products; and (3) establish good ephedrine alkaloids and to make very serious, and that action must be manufacturing practice (GMP) specific recommendations on how to taken to protect the public health. requirements, including proper resolve the public health concerns A. Summary of Initial Considerations botanical identification and surrounding their use (Ref. 25). The standardization of the ephedrine Food Advisory Committee reviewed the Between 1993 and 1996, FDA alkaloid and ephedrine content in evidence that had been presented to the received a rapidly escalating number of concentrated extracts. Several members Working Group as well as new data and AER’s associated with the use of dietary of the Working Group suggested that information that had become available supplements, some that contained ephedrine alkaloids be limited to 25 mg since the October 1995 Working Group ephedrine alkaloids, some that did not per single serving and 100 mg total daily meeting. (Refs. 32 through 34). Figure 1 shows use. Other members suggested a variety Following a review of the totality of that in the 3 years since the initiation of of lower levels of ephedrine alkaloids the available evidence, the October 1995 an adverse event monitoring system for per serving. The Working Group also recommendations of the Working special nutritional products, the number discussed specific warning label Group, public comments, and of AER’s received by the agency on statements but failed to agree on the considerable discussion, the Food dietary supplements has quadrupled. wording of the warning statements. Advisory Committee agreed that FDA BILLING CODE 4160±01±P Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30681

BILLING CODE 4160±01±C 30682 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

Many of these reports have been for to the age and gender of individuals believed to contain an ingredient source clinically significant events (e.g., heart experiencing an adverse event). When of ephedrine alkaloids. Thus, FDA attack, stroke, seizures) that were FDA examined the products reported to focused its investigation on the observed most often in young adults for be associated with the CVS and NS ephedrine alkaloids in dietary whom the risk of these types of events effects, the most common element supplement products. are generally low (see Figure 2, which among them was that they involved summarizes data from the AER’s relative products that contained or were BILLING CODE 4160±01±P

BILLING CODE 4160±01±C Nonetheless, FDA remained aware of physiological and pharmacological However, many of the ephedrine the possibility that other ingredients in effects of single sources of the alkaloids alkaloid-containing products also these dietary supplement products that are used as ingredients in several contained other ingredients (e.g., amino contributed to the adverse events drugs (e.g., ephedrine in OTC acids, vitamins and minerals, other reported. For example, other stimulants bronchodilator products, botanicals) whose possible influence on in the ephedrine-containing dietary pseudoephedrine in cough and cold the observed AER’s could not be supplements could enhance the known preparations, and phenylpropanolamine ignored. Upon examination of the types stimulant effects of ephedrine alkaloids. in anoretic products). However, the of other ingredients, FDA tentatively Likewise, substances that affect kidney agency was not able to find definitive concluded that these other ingredients function (e.g., sources of salicin, evidence to evaluate whether ephedrine should not be the primary focus of its alkaloids from botanical sources are evaluation because these ingredients, concentrated amino acids) could influence the body’s ability to ‘‘clear’’ or metabolized differently than those from unlike the ephedrine alkaloids, did not pharmaceutical sources, and in the have a history (in the amounts likely to rid itself of ingested ephedrine alkaloids. absence of more directly relevant data be found in dietary supplements) of for dietary supplement products, the being able to produce the types of The agency also considered in its agency considered it appropriate to rely serious adverse events being observed. evaluation the fact that botanical on evidence from pharmaceutical For example, many ephedrine alkaloid- sources contain mixtures of ephedrine sources of single ephedrine alkaloids in containing dietary supplements also alkaloids that may have slightly assessing the effects of botanical sources contain known stimulants (e.g., sources different effects (e.g., additive or (see section II.C.2. of this document). of caffeine). While caffeine is known to interactive effects) than those from a stimulate the NS, in the amounts likely single ephedrine alkaloid, as found in B. FDA’s Strategy for Evaluation to be found in dietary supplements it is over-the-counter (OTC) products. The FDA considered five questions in not expected to produce effects such as agency compared the observed effects of evaluating the reports of adverse events stroke, heart attack, and seizure. supplement products with the known involving ephedrine alkaloids that it Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30683 had received. These questions were 7, 1996 (Refs. 31 and 38). The adverse (Refs. 27, 31, and 38). Of these, where designed to help the agency discern events associated with ephedrine there was sufficient information to relationships among AER’s where direct alkaloid-containing dietary supplement evaluate how the product was marketed and readily interpretable clinical studies products ranged from those with or used, approximately 92 percent of the were not available, and where multiple clinically serious sequelae (such as adverse events were related to the use host or product factors may have abnormal heart rhythms, chest pain, of products marketed for weight loss affected any association (Refs. 35 heart attack, stroke, significant and energy purposes, and 5 percent through 37). The questions focused the elevations in blood pressure, seizure, were related to products promoted for evaluation on whether there was a likely hepatitis, coma, psychosis, and death) to enhancing athletic performance or body association between the ephedrine those with less clinically significant building, although there was overlap alkaloids and the adverse events that signs and symptoms (such as among these uses. Approximately 2 had been reported and on the strength, nervousness, dizziness, tremor, minor percent of the adverse events were nature, and biological plausibility of any alterations in blood pressure or heart related to products marketed as association. These questions were: rate, headache, and gastrointestinal alternatives to illicit street drugs or for (1) Using the AER’s on marketed distress) (see Table 1). Although many euphoric purposes. (This distribution of ephedrine alkaloid-containing dietary of the AER’s crossed clinical categories, types of products parallels the supplements from FDA’s passive approximately 15 percent of the reports observations made from FDA’s market surveillance system, are there consistent described serious cardiovascular effects, review, which found that most of the patterns of signs and symptoms including abnormal heart rhythms, dietary supplements containing associated with the use of a number of stroke, heart attack, and ephedrine alkaloids bear weight loss different ephedrine alkaloid-containing cardiomyopathy (disease of the heart and energy claims on their labels or in dietary supplement products? muscle). Approximately 16 percent of their labeling (Refs. 1 and 2).) Moreover, (2) Are the patterns of the signs and the reports mentioned serious NS specific types of adverse events did not symptoms consistent with the available effects, including seizure, psychosis, appear to be limited to products scientific evidence and known mania, severe depression, vestibular promoted for any single use, such as physiologic and pharmacologic effects (inner ear) disturbances, and loss of weight loss, energy, or euphoria. of ephedrine alkaloids? consciousness. Other clinically serious The adverse events were reported to (3) Is there sufficient evidence that the or potentially serious adverse effects occur in both healthy individuals and in relationships are temporally correct, reported to be associated with the use of individuals with underlying diseases or that is, does exposure occur temporally these products included elevations of conditions that may have influenced the before the onset of the observed patterns liver function tests or overt hepatitis (4 frequency, pattern, or severity of the of signs and symptoms? percent), myopathies (disease of muscle, adverse event (Refs. 25, 27, 31, and 38). (4) Is there other evidence of particularly skeletal muscle) (3 percent), Of great concern to the agency are the causality, even in the absence of disturbances of the genitourinary system heart attacks, strokes, seizures, and controlled trials, e.g., evidence of (e.g., urinary retention, urinary other clinically serious illnesses and dechallenge (improvement or resolution infection, prostatitis (inflammation of injuries reported to occur in young of the signs and symptoms when use of the prostate gland), and epididymitis adults (Figure 2). In approximately 56 the product is discontinued) or positive (inflammation of the epididymis, part of percent of the reported adverse events, the injured party was less than 40 years rechallenge (reoccurrence of the signs the male genitourinary tract)) (3 of age, and approximately 25 percent of and symptoms when reexposed to percent), and dermatologic injuries occurred in those between 40 ephedrine alkaloids)? manifestations (including systemic and 49 years of age. Generally, (5) Considering the totality of the rashes which appear to be immune significant CVS or NS risk factors are available information, is there a mediated or allergic in nature) (6 not expected in these age groups. biologically plausible explanation for percent). Approximately 30 percent of Almost 75 percent of the adverse events the adverse events? the reports mentioned other effects, were reported to occur in females, often Finally, in fully evaluating the public including gastrointestinal distress, using products promoted for weight health concerns associated with these abnormal blood sugar levels or diabetes, products, the agency evaluated the loss. The higher frequency of adverse blood disorders (including increased events in women most likely reflects a potential impact of other factors that bleeding tendencies and abnormal blood could influence final decisions on the difference in product use (i.e., women cell counts), thyroid disorders, and predominantly use products marketed best approach to addressing the public addiction to the product. Finally, health concerns. for weight loss and energy purposes). approximately 60 percent of the adverse However, gender predominance in these C. Evaluation and Tentative events were characterized by general ratios may also occur because of gender- Conclusions of the Agency stimulant effects on the CVS and NS of related differences in metabolism of a ‘‘less clinically serious’’ nature, 1. Using the AER’s From FDA’s Passive ephedrine alkaloids, or gender-related including anxiety, nervousness, differences in the numbers and types of Surveillance System for Dietary hyperactivity, tremor, insomnia, and tissue receptors interacting with Supplements, FDA Has Tentatively altered heart rate or rhythms. However, ephedrine alkaloids (Refs. 39 through Concluded That There Are Consistent FDA recognized that these reports of 41). Patterns of Signs and Symptoms less clinically significant effects could Data on duration of use of ephedrine Associated With the Use of a Number of be indicative of early warnings of alkaloid-containing dietary supplements Different Ephedrine Alkaloid- serious cardiovascular or nervous relative to the occurrence of AER’s can Containing Dietary Supplement system risks if product use were to also be used to examine the similarity Products continue. of patterns of adverse events across In preparation for its August 27 and Serious adverse events were reported different types of exposures and 28, 1996, Food Advisory Meeting, FDA for a number of different products individual sensitivities. Figure 3 reviewed each of the approximately 600 promoted for a variety of uses and summarizes the duration of use data AER’s that it had received before June marketed in a variety of formulations collected from the AER’s associated 30684 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules with products containing ephedrine dietary supplement (Ref. 38) (see ARMS short time period after consumers began alkaloids. As shown in Figure 3, this No. 10009 and 11619 in the Appendix to use the products or consumers began information reveals that about 59 to this document) and, in a few cases, to start using the products after having percent of the adverse events were on the initial use (Ref. 38) (ARMS No. stopped use for a period of time (ARMS reported to occur within 4 weeks of 11401 in the Appendix to this No. 11076 in the Appendix to this starting to use the product. About 14 document). Of equal concern to the document). percent of the reported adverse events agency are reports of serious adverse occurred on the first day of using the events occurring within a relatively BILLING CODE 4160±01±P

BILLING CODE 4160±01±C suggesting an unpredictable pattern and susceptibility to the acute or chronic Adverse events appear to reflect severity of adverse events when effects of ephedrine alkaloids. different inherent types of individual consuming ephedrine alkaloid- In summary, in reviewing the AER’s sensitivities relative to dose levels, containing dietary supplements, even associated with ephedrine alkaloid- frequency or duration of use, and when used according to package containing dietary supplements, the subsequent results of sympathomimetic directions or under ordinary conditions agency noted a consistency of signs and stimulation. In some cases, particular of use. In other cases, some of the symptoms across a large number of events appear to occur as the result of adverse events were associated with products, across a range of products increased individual susceptibility to consumption of relatively low levels of with a variety of intended uses, across the effects of sympathetic stimulation ephedrine alkaloids (e.g., approximately products with many different (Refs. 39 through 42). For example, in 10 mg or less total ephedrine alkaloids formulations, and across a one report (ARMS No. 10862 in the per serving), some occurring shortly heterogeneous group of individuals with Appendix to this document), three respect to gender, age, and health after onset of use. young adult males consumed similar condition. Generally, the overall pattern amounts of a dietary supplement These variations in the occurrence of of observed results was consistent with containing ephedrine alkaloids, yet only adverse events relative to duration, stimulant CVS and NS effects, even one male experienced serious adverse frequency, and levels of exposure are though not every product showed the effects, which resulted in his death (see suggestive that multiple factors same effect or the same seriousness of Police and Medical Examiner’s Reports influence sensitivity to ephedrine effect, not every case involved CVS or in ARMS No. 10862 in public docket alkaloid intakes and could be indicative NS effects, and not all reports were number 95N–0304). This report is that some of the adverse effects are the complete or uncomplicated. The illustrative of numerous AER’s result of increased individual patterns of duration of use and dosage Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30685 levels suggest patterns of adverse events product for 10 months (1 capsule per antioxidant supplement. She developed that are influenced by variations in day) for energy. His father found him a rash over her entire body and stopped individual sensitivities. Overall, bloody and responding inappropriately. all three products. She restarted the however, there was a remarkable In the emergency department, his blood ephedrine alkaloid-containing product 3 consistency in the types of signs and pressure was 168/90, with a pulse of days after the onset of her rash. Three symptoms of adverse effects reported. 116. Results of extensive clinical and days later, on a visit to her doctor for a This consistency was recognized by the laboratory evaluations were all within nonproductive cough and congestion, Working Group (Ref. 27). normal limits. He was diagnosed with she was found to be seriously The foregoing discussion summarizes syncope and a closed head injury. His hypertensive (170/114). She had no the AER’s from a descriptive statistical neurologist concluded that ‘‘most likely history of hypertension and had been perspective. Many of these reports are he had a seizure secondary to seen by her gynecologist 1 week before summarized in the Appendix to this ephedrine’’ from the health food starting the ephedrine alkaloid- document. An abbreviated description substance he was taking. He was containing product, where a normal of all reports is in public docket number advised to avoid the product and blood pressure (120/78) was 95N–0304. A few examples of dispose of it. This man was on no other documented. experiences of particular individuals are medications and had no significant past 2. The Patterns of the Signs and given below. medical history. In particular, he never Symptoms of Adverse Events ARMS No. 11134—A 23-year-old had problems with dizziness or passing Associated With Ephedrine Alkaloid- male college student used an ephedrine out. alkaloid-containing ergogenic product ARMS No. 10974—A 19-year-old Containing Dietary Supplements Are for approximately 2 years, along with woman took an ephedrine alkaloid- Consistent With the Available Scientific several other dietary supplement containing product, one before each Evidence and Known Physiologic and Pharmacologic Effects of Ephedrine products. He was previously healthy meal, three times per day (1⁄2 of and was known to have a healthy life recommended amount) for 1 month, for Alkaloids style. He was found dead by his sister weight loss. Her family witnessed The observed CVS and NS effects in the apartment that they shared. The seizure activity at mealtime and took associated with use of ephedrine Medical Examiner’s report stated that her to the emergency room. Evaluations alkaloid-containing dietary supplements the cause of death was due to ‘‘patchy there were essentially normal (CT scan are consistent with the known myocardial necrosis associated with of the head and electroencephalogram pharmacologic and physiologic effects ephedrine toxicity from protein drink or EEG). The neurologist’s evaluation of ephedrine alkaloids. Because there is containing Ma huang extract.’’ found no other risk factors for seizure. a general paucity of scientific data or ARMS No. 9552—A 35-year-old No other products had been used, and other information on the physiologic or female, who was on no medications and there was no significant past medical pharmacologic properties of ephedrine who had a negative past medical history. alkaloids from botanical sources, and history, developed a non-Q wave ARMS No. 10088—A 38-year-old particularly from marketed dietary myocardial infarction (heart attack) female took two products containing supplement products, FDA reviewed while using an ephedrine alkaloid- ephedrine alkaloids for 4 days, and she other available evidence on ephedrine containing dietary supplement within developed syncope (light-headedness) and other ephedrine alkaloids for the dosage recommended on the label. and an extremely elevated blood information on their effects. This She used the product for approximately pressure, measured at 180/110. She was evidence included data from clinical 30 days, stopped for 1 week while on seen in the emergency department with and animal studies in support of drugs vacation, and then reinitiated the use of severe headache, nausea, and sweating. containing a single, synthetic ephedrine the product. About 11 days after The consumer had been seen every 3 to alkaloid in a well-defined and restarting the product, she developed 4 months for the 5 years before this characterized product, case reports from acute throbbing, anterior chest pain at event and had no history of high blood the literature of adverse events with rest, with radiation to the left shoulder, pressure. After stopping the products, ephedrine alkaloid-containing products, numbness of the left arm and hand, her blood pressure returned to normal. and traditional medical uses of diaphoresis (sweating), and shortness of ARMS No. 10919—A 49-year-old ephedrine alkaloid-containing breath. In the hospital, clinical woman used an ephedrine alkaloid- botanicals. evaluations (electrocardiogram and containing product, 3 capsules three Although there may be some cardiac enzymes) indicated an acute times daily for 3 weeks for weight loss. differences in the pharmacokinetic non-Q wave myocardial infarction, She developed weakness, dizziness, properties of synthetic ephedrine thought to be secondary to coronary nausea, vomiting, and palpitations and alkaloids used in drug products as artery spasm. Cardiac catheterization went to the emergency room, where she compared to the botanical sources of showed normal coronary arteries. was found to have vertigo (type of these alkaloids as used in dietary ARMS No. 10009—A 35-year-old dizziness), serous otitis media (middle supplements (e.g., differences in male took an ephedrine alkaloid- ear inflammation) bilaterally, enantiomer forms, dissolution, containing dietary supplement (2 hypertension (150/102), and elevated absorption, and bioavailability or capsules at noon, 3 capsules at 4:30 liver enzymes. The consumer reported differences that result from interactions pm). He worked out from 5:30 to 6:30 that when she stopped the product, her with other components of the botanical), pm, developing chest pain at 7:30 pm. blood pressure returned to normal given that once absorbed, the botanical He was admitted to the hospital with an without any medical treatment. She did and synthetic sources of ephedrine acute myocardial infarction (by not have a history of high blood alkaloids undergo similar metabolic electrocardiogram and cardiac enzymes) pressure. processes (Refs. 24 and 43), the agency and was treated medically. Subsequent ARMS No. 10946—A 42-year-old considered it appropriate to rely on cardiac catheterization demonstrated female used an ephedrine alkaloid- evidence from pharmaceutical sources normal coronary arteries. containing product, 1 capsule twice of single ephedrine alkaloids in ARMS No. 11144—A 28-year-old man daily for 3 days for weight loss. She was assessing the effects of botanical used an ephedrine alkaloid-containing also taking vitamin B12 and an sources. This judgment is supported by 30686 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules the fact that adverse events reported for sympathetic nervous system and thus ephedrine, pseudoephedrine, dietary supplements containing are classified as sympathomimetic phenylpropanolamine (dl- ephedrine alkaloids from botanical agents (i.e., agents stimulating the norephedrine), and norepinephrine.) sources are similar to those that are sympathetic nervous system) (Refs. 7, 9 Some of the physiological roles of alpha reported in the literature for drugs through 13, and 44 through 48). receptors are central NS stimulation, containing an ephedrine alkaloid from Ephedrine, pseudoephedrine, and vasoconstriction (i.e., narrowing of synthetic sources. FDA’s Working norephedrine are naturally occurring blood vessels), uterine contraction, Group agreed that evidence on synthetic sympathomimetic amines in some centrally mediated cardiovascular sources of ephedrine alkaloids could be botanicals. Ephedrine, depression, and decreased insulin considered in evaluating botanical pseudoephedrine, and norephedrine secretion. Alpha receptors also have an sources (Ref. 27). Ephedrine and its related alkaloids each have varying effects because of effect on the urinary bladder, which can are known to elicit physiological interaction with specific receptors in the result in urinary retention. The major responses similar to catecholamines human body (i.e., alpha, beta-1, and physiological roles of beta receptors (i.e., groups of chemically related beta-2 adrenergic receptors) (Refs. 9 include cardiac (i.e., heart) stimulation neurotransmitters, such as epinephrine, through 13). (Table 2 summarizes some and bronchodilation (enlargement of the norepinephrine, and dopamine) that of the major receptor effects, and Table bronchial or breathing tube secondary to have stimulant effects on the 3 summarizes the adrenergic activity of relaxation of bronchial smooth muscle).

TABLE 2.ÐADRENERGIC ACTIVITY OF SYMPATHOMIMETIC AGENTS (MODIFIED FROM REF. 9)

Type of effects adrenergic receptors Organ/system Other effects α β1 β2

Nervous system (NS) ...... Central NS Stimulation ...... Indirect Effects on Neurotransmitters Result in NS Stimulation. Cardiovascular system ...... Vasoconstriction ...... Cardiac stimulation: ...... Cardiac stimulation: ...... ↑contractility (force & ve- ↑heart rate ...... locity). darteriolar tone ...... ↑heart rate ...... dperipheral resistance ..... ↑impulse conduction ...... ddiastolic pressure ...... ↑cardiac output ...... dcardiac afterload ...... ↑O2 consumption ...... vasodilation. ↑stroke volume ...... ddiastolic coronary perfu- sion time. dventricular filling ...... dresidual (end-systolic) volume. Other ...... ↑uterine contraction ...... lypolytic activity ...... bronchodilation ...... ↑ureter motility & tone ...... ↑renin secretion ...... ↑insulin secretion ...... pupillary dilation ...... muscle & liver glyco- dGI motility & tone ...... genolysis. dpancreatic secretion (is- dGI motility & tone ...... lets/acini). urinary bladderÐrelaxation contraction, urinary, blad- of detrusor muscle. der, sphincter & trigone. relaxation of uterus cere- bellumÐ synaptic re- modeling.

TABLE 3.ÐADRENERGIC ACTIVITY OF SYMPATHOMIMETIC AGENTS (MODIFIED FROM REF. 9)

β α β 2-Receptor Sympathomimetic agent -Receptor effects 1-Receptor effects effects CNS effects

Ephedrine ...... moderate ...... strong ...... strong strong. Pseudoephedrine ...... moderate ...... moderate ...... moderate moderate. Phenylpropanolamine (dl-norephedrine) ...... strong ...... very little ...... very little strong. Norepinephrine ...... very strong ...... very little ...... none none.

The different types of ephedrine and by cardiac stimulation, resulting in certain medications. Other actions of alkaloids exhibit some similar effects increased heart rate and cardiac output. ephedrine include stimulation of but vary in the intensity of these effects The magnitude of these cardiovascular oxygen uptake and thermogenesis (heat (Refs. 10 through 13). For example, responses can vary on an individual or energy production). Pseudoephedrine ephedrine increases arterial blood basis and may be dependent on a is less potent than ephedrine both in its pressure in humans both by peripheral number of factors, including genetic bronchodilatory and vasopressor effects vasoconstriction (narrowing of the blood characteristics, a history of certain (i.e., effect of elevating blood pressure). vessels in the periphery of the body) diseases or conditions, or the use of It produces about one half the Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30687 bronchodilation and one quarter of the attacks and strokes. These events have b. Physiologic and pharmacologic vasopressor effects of ephedrine (Refs. 9 occurred in asymptomatic, otherwise evidence: NS effects of ephedrine and 13). healthy young adults with normal alkaloids. The adverse events involving a. Physiologic and pharmacologic coronary or cerebral blood vessels (Ref. the NS reported to FDA that are evidence: cardiovascular effects of 25), a finding also noted with associated with dietary supplements ephedrine alkaloids. The adverse events pharmaceutical preparations of containing ephedrine alkaloids are involving the CVS reported to FDA that ephedrine alkaloids (Refs. 60, 61, and consistent with the known effects of are associated with dietary supplements 65), where vasospasm with subsequent sympathomimetic agents on the NS. containing ephedrine alkaloids are ischemia is a proposed mechanism of These effects, such as seizure (Refs. 63, consistent with the known effects of tissue injury. Besides causing damage 65, and 80), psychosis, and mania (Refs. sympathomimetic agents on the CVS. by affecting blood flow, 81 through 99), have been reported with Cardiovascular effects resulting from the sympathomimetic agents, such as the use and the abuse of ephedrine use of sympathomimetic agents are well ephedrine, can damage the heart and alkaloids. More recently, a case report in documented in the literature (Refs. 49 other tissues or organs by other the scientific literature reported through 52). For example, use of mechanisms. Cardiomyopathy (i.e., ephedrine-induced mania associated ephedrine has been reported to interfere disease of the heart muscle) related to with the use of a botanical dietary with the regulation of serum potassium catecholamine mediated cytotoxicity supplement (Ref. 100). levels (Refs. 53 through 55) and thus (cell damage) has been reported with may predispose certain individuals to chronic use of ephedrine alkaloids Neuropsychiatric effects reported in cardiac dysrhythmias (i.e., abnormal (durations of use generally at or above AER’s related to ephedrine alkaloid- heart rhythms) (Refs. 18 and 56); the recommended dose that occur over containing dietary supplements also are myocardial ischemia (i.e., inadequate many months or years) (Refs. 62 and 66 consistent with the known physiologic circulation of blood and oxygen to the through 68). Fatal cardiomyopathies and pharmacologic actions of ephedrine heart muscle); and infarction (i.e., death have also been reported with chronic alkaloids documented in the scientific or damage of heart cells, also called use of ephedrine alkaloid-containing literature. Mania and psychosis have heart attack) (Refs. 57 through 61). dietary supplements (ARMS No. 11134 occurred in individuals without Cardiac damage has also been reported in Ref. 149a). identifiable risk factors who have used with the use of pseudoephedrine and Ephedrine and pseudoephedrine have these products, as well as in people who phenylpropanolamine (norephedrine) been implicated also in stroke used them who had possible (Refs. 16, 56, 60, and 62 through 64). secondary to intracranial (i.e., inside the predisposing factors, such as a personal Results of several studies on blood brain) and subarachnoid (i.e., history of mood disorders (i.e., pressure effects with the use of underneath the membrane that covers depression or manic depression), a ephedrine alkaloids have indicated that the brain and spinal cord) hemorrhage family history of manic depression, or individuals with hypertension may be at and vasculitis (i.e., inflammation of concurrent use of products that increase greater risk of blood pressure elevations blood vessels), as well as in ischemic sensitivity of an individual to the effects with the use of ephedrine (reviewed in strokes (Refs. 9 and 69 through 71), of ephedrine alkaloids (see Table 4). (Ref. 64)). particularly when used in combinations AER’s noting neuropsychiatric adverse The signs and symptoms observed in with phenylpropanolamine effects in persons using non-MAOI the AER’s are consistent with the (norephedrine) or caffeine (Refs. 65 and antidepressant drugs concurrently with available scientific literature on the 72 through 78) or in the presence of dietary supplements containing effects of ephedrine alkaloids. Serious monoamine oxidase inhibitors (MAOI) ephedrine alkaloids are consistent with cardiovascular adverse events are the (Ref. 72). These effects are noted to be a report of the serotonin syndrome major cause of death reported in the similar to the necrotizing angiitis associated with the concurrent use of AER’s with the use of ephedrine (severe inflammation with destruction serotonin reuptake inhibitors (a new alkaloid-containing products and of the blood vessels) seen in chronic class of antidepressant drugs) and OTC primarily involve ischemia (inadequate amphetamine abuse (Refs. 16, 74, and cold remedies containing blood flow) which can cause heart 77 through 79). pseudoephedrine (Ref. 101).

TABLE 4.ÐFACTORS INFLUENCING SENSITIVITY TO SYMPATHOMIMETIC AGENTS

Factor Examples

Age ...... Children, elderly. Genetics ...... Metabolizer genotype; adrenergic receptor genotype and numbers. Physiological states ...... Hyperdynamic (exercise), underweight. Dieting practices ...... Severe caloric or fluid restriction. Medications and food ...... MAOI, methyldopa, β-receptor blocking agent, caffeine or other stimulants. Diseases or health-related conditions ...... Heart disease, thyroid disease, diabetes, renal disease, high blood pressure, depression, psychiatric conditions, glaucoma, prostate enlargement, seizure disorder. Duration of use ...... Vascular spasm; stroke and myocardial infarction may influence the type and severity of adverse events in the sensitive individual.

c. Variability in individual responses known about the physiological and investigations (Refs. 5 and 102 through to ephedrine alkaloids. The pharmacological properties of these 104). The marked sensitivity of some unpredictability of individual responses alkaloids (Refs. 7, 10 through 12, 39 individuals to the effects of ephedrine to ephedrine alkaloid-containing dietary through 41, and 48). Individual has been recognized in the Western supplement products, as reported in variability in the effects of ephedrine scientific literature almost from the time AER’s, is also consistent with what is has been reported in several clinical that ephedrine was introduced as a 30688 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules therapeutic agent in the mid-1920’s A Danish group of researchers compared to 43 percent of the DF group (Refs. 5 and 102). Two early studies by investigated the usefulness of ephedrine experienced adverse reactions. The different investigators recommended a and caffeine alone and in combination majority of these occurred within the 10 mg initial oral test dose to assess the for the treatment of obesity (Refs. 105, first 4 weeks. At week one, 38 percent individual’s sensitivity to sources of 106, and 112). One hundred and eighty of the EC group subjects experienced ephedrine (Refs. 5 and 102). subjects were randomized to one of four adverse drug reactions compared to 30 Factors that appear to influence treatment groups: (1) Ephedrine—20 mg, percent in the DF group. NS effects individual susceptibility to (2) ephedrine—20 mg and caffeine—200 (particularly insomnia and agitation) sympathomimetic agents are diverse mg, (3) caffeine—200 mg, and (4) were statistically increased (p < 0.05) in (see Table 4) and are not yet well placebo control. The treatments were the EC treatment group (46 percent) defined by biological bases. These administered three times a day for 24 compared to the DF group (26 percent), factors include genetics, particularly weeks in conjunction with a defined whereas gastrointestinal adverse effects those genes controlling metabolic low calorie diet. One hundred and forty- were significantly increased in the DF functions; receptor numbers and types; one individuals completed the trial. group. Eight percent of the EC group gender; age; and certain physiological Subject withdrawals were reported to be reported cardiovascular symptoms. All states or disease conditions (reviewed in equally distributed across the four symptoms remitted after cessation of the Refs. 39 through 42). In addition, the groups with no statistical differences trial drugs. dosage and duration of use may among the groups. More side effects The above studies demonstrate that influence the effects seen with were noted in the treatment groups adverse effects can occur with the use ephedrine alkaloids, as tachyphylaxis compared to the placebo control group of ephedrine in the treatment of obesity (i.e., decrease or diminution of some in both those subjects continuing in, even in carefully designed and effect) is known to occur with chronic and those withdrawing from, the trial. conducted, physician-monitored use of these agents (i.e., there are Study results showed that 60 percent of clinical trials and even in persons decreases in certain effects with chronic the ephedrine and caffeine treatment prescreened to be in good health, free of use that are thought to be due to group, 44 percent of the ephedrine known risk factors, and not using occupation of all adrenergic receptor treatment group, and 36 percent of the medications or other products known to sites; discontinuation of ephedrines for caffeine treatment group experienced adversely interact with ephedrine-like a few days results in receptor side effects compared to 24 percent of drugs. Furthermore, the study availability and receptor mediated the placebo control group. These results population of obese individuals is effects). An example of tachyphylaxis were statistically significant (p<0.05) recognized to be less sensitive to the could be tremor or insomnia, which (Ref. 105). This study showed that there effects of sympathomimetic agents than occurs soon after starting ephedrine was a possibility of rebound symptoms the general population (Ref. 120). alkaloid-containing products but which (symptoms occurring as a consequence Certain of these studies also evidence may resolve in certain individuals with of withdrawal of an agent, especially that there is an increased frequency of continued use of ephedrine alkaloids. headache and fatigue) once the adverse effects occurring in lean d. Clinical trials using ephedrine in treatment was stopped. Rebound subjects, secondary to sympathetic the treatment of obesity. Although many symptoms were seen most in the stimulation, compared to obese subjects dietary supplements containing ephedrine and caffeine treatment group that is unrelated to dose per body ephedrine alkaloids are marketed for but also occurred in the ephedrine alone weight (Ref. 119). Thus, these studies weight loss or energy purposes, there is group (Refs. 105 and 106). suggest that the general population may a paucity of meaningful data on the safe Astrup et al. enrolled 127 of the be more sensitive to the effects of use of these products for this purpose. subjects completing the above clinical ephedrine alkaloids than the obese A number of controlled clinical trials trial into an open label study where all population. reported in the scientific literature subjects received the same treatment There are a number of recognized evaluated the effects of pharmaceutical (diet and ephedrine plus caffeine) for 24 limitations inherent in these published preparations of ephedrine, either singly weeks (Refs. 106 through 108). Five of trials, including those associated with or combined with caffeine or aspirin, on the 38 subjects that withdrew or study design, methods, and conduct weight loss in the treatment of obesity dropped out of this study did so because (e.g., small number of subjects enrolled (Refs. 105 through 119). While the they experienced adverse drug reactions in these trials, narrow targeted primary purpose of these trials was to (NS and CVS effects). Adverse drug populations, short evaluation periods, evaluate efficacy of ephedrine for reactions occurred in 102 subjects and selective presentation of data are purposes of weight loss in grossly obese during weeks 1 through 24 of the open among the concerns) as are the multiple individuals, these clinical trials also trial. Most symptoms (75 percent) publications of the same data. Yet document that clinically significant started during the first 4 weeks of despite these factors, the adverse effects adverse effects can occur in populations treatment and lasted about 4 weeks. observed in these studies remain a cause with no known risk factors with the use Symptoms related to the CVS were for concern, although these factors make of ephedrine, and that synergistic primarily palpitations and tachycardia. it difficult to identify subpopulations adverse effects can result when The most frequent NS symptoms were that may be particularly sensitive to the ephedrine and caffeine are combined. tremor, agitation, insomnia, increased effects of ephedrine or to identify The patterns and types of the adverse sweating, and nervousness. adverse effects that occur infrequently. effects reported in these trials are Breum et al., in another clinical trial These studies were carefully monitored, consistent with the known effects of in which the effects of ephedrine plus so that subjects were withdrawn from sympathomimetic agents, that is, they caffeine (EC) were evaluated, conducted the study when adverse effects became mainly involved NS and CVS effects. A a randomized, double blind, controlled evident. Therefore, although the summary of these studies follows. (In 15 week clinical trial comparing the observed adverse effects in these studies this document, the agency makes no effects of EC to that of dexfenfluramine were not as severe or as serious as some evaluation or judgment of the (DF), a serotoninergic agonist, in the observed with dietary supplement use effectiveness of the use of ephedrine in treatment of obesity (Ref. 113). Fifty four (e.g., heart attacks, seizures, strokes), the treatment of obesity.) percent of the subjects in the EC group they are indicative of the potential for Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30689 greater risk with continued use. pharmacologic effects of ephedrine Traditional treatment was prescribed by Moreover, their occurrence is alkaloids, are consistent with adverse a trained health practitioner based on remarkable given the careful effects reported in published case the evaluation of a particular patient prescreening of study subjects such that reports. For example, there are more and was predominately for short term high risk persons were not included in than 11 published case reports, at least use. Commonly used dosages of the raw the study. 12 patients, of systemic dermatologic botanical ranged from 1.5 to 9 grams (g), The greatest limitation, however, is reactions, including rashes occurring in generally averaging 5 to 6 g of Ephedra that these studies were designed to a particular distribution on the body, per dose (Refs. 14 and 146). Tyler has evaluate the effectiveness of ephedrine contact dermatitis (inflammation of the estimated that a tea made from 2 g of the in the treatment of obesity. They were skin resulting usually from local contact raw botanical Ephedra (containing 1.25 not designed to test the safety of the use with a substance), a toxic shock-like percent ephedrine) will yield a dose of of ephedrine in the obese, or any other syndrome, angioedema (extreme 15 to 30 mg ephedrine (cited in Ref. population (Ref. 121), or to test its safety swelling of tissues and structures of the 147). Thus, use of 5 to 6 g of the raw under the conditions under which body secondary to leaking of fluids from botanical Ephedra, an average amount marketed dietary supplements capillaries (small blood vessels)), and used in a tea could yield a dose of containing sources of ephedrine erythematous (reddish) rash and ephedrine ranging from approximately alkaloids are used. Therefore, these subsequent desquamation (loss of part 38 mg to 75 mg. study results cannot be used to of the skin surface) that occurred with FDA has no knowledge of any definitively demonstrate safety, or the the use of ephedrine or systematic collection of morbidity and lack of safety, of ephedrine alkaloid- pseudoephedrine (Refs. 114 and 129 mortality data on individuals treated containing supplements for use by the through 138). with Ephedra in traditional medicine. general population. Nonetheless, Concerns about toxicity to the fetus Ephedra was historically considered a despite the shortcomings of these with maternal exposure to ephedrine medium or middle class herb, meaning studies, the results raise serious alkaloids during pregnancy remain that recognized toxicities could be concerns about the safety of using unresolved. Increased fetal heart rate associated with its use (Refs. 14, 146, ephedrine, from any source, including has been associated with maternal use and 148). Several reference texts, in fact, dietary supplements, in both obese of pseudoephedrine (Ref. 139). In list precautions and contraindications individuals and the general public in addition, the administration of for the use of the botanical Ephedra in nonmedically monitored situations. intramuscular ephedrine to treat traditional medicinal preparations (Refs. e. Other physiologic and maternal hypotension has been 14 and 146). Another reference warns pharmacologic effects. Some of the associated with increases in fetal heart against overdosage (Ref. 25). adverse events reported to FDA that rate and beat-to-beat variability (cited in While there is a paucity of data in the were unrelated to the CVS and NS also Ref. 139). Certain animal studies also scientific literature on the safety of the bear a recognized relationship to the raise concern about potential teratogenic use of Ephedra, several scientific known physiologic and pharmacologic effects that may be caused by the use of references report adverse effects effects of ephedrine alkaloids. For ephedrine during pregnancy (Refs. 140 associated with the use of Ephedra. One example, urinary retention, particularly through 143). Potential toxicity for a early study in the United States reported in males with no history of prostatic breast-fed infant whose mother is using two cases of urinary retention in men hypertrophy (enlargement of the a dietary supplement containing aged 56 and 65 years. These men all prostate gland), has been associated ephedrine alkaloids is unknown, but noted bladder pain and difficulty in with the use of ephedrine (Refs. 102, toxicity has been reported in a breast- voiding which developed after one to 103, and 122 through 124). Urinary fed infant whose mother had been three doses of a fluid extract of Ephedra. retention has a well recognized taking a long-acting oral decongestant The symptoms resolved after the use of relationship with urinary tract containing d-isoephedrine for the relief the extract was discontinued. More infections, which have been reported to of allergy symptoms (Ref. 144). recently, a published case report notes FDA with the use of products Little is known about the potential the occurrence of erythroderma containing ephedrine alkaloids. consequences of long term use of associated with the use of an herbal Myopathy (disease of muscle), besides ephedrine alkaloids, other than the risk product containing Ma huang which being reported for the heart (Refs. 62 of cardiomyopathy as stated above. Park was obtained from a Chinese herbalist and 66 through 68), is also recognized et al., however, recently implicated β- for the relief of cold-like symptoms (Ref. to involve skeletal muscles and may adrenergic agents like ephedrine in the 138). The woman who was the subject result in acute renal failure (Ref. 125). etiology of a type of lung cancer, of this report had a history of similar Certain gastrointestinal adverse effects, particularly in persons simultaneously episodes following usage of OTC cold including impaired colonic motility and exposed to carcinogenic environmental preparations containing ephedrine ischemic colitis, have been associated factors such as smoking (Ref. 145). This alkaloids. These references document with the usage of amphetamines (Refs. report indicates the need for long-term that adverse effects occurred with the 102 and 126). Similarly, ischemic colitis followup to adequately assess the risks traditional use of Ephedra, and that has also been reported with the usage of associated with product use, as well as these effects are consistent with effects a long-acting decongestant containing the importance of particular group occurring with modern pharmaceutical pseudoephedrine (Ref. 127). characteristics (e.g., smoking status) in preparations of synthetic ephedrine. Additionally, acute hepatitis evaluating risk. (inflammation in the liver) has been f. Traditional uses of botanical 3. The Relationship is Temporally associated with the use of a Chinese sources of ephedrine alkaloids: adverse Correct medicinal product containing Ma huang effects. In the traditional medicinal use One possible source of serious error in (Ref. 128). of Ephedra, the raw botanical was evaluating observational data, such as Other types of adverse effects, such as administered, either alone or more that found in FDA’s postmarketing the reports of dermatologic reactions, commonly combined with other specific surveillance system, is the potential for while not known to be related to the botanicals, in the form of a water inappropriately assuming that a cause recognized physiologic or infusion (tea), three times a day. and effect relationship exists between a 30690 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules particular exposure and a particular over 26 percent of AER’s provided ephedrine alkaloids. This tentative adverse event without evaluating the information suggesting successful conclusion derives from the previous true relationship of the adverse event to dechallenge, and 4 percent of reports discussions in this document. The the exposure. Unless there are data that provided information of rechallenge, observed adverse effects predominately ensure that there is the correct temporal suggesting that the product was the involve the CVS and NS and are relationship between exposure and direct cause of the adverse event. A consistent with the known physiological effect (i.e., that the adverse effects number of the previously described and pharmacological effects of follow exposure), there is a potential for cases are particularly good examples of ephedrine alkaloids noted in medical/ serious misinterpretation of data. To positive dechallenge in that symptoms pharmacological texts. Furthermore, evaluate this potential source of serious resolved spontaneously on cessation of similar patterns of CVS and NS effects error, FDA evaluated the AER’s to use of the product without medical have been documented both in determine whether there was clear treatment (see Arms Nos. 10088, 11065, anecdotal reports in the scientific evidence of the correct temporal and 11112 in the Appendix to this literature and in the published results of sequence having occurred. FDA found document). controlled clinical trials using evidence of the correct relationship in Furthermore, some specific AER’s pharmaceutical preparations of various the AER’s that it received (see, e.g., suggest that a pattern of starting and ephedrine alkaloids. The available data ARMS Nos. 10088, 8475, 9747, and stopping use of dietary supplements further suggest that these types of 11112). containing ephedrine alkaloids may adverse events should be anticipated Further support that the temporal increase an individual’s susceptibility to and expected with the use of ephedrine relationship is correct can be found in experiencing adverse events as has been alkaloid-containing products by the clinical studies that described the suggested in reviews of adverse events general population. pharmacological and physiological occurring with the use of D. Additional Concerns effects of different ephedrine alkaloids phenylpropanolamine (Ref. 73). One and in the clinical trials with obese case described above, ARMS No. 9552, The agency is aware of a number of subjects. in which a woman suffered a heart factors related to currently marketed attack soon after she restarted using an dietary supplements that may contribute 4. There is Other Evidence, Even in the ephedrine alkaloid-containing product, to the likelihood of adverse events but Absence of Controlled Trials, Such as may be an example of such increased that the available data are inadequate to Evidence of Dechallenge That Suggests sensitivity. evaluate fully. These factors weighed a Causal Relationship Between the Use Thus, FDA tentatively concludes that heavily on the minds of many members of Ephedrine Alkaloid-Containing there is evidence of dechallenge and of the Food Advisory Committee as they Dietary Supplements and Adverse rechallenge from the AER’s that discussed the public health concerns Events supports a causal relationship between associated with the use of these Causality is most readily the ingestion of ephedrine alkaloids and products. These factors include: demonstrated in well-designed and the types of CVS and NS and other (1) The size of the population that is conducted clinical trials, in which the effects observed with use of the susceptible to experiencing adverse multiple factors that may influence ephedrine alkaloid-containing dietary events with the use of ephedrine study results and interpretations can be supplement products. Additional alkaloids, because there are neither good controlled. However, evidence of support for this conclusion is also data on the number and pattern of causality can be inferred from provided in the published clinical trials supplement users in the United States observational studies, including in the treatment of obesity described nor good data on the full range of individual case reports, particularly above. characteristics that cause or increase where there is evidence of positive risk. Nonetheless, the potential dechallenge and rechallenge, that is, 5. A Biologically Plausible Explanation population at risk is quite large if one where, when the consumer stopped for the Adverse Events considers the following likely risk using the product, the signs and Considering the totality of the factors: symptoms resolved or improved, and available information, FDA tentatively (a) The large number of persons who when the consumer began using the concludes that the available evidence have diseases or conditions, or who are product again, the symptoms strongly supports that the adverse at risk for such conditions, for whom reoccurred. Although many of the AER’s effects that are occurring with the use of the use of ephedrine alkaloid-containing did not provide enough information to dietary supplements containing dietary supplements is inappropriate adequately evaluate these questions, ephedrine alkaloids are caused by the (Table 5).

TABLE 5.ÐIDENTIFIABLE AT RISK POPULATION WITH USE OF EPHEDRINE ALKALOIDS

Estimated number of affected persons in Disease or condition the United States (in millions)

Cardiovascular disease ...... 50 (Ref. 158). Hypertension ...... 50 (Ref. 158). Kidney trouble ...... 3.5 (Ref. 159). Prostate disease ...... 2.6 (Ref. 159). Glaucoma ...... 2.4 (Ref. 160). Diabetes ...... 16 (8 million undiagnosed) (Ref. 161). Depressive, anxiety or schizophrenic disorders ...... 42.3 (Ref. 162). Thyroid disease ...... 11 (6 million undiagnosed) (Ref. 163). Pregnancy ...... 4 (each year) (Ref. 179). Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30691

(b) The large number of factors that and hyperactivity (Refs. 25 and 27). The Conventional food products that may increase susceptibility or type and patterns of these adverse contain ephedrine alkaloids, including sensitivity to the effects of ephedrine effects are consistent with the CVS and snack bars, cookies, and beverages, are alkaloids and other sympathomimetic NS effects known and expected to occur not covered by this proposal. agents (Table 4). These variables include with the use of sympathomimetic Conventional food products are subject gender, age, genetics, certain agents, such as the ephedrine alkaloids. to section 409 of the Federal Food, Drug, physiologic states, and the use of certain The known physiological and and Cosmetic Act (the act) (21 U.S.C. products (e.g., foods and drugs) (Ref. pharmacological activities of ephedrine 348) and, given the adverse events 25). alkaloids and the adverse events that associated with the use of ephedrine (2) The potential for interactive and have occurred in controlled clinical alkaloids, these substances are unpredictable effects from the mixture trials using ephedrine corroborate this unapproved food additives when used of ephedrine alkaloids found in conclusion. The biological plausibility in conventional foods. botanical sources, which may serve to of these types of adverse events Use of botanical sources of ephedrine increase the likelihood, frequency, or occurring with the use of ephedrine severity of an adverse event. Unlike alkaloids in traditional herbal therapies alkaloids, the temporal relationship is beyond the scope of this proposal. drugs which contain only a single, well- between the use of the dietary Although several Ephedra species characterized ephedrine alkaloid, supplements and the onset of the (including those considered as Ma botanical sources contain a mixture of adverse events, and the evidence of huang) have been reported to have a these alkaloids. The potential for dechallenge and rechallenge also long history of use in traditional Asian interactive effects among these alkaloids support a causal relationship between medicine for the treatment of the is likely but largely unknown (Ref. 25). the use of ephedrine alkaloid-containing symptoms of colds, to relieve (3) The potential for other ingredients products and subsequent adverse respiratory symptoms, and to regulate in the dietary supplement products to events. interact with the ephedrine alkaloids to water metabolism (Refs. 4, 6, 14, and increase the likelihood or severity of an Both the Working Group and the Food 146), products bearing claims adverse event (Ref. 25). Advisory Committee reviewed the evidencing that they are intended for (4) The natural or formulation available data and information on the therapeutic use are regulated as drugs variations in levels and relative occurrence of adverse events associated under the act. with the use of dietary supplements proportions of the ephedrine alkaloids This proposal also does not cover in marketed dietary supplement containing ephedrine alkaloids in certain individuals. The Working Group OTC or prescription drugs that contain products and the resultant risk for ephedrine alkaloids. Ephedrine is persons who can tolerate one level or was specifically asked whether the available information contains sufficient approved as an active ingredient in oral mixture but who unknowingly are OTC bronchodilator drugs for use in the exposed to different levels or mixtures evidence to demonstrate that the use of dietary supplements containing treatment of medically diagnosed mild because they change brands, or because asthma (21 CFR 341.76). However, in the composition of the brand that they ephedrine alkaloids may cause consumers to experience serious the Federal Register of July 27, 1995 (60 typically use is altered (Ref. 25). F.R. 38643), FDA proposed to amend (5) The formulations of the products adverse events. The Working Group concluded that it was. Although not the final monograph for OTC themselves (including the numbers, bronchodilator drug products to remove types, and forms of ingredients used in asked this question, those members of the Food Advisory Committee who the ingredients ephedrine, ephedrine the product and the form of the final hydrochloride, ephedrine sulfate, and product) may influence the likelihood, addressed the question agreed with the Working Groups’s conclusion. racephedrine hydrochloride and to frequency, or severity of adverse effects classify these ingredients as not because product characteristics may Thus, FDA tentatively concludes that generally recognized as safe and influence dissolution, absorption, there is a consistent, large, and growing effective for OTC use. bioavailability, and metabolism of active body of evidence that establishes a and inactive ingredients in the product causal association between the use of FDA issued the proposal to amend the and thus influence the effects of the ephedrine alkaloids and subsequent final monograph for OTC bronchodilator product (Ref. 25). adverse events. The agency also products in response to a request from tentatively concludes that the use of the U.S. Department of Justice, Drug E. General Summary and Tentative Enforcement Administration (DEA), to Conclusions ephedrine alkaloid-containing dietary supplements is associated with a serious restrict OTC availability of ephedrine FDA has received more than 800 and significant public health concern because of its illicit use as the primary AER’s involving more than 100 dietary because of the nature of the adverse precursor in the synthesis of the supplement products. Among these events and the size of the population at controlled substances products the most common and risk. methamphetamine and consistent finding is the presence of methylcathinone. The agency also ephedrine alkaloids. The products III. The Proposed Regulation issued the proposal because of new associated with these adverse events are A. The Scope of This Proposal information that showed that misuse marketed in diverse formulations and and abuse of OTC ephedrine drug for a variety of uses. This proposal applies to dietary products can cause potential harm, and Sympathetic nervous system and supplements containing one or more because of comments made by FDA’s cardiovascular system stimulant effects ephedrine alkaloids and related Pulmonary-Allergy Drugs Advisory account for the majority of the reported alkaloids, including those from the Committee and the Nonprescription adverse events associated with dietary botanical species Ephedra sinica Stapf, Drugs Advisory Committee. FDA is supplements containing ephedrine Ephedra equistestina Bunge, Ephedra currently evaluating public comments to alkaloids. These effects include heart intermedia var., tibetica Stapf, Ephedra that proposal and will be addressing attack, stroke, seizure, chest pain, distachya L., and Sida cordifolia or their this subject in a future issue of the psychosis, anxiety, nervousness, tremor, extracts. Federal Register. 30692 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

B. Rationale for the Proposal histamine at which FDA is likely to take adverse events may occur on the first It is incumbent upon the agency to action against the fish because it is use or with very short-term use. respond to the concerns raised by the adulterated (Ref. 151). Moreover, in Therefore, the agency has tentatively number, seriousness, and pattern of § 109.4(b) (21 CFR 109.4(b)), the agency determined that several measures are adverse events associated with the use has said that it will establish regulatory needed if the observed adverse events of ephedrine alkaloid-containing dietary limits that represent the level at which associated with the use of ephedrine supplements. Given the AER’s, the case an added poisonous or deleterious alkaloid-containing dietary supplements reports in the scientific literature, substance adulterates a food within the are to be effectively addressed. These controlled clinical trials, published meaning of section 402(a)(1) of the act measures are discussed below. reports of adverse effects with (21 U.S.C. 342(a)(1)). The agency has attempted to be C. Proposal for Dietary Supplements traditional uses of ephedrine alkaloid- flexible and practical in tailoring its Containing Ephedrine Alkaloids containing botanicals, and other data, it strategy for dealing with public health is apparent that there are serious and 1. Dietary Ingredient Limit for risks, taking into account the nature and well-documented public health risks Ephedrine Alkaloids: Per Serving Basis type of the risk and the potential One possible strategy for addressing attendant to the use of ephedrine effectiveness of various alternative the significant number of adverse effects alkaloids in marketed dietary approaches. In the case of ephedrine associated with ephedrine alkaloids in supplement products, and that the alkaloids in dietary supplements, there agency needs to propose actions to are many factors and underlying dietary supplements is to restrict the address these risks. etiologies that can influence individual level of the ephedrine alkaloids in these Over the years, FDA has employed a sensitivity to these substances. Some of products. In considering this possibility, variety of strategies in addressing food these factors are easily identified or FDA evaluated two issues: (a) Is there a ingredients that created significant readily controlled; many are not. Factors level at which ephedrine alkaloids public health risks. In cases where small that are known to influence the cause safety concerns; and (b) if there is, subpopulations have faced serious, even likelihood, frequency, and severity of will restricting dietary supplements potentially deadly, risks because of adverse events associated with the use from containing ephedrine alkaloids at ingredients with allergic potential (e.g., of sympathomimetic agents, including or above that level be adequate, alone, nuts and shellfish), FDA has required ephedrine alkaloids, include genetics, to protect the public health, or will that the presence of the allergen be age (e.g., children and the elderly are at additional steps be necessary. declared on the food label so that increased risk), preexisting conditions In considering these questions, FDA consumers who are at risk can avoid (e.g., kidney disease, heart disease, evaluated the evidence that provides products that contain the problem hypertension, diabetes, thyroid disease, information on the adverse effects of ingredient (§ 101.4 (21 CFR 101.4)). In glaucoma, and enlarged prostate), ephedrine alkaloids that is most other cases where a food or food pregnancy, concurrent use of relevant to the uses and formulations of ingredient has presented special health medications (e.g., MAOI, methyldopa), marketed dietary supplement products: risks to consumers under certain use or excessive consumption (see Table 4) (a) The published findings from the conditions, the agency has required (Refs. 39 through 42, 152, and 153). clinical studies investigating the use of warning label statements to ensure that Other factors that may increase an ephedrine for weight loss for the consumers are alerted to the potential individual’s susceptibility to experience treatment of obesity, and (b) the health hazards associated with use of adverse events with the use of numerous AER’s associated with the the product. For example, FDA has ephedrine alkaloids include exercise, consumption of dietary supplements required a special warning statement to body size (i.e., lean and normal weight containing ephedrine alkaloids. appear on the label of protein products individuals appear to be more First, the agency reviewed clinical intended for use in weight reduction, susceptible than obese individuals), and trials that have been performed to stating in part that very low calorie dietary intake (i.e., severe caloric and explore therapeutic uses for ephedrine protein diets may cause serious illness fluid restrictions increase the likelihood alone and in combination with other or death (§ 101.17(d) (21 CFR of adverse events) (Refs. 39, 42, 119, and pharmaceutical substances (see earlier 101.17(d))). In other cases, e.g., the 154 through 156). discussion in section II.C.2.d. of this proposed regulations for poisonings in Significantly, however, many adverse document (Refs. 105 through 119)). young children because of high intakes events associated with ephedrine Information from these trials show that of iron-containing dietary supplements, alkaloid-containing dietary supplements 20 mg ephedrine per dose can cause the agency was concerned that, for high occur in individuals who have no adverse events to occur in a significant potency products, warning labels alone apparent risk factors, or who are percentage of obese persons (up to 60 would not be effective in preventing unaware that they are at risk. percent) prescreened to be free of serious harm. Therefore, the agency has Additionally, approximately 40 percent known risk factors while using these decided to require, at least in some of the reported adverse events occur products for a relatively short time (i.e., cases, warning labels plus special with the first use or within 1 week of most adverse events occurred during the packaging requirements to reduce the first use, providing little or no warning first 4 weeks of use). Thus, these studies risk of serious harm (Ref. 150). to consumers of potential risk (see establish that 20 mg per serving of In other cases, where a substance Figure 3). The agency tentatively ephedrine presents potential risks for a contained in a food may be harmful to concludes, therefore, that neither subpopulation of morbidly obese health, it has been the agency’s policy disclosure of the presence of ephedrine persons but provide no information on to define a level at which the harmful alkaloids on the product label nor the risk at levels below 20 mg per serving substance may render the food use of a warning statement, alone, will for obese persons. These studies also adulterated. For example, to address the be sufficient to protect consumers provide no information on risk at levels public health problem of histamine because many individuals are not below 20 mg per serving for use by poisoning associated with the aware, and are unable to determine, that persons in the general population (e.g., consumption of certain fish, the agency they are at risk from consuming lean or moderately overweight persons), issued guidance on the level of ephedrine alkaloids, and serious who are known to be more sensitive to Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30693 sympathomimetic substances like threshold level of ephedrine alkaloids contain this or higher levels of ephedrine alkaloids than are the below which the general population and ephedrine alkaloids are adulterated. 1 morbidly obese persons who constituted susceptible individuals will not To reflect this tentative conclusion, the study population (see section experience serious adverse events. The FDA is proposing to adopt II.C.2.d. of this document). FDA is not shape of an intake-response curve for § 111.100(a)(1) which states that dietary aware of any well-designed and any particular adverse effect related to supplements that contain 8 mg or more conducted studies that evaluate the ephedrine alkaloid intakes is not ephedrine alkaloids (the total of risks of intakes of ephedrine levels known. In the absence of data that allow ephedrine, pseudoephedrine, below 20 mg per serving in any a systematic evaluation of intakes of norpseudoephedrine, norephedrine, population group. ephedrine and other related alkaloids methylephedrine, Second, FDA, through its below 10 mg per serving, it is not methylpseudoephedrine and related postmarketing surveillance program, has alkaloids) per single serving shall be possible to adequately define or found consistent patterns of adverse deemed to be adulterated under section describe the potential risks and at-risk events across a broad range of marketed 402(a)(1) and (f)(1)(A) of the act. FDA is dietary supplement products that groups from ephedrine alkaloids. proposing to adopt this provision under contain a variety of ephedrine alkaloid However, the available data, including sections 402(a)(1), (f)(1)(A), and 701(a) levels per serving. FDA’s laboratory the AER’s and the known physiological (21 U.S.C. 371(a)) of the act. analyses of the ephedrine alkaloid levels and pharmacological effects of Under section 402(a)(1) of the act, a in the small number of available dietary ephedrine, provide convincing evidence food, including a dietary supplement, is supplement products that consumers that clinically serious adverse events adulterated if it bears or contains any who suffered adverse events turned over will occur at intake levels above 10 mg added poisonous or deleterious to the agency showed that these adverse ephedrine alkaloids per serving. substance that may render it injurious to events were related to ephedrine FDA recognizes, however, that this health. Section 402(f)(1)(A) of the act alkaloid levels from approximately 1 to 10-mg level is also subject to some provides that a dietary supplement is over 50 mg per serving (Ref. 149). These uncertainty because of such factors as adulterated if it, or one of its data, as well as analytical data from ingredients, poses a significant or samples collected from the marketplace intra-assay variabilities (i.e., difference in analytical results from one run to the unreasonable risk of injury or illness after FDA received AER’s from when used as directed or under consumers who no longer possessed the next with the same method), natural variabilities in the alkaloid content of ordinary conditions of use. Under product, show a pattern of clinically section 701(a) of the act, FDA has botanical ingredients, variations in significant adverse events, including authority to issue regulations for the formulation levels from batch to batch, neuropsychiatric effects (e.g., severe efficient enforcement of the act. These depression, seizure), malignant (i.e., and inaccuracies in the amounts sections authorize FDA to issue a extremely high) blood pressure, and reported to be taken by consumers. regulation that establishes a level of myocardial necrosis (i.e., death of the When these sources of variability are ephedrine alkaloids that, the available heart muscle) with subsequent cardiac considered, given that they are likely to evidence makes clear, will render a arrest and death, with the use of be additive, the range around the 10 mg dietary supplement adulterated as a ephedrine alkaloids at levels per serving estimated intake can be matter of law. approaching and above 10 mg per expected to deviate by ±10 to 20 FDA tentatively concludes that such a serving (e.g., seven reports of clinically percent. Thus, FDA tentatively regulation will advance the purposes of serious adverse events were associated concludes that the life-threatening the act in two significant ways. First, it with products that contained 10 to 15 adverse events associated with the use will provide guidance to the dietary mg per serving) (Ref. 149a). Clinically of ephedrine alkaloids can reasonably supplement industry as to a level of significant adverse events were also be expected to occur at intake levels as ephedrine alkaloids that can be used in reported with the use of ephedrine low as 8 to 9 mg ephedrine alkaloids per their products with some confidence alkaloids at levels that exceeded this serving. However, given the limitations that such products will not be subject to range. regulatory action. Second, it will make FDA has also received a few reports in the available data, the agency clear that if products that contain higher of adverse events, some clinically requests comments on whether it is levels of ephedrine alkaloids are significant, including tremor, extremely more appropriate to focus on the 10 mg marketed; such products will be high blood pressure, severe headache, level. considered unsafe and adulterated and nausea, chest pain, increased heart rate, Based on the available evidence and will be subject to all the relevant and insomnia, associated with the use of the likely sources of measurement error sanctions under the act. ephedrine alkaloids at levels below 8 around estimated intake levels, the Eight mg per serving and above mg (e.g., 2 to 8 mg ephedrine alkaloids agency tentatively concludes that the represent levels at which the presence per serving) (Ref. 149a). The true use of dietary supplements containing 8 of ephedrine alkaloids in a dietary clinical significance of these levels of mg or more ephedrine alkaloids per supplement may render the product ephedrine alkaloids is difficult to serving may render the dietary interpret because of the lack of the data injurious to health and presents a supplement injurious to health. The (e.g., too few reports with analysis to significant and unreasonable risk. FDA agency also tentatively concludes that identify a pattern of clinically serious cannot say that it is a safe level, nor has consumption of dietary supplements adverse events at any specific level). that contain this level or more of 1 FDA has limited information on which Thus, the available information from the ephedrine alkaloids presents a ingredients dietary supplement manufacturers are AER’s and the scientific literature does likely to substitute for ephedrine alkaloids. Given not provide sufficient data to adequately significant and unreasonable risk of this uncertainty, FDA cannot comment on the safety evaluate risk below approximately 10 illness or injury under the conditions of of potential substitutes. FDA notes that mg per serving. use recommended or suggested in the manufacturers bear the burden of ensuring that any labeling or under ordinary conditions of ingredients that they may substitute for sources of Given the available evidence, it is ephedrine alkaloids meet all safety standards for difficult to ascertain whether there is a use, and that, therefore, products that dietary supplements. 30694 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules it been arrived at in a way that factored CVS stimulatory effects of ephedrine in a manner that increases the in some margin of safety. The evidence and thus exacerbate the adverse effect. likelihood, frequency, and severity of does not exist to establish a safe level. The agency requests comments on adverse events. Intake of multiple FDA notes that many members of the whether a separate dietary ingredient servings of ephedrine alkaloid- Food Advisory Committee stated that limit should be established for containing dietary supplements, they were unaware of a basis for ephedrine in addition to ephedrine particularly when such intake occurs determining a safe level (Ref. 25). Thus, alkaloids, and if so, what that limit within a relatively short timeframe (e.g., the agency is concerned about the should be. hours or within a day), can result in an potential for risk at levels below 8 mg excessive level of ephedrine alkaloids in 2. Proposed Compliance Procedures per serving for individuals who are the body that will increase the particularly sensitive to the effects of In proposed § 111.100(a)(2), the likelihood of an acute adverse event and ephedrine alkaloids, or whose agency states that it will use the high the severity of the event that occurs. sensitivity could be increased through performance liquid chromatography Concern over the hazards of taking chronic use of these products or other (HPLC) method as specified in LIB No. several servings of ephedrine alkaloid- processes (e.g., physical exercise). 4053 to determine the level of ephedrine containing dietary supplements in a Given the seriousness of the public alkaloids in a dietary supplement. The short period of time led several health concerns and the uncertainty agency developed this HPLC analytical members of the Working Group and of surrounding the risks attendant upon method to identify and quantify the Food Advisory Committee to consumption of ephedrine alkaloids ephedrine alkaloids from botanical recommend that FDA limit the intake of below 8 mg per serving, the agency sources. It was necessary for the agency dietary supplements containing solicits comments, and asks that they to develop an analytical method because ephedrine alkaloids to no more than include data, particularly clinical data, the official analytical methods used for four to five times per day and establish on the safety of the use of less than 8 the determination of ephedrine daily use limits, e.g., the amount of mg of ephedrine alkaloids per serving in alkaloids in pharmaceutical dosage ephedrine alkaloids the consumer dietary supplements. Should data and forms are unsuitable for botanical should not exceed in a day. In light of information become available that products. Current official analytical this, FDA evaluated the risks associated demonstrate that the use of less than 8 methods do not discriminate between with different patterns of daily intake of mg of ephedrine alkaloids per serving in ephedrine alkaloids and other alkaloids ephedrine alkaloid-containing dietary dietary supplements poses a hazard to that may be in the botanicals (e.g., supplements. the public health, or that the level of ephedroxane and methylbenzylamine) The average plasma half-lives for ephedrine alkaloids that will render a (Ref. 157). This HPLC method has made pharmaceutical ephedrine, product adulterated is higher than 8 mg possible the resolution and pseudoephedrine, and per serving, the agency will consider quantification of the several different phenylpropanolamine are modifying § 111.100 accordingly. ephedrine alkaloids known to occur in approximately 6 hours (range 3 to 11 At this time, the agency is not the Ephedras and other botanicals, hours), 6 hours, and 4 hours, proposing a level at which ephedrine, as including ephedrine, pseudoephedrine, respectively (Refs. 10 through 12, 20, opposed to the mixture of ephedrine norephedrine, methylephedrine, and 46). Generally, this means that after alkaloids found in products containing methylpsuedoephedrine, one half-life (e.g., 4 to 6 hours) half of botanicals, may render a product norpseudoephedrine, and related the ephedrine alkaloids still remain in adulterated, even though some members alkaloids. This method is currently the blood. More than 24 hours are of FDA’s Working Group and of the undergoing collaborative evaluation and needed for complete clearance of a Food Advisory Committee testing. single serving of ephedrine alkaloids recommended that the agency establish FDA strongly recommends that from the body. Because ephedrine a separate level for ephedrine (Refs. 25 manufacturers also use this or other alkaloids remain in the body for hours, and 27). There is some reason to believe methods that the agency adopts, when additional servings of an that ephedrine may be particularly although manufacturers will be free to ephedrine alkaloid-containing dietary significant in contributing to the use any alternative method that they supplement are consumed, the ingested occurrence of many of the find appropriate. However, FDA will alkaloids are additive to those already in cardiovascular effects seen in the use whatever method it adopts in this the body. This process will result in an reports of adverse events because proceeding as the basis for its increase in blood and tissue ephedrine is often the predominant enforcement actions, and this method concentrations of ephedrine alkaloids. alkaloid in botanical sources. In will be the legally established method. Generally, the higher the blood and addition, ephedrine is known to exhibit Therefore, manufacturers would be other body tissue levels of ephedrine more intense cardiovascular effects advised to compare their method of alkaloids, the greater the likelihood and relative to the other ephedrine alkaloids choice to the HPLC method to ensure severity of adverse events (Ref. 46). (Refs. 5 and 9 through 13). For example, that the alternative method produces Given the pharmacological evidence serious adverse events have been similar results. that average plasma half-lives of reported with the use of dietary ephedrine alkaloids are approximately 4 supplements containing less than 5 mg 3. Proposed Limit for Ephedrine to 6 hours, elevated blood levels of ephedrine. However, the available data Alkaloids: Frequency and Per Total ephedrine alkaloids will be maintained are difficult to interpret because of the Daily Intake Basis if a serving is consumed every 4 to 6 uncertainties about the potentially In addition to proposing a level for hours. Because ephedrine alkaloids are interactive effects of the other ephedrine ephedrine alkaloids in dietary stimulant substances, they can cause alkaloids in the raw botanical or supplements at or above which their insomnia if taken close to sleeping botanical extract and the presence of presence will render the product hours. Thus, if 6 to 8 hours in a day are other physiologically and adulterated, the agency is proposing to typically used for sleeping, there is a pharmacologically active ingredients in address its concern that products period of 16 to 18 hours per day in the dietary supplement products that containing ephedrine alkaloids below which consumers of ephedrine- may act to potentiate the overall NS and the dietary ingredient limit may be used containing dietary supplements would Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30695 have interest in consuming this per serving, not to exceed 3 tablets per For these reasons, FDA tentatively substance. By dividing the 16 to 18 day.’’ In the later example, the concludes that ephedrine alkaloid- waking hours in a day by the largest consumer may believe that it is safe to containing dietary supplements that do average half-life for ephedrine alkaloids consume 3 tablets (21 mg ephedrine not bear the statement ‘‘Do not use this (i.e., 6 hours), the results reveal the alkaloids) at one serving or servings product for more than 7 days’’ present possibility of taking a maximum of three separated by less than 6 hours. a significant and unreasonable risk of servings per day. Examples where the agency would not injury and illness under the Three servings of a dietary consider that the directions for use recommended or suggested conditions supplement that contains the proposed would cause consumers to exceed the of use. Therefore, under sections maximum per serving amount of per serving limit or take serving more 402(f)(1)(A) and 701(a) of the act, to ephedrine alkaloids (less than 8 mg) frequently than every 6 hours include reduce the potential for adverse events would yield a daily intake level of less ‘‘take 1 tablet per day,’’ ‘‘take 1 tablet occurring as a result of consumers using than 24 mg ephedrine alkaloids. Thus, every 6 hours, do not take more than 3 ephedrine alkaloids for more than a a dietary supplement product that tablets per day,’’ or ‘‘take 1 tablet not period of 7 days, FDA is proposing to contains ephedrine alkaloids and whose more than every 8 hours, do not take require in § 111.100(c) that the label of label or labeling instructs consumers to more than 2 tablets per day.’’ dietary supplements that contain take 24 mg or more per day would ephedrine alkaloids state ‘‘Do not use 4. Proposed Limitation on Duration of present a significant and unreasonable this product for more than 7 days.’’ Use risk of injury and illness under the The agency notes that this warning conditions of use suggested or The available data suggest that some focuses on duration of use, not on when recommended in the labeling and thus types of adverse events may be related reinstitution of use of ephedrine would render the product adulterated to the duration of using ephedrine alkaloids is appropriate. FDA is not under section 402(f)(1)(A) of the act. alkaloids. Long-term use of aware of definitive data on whether Similarly, an ephedrine alkaloid- sympathomimetic agents, such as there is a period of time when the containing product whose label or ephedrine alkaloids, even at relatively reinstitution of use of ephedrine labeling instructs consumers to take 8 low levels, is related to serious adverse alkaloids will not present a risk of mg or more during a 6-hour period events, including cardiomyopathy (i.e., adverse events. FDA solicits comments, would instruct consumers to consume disease of the heart muscle) and particularly data, on this matter. In an amount of ephedrine alkaloids that myocardial necrosis (death of heart cells addition, FDA solicits comments on has been shown to cause injury. This and tissue), that can result in death how consumers will interpret this label labeling also would present a significant (Refs. 7, 16, 49, 51, and 52). The statement in terms of reintroducing and unreasonable risk and render the scientific literature establishes that use dietary supplements containing product adulterated under section of ephedrine alkaloids for a period of ephedrine alkaloids in their diets. 402(f)(1)(A) of the act. several months or years can result in FDA tentatively concludes that cardiomyopathy (Refs. 66 through 68). 5. Proposed Prohibition of Ingredients without a daily use limit, the per Similarly, fatal cardiomyopathies have With Stimulant Effects serving limit cannot be effective in reducing the potential for adverse been seen in the AER’s associated with As previously discussed, because the events because consumers may chronic use of ephedrine alkaloid- nature and patterns of adverse events unknowingly consume an excessive containing dietary supplements at observed in the AER’s were consistent amount of ephedrine alkaloids by taking serving levels close to the dietary with the known physiological and several servings of dietary supplements ingredient limit the agency proposed pharmacological effects of the ephedrine in a relatively short period of time. above (ARMS No. 11134 in Refs. 29 and alkaloids, the agency focused its Therefore, FDA is proposing in 149a). evaluation on the ephedrine alkaloids. § 111.100(b) that the labeling of dietary Concern about these types of adverse However, the majority of the adverse supplements that contain ephedrine events with the long-term use of events that have been reported to FDA alkaloids shall not suggest or ephedrine alkaloids led several have involved the use of dietary recommend conditions of use that members of the Working Group (Ref. 27) supplements that contain ephedrine would result in intake of 8 mg or more and of the Food Advisory Committee alkaloids in combination with other ephedrine alkaloids within a 6-hour (Ref. 25) to recommend that, in ingredients, some with known period or a total daily intake of 24 mg conjunction with a per serving dietary physiological or pharmacological or more of ephedrine alkaloids. FDA is ingredient limit, FDA require a effects, including kola nut, yohimbe, proposing this regulation under sections statement on the label of ephedrine willow bark, senna, and Uva ursi (Ref. 402(f)(1)(A) and 701(a) of the act to alkaloid-containing dietary supplements 164). In many cases, the AER’s showed ensure that ephedrine alkaloid- to warn consumers not to use the that more severe adverse effects (e.g., containing dietary supplements do not product for a period longer than 7 days. heart attack, stroke, seizure) occurred bear directions for use that will create These members stated that a 7-day use with the use of dietary supplements that a significant and unreasonable risk. limit is standard guidance for the use of contained ephedrine alkaloids at levels In some cases, the label directions for pharmacoactive drug substances, below 20 mg together with other use of dietary supplements containing including ephedrine alkaloids, and may ingredients than were noted in the ephedrine alkaloids can cause reduce the occurrence of adverse events scientific literature with the use of consumers to exceed the per serving related to long-term use of ephedrine ephedrine at 20 mg (Ref. 149a). These limit or to consume servings more alkaloids (Ref. 25). Moreover, a 7-day observations suggest that the other frequently than every 6 hours. For limit on the use of ephedrine alkaloids ingredients may act, in combination example, FDA would consider the is supported by the AER’s data, which with the ephedrine alkaloids, to following label instructions to increase show that over 60 percent of the adverse produce more frequent, more severe, or the risk of adverse events: ‘‘take what events occurred when ephedrine potentially different patterns of adverse your body needs’’ or ‘‘take 1 tablet alkaloid-containing dietary supplements effects than those noted with the use of (containing 7 mg ephedrine alkaloids) were used for more than 7 days. an ephedrine alkaloid alone. 30696 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

Moreover, the clinically significant effects include an increased frequency labeled conditions of use and adverse events that occurred with of certain signs and symptoms, e.g., consequently are adulterated under amounts of ephedrine alkaloids below increased heart rate, insomnia, section 402(f)(1)(A) of the act. the 8 mg per serving limit may have nervousness, and increased blood The agency is concerned that many of been related to the compounding effects pressure, that are considered the dietary supplements implicated in of ephedrine alkaloids in combination characteristic of sympathomimetic the AER’s contained substances that are with other ingredients. Because of the stimulation. known to have physiological or known additive effects that occur when Other substances with stimulant pharmacological effects that could ephedrine alkaloids are combined with effects in combination with ephedrine increase the risk of adverse events when certain types of other ingredients, such alkaloids may act to increase the taken in combination with ephedrine as stimulants, proposed § 111.100(a)(1), likelihood of an adverse event. alkaloids. For example, substances that by itself, will likely not be effective in Yohimbine from the botanical yohimbe, reduce renal clearance interfere with the reducing the potential for adverse in small doses, is reported to stimulate elimination of ephedrine alkaloids from events. Certain types of other substances part of the nervous system and to cause the body by the kidneys (i.e., renal interact with the ephedrine alkaloids to elevated blood pressure, increased heart excretion) (Refs. 180 and 181) and thus increase the effects of the ephedrine rate, tremor, and anxiety (Refs. 176 may increase the risk of adverse effects alkaloids, thereby acting like more through 178). Because of their stimulant when consumed in combination with ephedrine alkaloids were contained in effects on the nervous system, ephedrine alkaloids. These substances the product. combining sources of yohimbine with include salicin, which is found in the For example, caffeine is a nervous the ephedrine alkaloids may increase botanical commonly known as willow system stimulant that can induce the likelihood, frequency, and severity bark, and amino acids in high nervousness, insomnia, and tachycardia of adverse events. concentrations (Refs. 181 and 182). By (increased heart rate) (Refs. 7, 165, and Therefore, the agency tentatively reducing renal clearance, higher levels 166). Intake of toxic levels of caffeine concludes that, based on the available of ephedrine alkaloids are maintained in can cause death resulting from CV evidence, adverse events may be related the blood for longer periods of time, stimulatory effects (Ref. 46). Various to the interactive or additive effects of thus prolonging the effects of ephedrine botanicals are known to be sources of stimulant substances in combination alkaloids. The maintenance of high caffeine, including green tea, guarana, with ephedrine alkaloids in dietary blood levels of ephedrine alkaloids yerba mate (also known as Ilex supplements. This tentative conclusion increases the likelihood of adverse paraguariensis), and kola nut (Refs. 167 is supported by statements made by events, particularly in those who may be through 172). several members of the Food Advisory sensitive to the effects of ephedrine The scientific literature reveals that Committee at the August 27 and 28, alkaloids. In addition, consumers may the frequency and severity of adverse 1996, meeting (Ref. 25). For these experience adverse events if more effects increase when ephedrine reasons, the agency tentatively ephedrine alkaloids are consumed while alkaloids and caffeine are combined concludes that any dietary supplement blood levels are maintained because the (Refs. 22, 73, 105, and 106). Recent that contains ephedrine alkaloids in absorption of additional ephedrine clinical trials have focused on whether combination with ingredients that alkaloids into the bloodstream will a combination of ephedrine and caffeine produce the aforementioned effects result in even higher blood and tissue would be more effective in the treatment presents a significant or unreasonable concentrations of ephedrine alkaloids of obesity than ephedrine alone. The risk of injury or illness under the and in any effects that may follow. usual dosage of ephedrine and caffeine conditions of use suggested in the Generally, the higher the blood levels of was 20 mg and 200 mg, respectively, labeling or under ordinary conditions of ephedrine alkaloids, the greater the risk given three times a day before meals. use and are adulterated. To eliminate of adverse events and the greater the The results of these trials, certain of this risk, under sections 402(f)(1)(A) and likelihood that the adverse effects that which were carefully designed and 701(a) of the act, FDA is proposing do occur will be severe (Ref. 46). conducted to eliminate potential § 111.100(d), which states that no Diuretics and laxative substances in confounders to the interpretation of ingredient, or ingredient that contains a an ephedrine-alkaloid-containing study results (e.g., concurrent substance, that has a known stimulant dietary supplement may also increase medication usage, underlying diseases effect (e.g., sources of caffeine, the likelihood, frequency, and severity and conditions or other risk factors), yohimbine) may be included in a of adverse events (Refs. 182 through indicate that the effects, including dietary supplement that contains 186). Uva ursi is a botanical diuretic adverse effects, of combining ephedrine ephedrine alkaloids. contained in many ephedrine alkaloid and caffeine are synergistic (Refs. 105, The agency is aware that several products (Ref. 184). The compounds 173, and 174). manufacturers and distributors of ursolic acid and isoquercetin found in Caffeine and ephedrine also appear to ephedrine alkaloid-containing dietary Uva ursi are mild diuretics. The be synergistic in thermogenesis, i.e., supplements also market caffeine- ephedrine alkaloids also exhibit diuretic they increase the rate of thermogenesis containing dietary supplements that are effects (Ref. 4). For example, ephedrine by influencing different parts of the intended to be used with a has a mild diuretic effect, and metabolic pathways (Refs. 173 and 175). ‘‘companion’’ ephedrine alkaloid- pseudoephedrine has a marked diuretic While the resulting effects of combining containing dietary supplement. The effect. The use of a product that ephedrine and caffeine could have a caffeine-containing dietary supplements contains ephedrine alkaloids in potentially positive impact on are often promoted as ‘‘boosters’’ or combination with other substances with thermogenesis because of their effects ‘‘enhancers’’ for the ephedrine alkaloid- diuretic effects increases the likelihood on metabolic pathways, it may also containing product. Under these and severity of consequent fluid and account for increased adverse effects conditions of use, both the caffeine- electrolyte imbalances, both of which seen with combinations of these agents containing and the ephedrine alkaloid- could affect CVS and NS risks. because of increased sympathetic containing dietary supplement products Senna and Cascara are examples of stimulation of other organ-systems (e.g., present a significant and unreasonable botanicals that contain potent stimulant CVS and NS). The synergistic adverse risk of illness and injury under their laxative substances called Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30697 anthraquinone glucosides (Refs. 185 term excessive consumption to achieve literature. A survey of weight control through 187). Use of excessive amounts more of the product’s purported effect practices among 1,431 adults indicated of stimulant laxatives can cause (Ref. 190). Finally, the agency found that the average respondent stomach cramps, nausea, vomiting, and that claims that suggest that the product participating in the survey had a weight diarrhea. Chronic use may lead to is intended to be used as a substitute for loss attempt lasting from 5 to 6 months laxative dependence, diarrhea, and, in an illicit street drug fostered abuse. and had averaged one attempt a year for severe cases, dehydration and Because claims in product labeling may the past 2 years (Ref. 196). In addition, electrolyte disorders (Ref. 188). influence how a consumer uses the approximately 30 percent of persons Ephedrine is known to influence product, claims in product labeling are trying to lose weight were chronic cellular potassium (an electrolyte) a condition of use for dietary dieters and had been on weight loss concentrations (Refs. 53 and 54). Use of supplements. plans at least 1 year (Ref. 196). Thus, laxative substances in combination with Several Food Advisory Committee this survey indicates that common ephedrine alkaloids may act to increase members identified a number of weight loss practices can be the likelihood, frequency, and severity significant risks attendant to using characterized as long-term in duration of adverse events. The agency requests dietary supplements containing and recurrent in nature. comments, particularly data, on the ephedrine alkaloids for purposes such Conversely, body building involves interactive effects of other ingredients as weight loss, energy, or as an illicit the building of lean muscle mass by and the ephedrine alkaloids in dietary street drug alternative, including strength and endurance training. The supplements. Based on the comments adverse events that are associated with addition of muscle mass can be and data received by FDA, the agency long-term use, excessive consumption, accomplished only through regular may prohibit the use of ingredients that and abuse of ephedrine alkaloids (Ref. muscle work (weight training or similar produce the aforementioned effects in a 25). Because the identified types of conditions) coupled with a caloric dietary supplement that contain claims promote use patterns that are increase (Ref. 197). To increase size and ephedrine alkaloids. associated with adverse events, the strength, a muscle must be exercised at agency has tentatively concluded that 60 to 80 percent of its capacity several 6. Proposed Prohibitions on Claims claim restrictions are necessary to times a week. In addition, a gain of 1 lb As described previously in section maintain the integrity of the limit on the of muscle requires about 2,500 extra II.C.1. of this document, FDA has level of ephedrine alkaloids in dietary calories, in addition to the calories received numerous reports of adverse supplements that it is proposing in needed for the training (Ref. 197). An events associated with ephedrine § 111.100(a)(1) and of the other increase of 700 to 1,000 calories (cal) to alkaloid-containing dietary supplements proposed restrictions on the conditions the daily diet should support a gain of promoted for use for weight loss, of use of these dietary supplements. 1 to 2 lb of lean muscle in 7 days (Ref. increased energy, body building, a. Claims that promote long-term use. 197). Body building systems that enhanced athletic performance, Claims in the labeling of dietary include intensive physical training increased mental concentration, and supplements that use of a product may programs, controlled diet, and dietary enhanced well-being and with products result in effects such as weight loss or supplementation purport to achieve promoted to be used as an alternative to body building promote long-term use of results in 6 weeks (Ref. 198), and the illicit street drugs. While many of the the product because these effects cannot individual must continue a training products that were associated with be achieved in a short period of time. program to maintain or increase the adverse events contained more than one Weight loss occurs when caloric intake muscle mass. type of claim or representation on their is reduced or energy expenditure (e.g., As previously mentioned in section label or in their labeling, the majority of exercise) is increased. To lose 1 pound III.C.4. of this document, long-term use adverse events reported to FDA are (lb), approximately 3,500 kilocalories of ephedrine alkaloids, even at related to the use of products promoted (kcal) must be expended by reducing relatively low levels, is related to or used for weight loss or energy caloric intake or by increasing energy serious adverse events, including purposes. Although fewer of the AER’s expenditures (e.g., physical activity) or cardiomyopathy (i.e., disease of the were associated with products promoted both (Ref. 191). Rapid weight loss is heart muscle) and myocardial necrosis for body building and enhanced well- associated with health risks, including (death of heart cells and tissue), that can being, clinically serious adverse events, increased protein loss from the body result in death. After reviewing the including seizure, heart attack, and stores and increased risk of gallstone scientific literature and the AER’s as death, have been reported to FDA that formation (Ref. 27). In fasting, over 50 well as recommendations by the were associated with the use of products percent of rapid weight reduction is Working Group and by the Food represented for these purposes. At least attributable to the loss of body fluids. Advisory Committee, FDA has one death in a young man has been Risks associated with rapid loss of tentatively concluded that ephedrine reported with the use of a product fluids from the body include alkaloid-containing dietary supplements promoted as an alternative to an illicit hypotension (i.e., reduction in blood must bear the statement ‘‘Do not use this street drug. pressure) and electrolyte disturbances. product for more than 7 days,’’ and that In reviewing the AER’s, it was evident Steady weight loss over a longer period those that do not present a significant that specific types of claims contained of time results in a true weight loss with and unreasonable risk of injury and in the labeling of dietary supplements a reduction of fat stores (Ref. 193). illness under the recommended or containing ephedrine alkaloids Guidelines recommend that a safe rate suggested conditions of use. promoted different patterns of use. of weight loss is 1⁄2 to 1 lb per week (Ref. Significant and safe results from Claims such as weight loss and body 194). Therefore, depending upon the weight loss or body building should not building encouraged long-term use to amount of weight loss that the and cannot be achieved within a period achieve the product’s purported effect individual desires to achieve, weight of 7 days. An individual could lose (Ref. 189). In addition, claims of loss programs may extend from weeks to approximately 4 lb of body fat in 7 days increased energy, increased mental months (Ref. 195). under complete fasting conditions if the concentration, or enhanced well-being, Long-term weight loss practices have normal energy requirements are 2,000 in a number of cases, encouraged short- been documented in the scientific cal per day. (This assumption is based 30698 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules on the fact that 3,500 kcal must be alkaloids that were promoted for one or receive information that is material with expended to achieve 1 lb of weight loss.) more of these purposes. In a number of respect to consequences that may result As discussed above, however, this rate instances, the consumer took more than from the use of the supplement under of weight loss is not safe or directed on the product label and its labeled conditions. recommended. experienced an adverse event (Ref. 190). Therefore, FDA is proposing in Regarding body building, lean muscle Claims that promote excessive § 111.100(f)(1) that the label or labeling mass cannot be built in 7 days (Ref. consumption, even for one or a very for dietary supplements that contain 197). Moreover, the scientific literature limited number of uses, are inconsistent ephedrine alkaloids that purport to be or evidences that the use of ephedrine with proposed § 111.100 (a)(1) and (b), are represented, either expressly or alkaloids during intense physical because they encourage the consumer to implicitly, to be used for short-term activity, such as body building, take more than directed in the effects, such as increased energy, increases the risks of serious adverse conditions of use set out on the label so increased mental concentration, or events. Use of ephedrine alkaloids that the consumer can achieve the enhanced well-being, must state during periods of intense physical purported effect. ‘‘Taking more than the recommended activity results in enhanced or In section II.C.2.a. and II.C.2.b. of this serving may cause heart attack, stroke, synergistic actions on the sympathetic document, FDA described data from the seizure, or death.’’ However, given the nervous system. It is through such clinical literature and AER’s that show significance and the potentially life- enhanced physiological processes that that consumption of an excessive threatening nature of the adverse events chronic effects on the heart, such as amount of ephedrine alkaloids in a that may occur when individuals myocardial necrosis (i.e., death of heart relatively short period of time is consume excessive amounts of cells and tissue), can occur with associated with serious adverse events, ephedrine alkaloids, the agency requests prolonged use of ephedrine alkaloids including seizure, psychosis, mania, comments on whether this statement (Refs. 16 and 197a). heart attack, and death. The agency should appear on the label of dietary Because safe and significant weight tentatively concludes that the potential supplements containing ephedrine loss and body building cannot be for these serious adverse events to occur alkaloids, regardless of any claims achieved in a 7-day period, claims that with excessive consumption of appearing on the label or in labeling. promote these uses promote long-term ephedrine alkaloids is a material fact FDA wants to provide an approach to use of ephedrine alkaloid-containing with respect to consequences that may placement of this information that will dietary supplements, which has been result from the use of a dietary give it a prominence that will ensure associated with serious adverse events. supplement promoted for short-term that it will be read and understood by For this reason, FDA tentatively effects that encourage excessive consumers but that will result in its concludes that any claims that promote consumption, and therefore a material presentation only once on the label long-term use of ephedrine alkaloid fact that must be disclosed on the label. panel or on each page of the labeling. dietary supplements, such as those for FDA’s authority to require disclosure Because the consequences of excessive weight loss and body building, promote statements in the labeling of dietary use of ephedrine alkaloids can be conditions of use that present a supplement products derives from serious, the agency tentatively significant and unreasonable risk of sections 201(n), 403(a)(1), and 701(a) of concludes that this information should illness and injury. Therefore, under the act. Section 201(n) of the act states, be on the same label panel or on the sections 402(f)(1)(A) and 701(a) of the ‘‘If an article (e.g., a food or dietary same page of the labeling (i.e., the same act, the agency is proposing in supplement product) is alleged to be field of vision) as the claim. However, § 111.100(e) to prohibit dietary misbranded because the labeling or FDA is proposing to provide for the use supplements that contain ephedrine advertising is misleading, then in of one disclaimer on the label panel or alkaloids from being represented, either determining whether the labeling or on each page of labeling in situations in expressly or implicitly, for use for long- advertising is misleading there shall be which multiple claims appear on the term effects such as weight loss or body taken into account (among other things) label panel or page of labeling where building. not only representations made or repetitive presentation of the disclaimer b. Claims that promote short-term suggested by statement, word, design, could be burdensome. FDA tentatively excessive consumption. Many claims device, or any combination thereof, but concludes that where the label panel or found on the labels of, or in the labeling also the extent to which the labeling or page of labeling contains multiple for, ephedrine alkaloid-containing advertising fails to reveal facts material claims, and the relationship between dietary supplements, including in light of such representations or each of those statements and the increased energy, increased mental material with respect to consequences disclaimer can be made obvious, the concentration, and enhanced well- that may result from the use of the disclaimer need only appear once on being, encourage the consumer to take article to which the labeling or each label panel or in each page of more of the product than is indicated on advertising thereof or under such labeling. the label to achieve more of the conditions of use prescribed in the FDA experience has been that one of purported effect. Several members of the labeling or advertising thereof or under the most effective ways of tying two Food Advisory Committee stated that such conditions of use as are customary label statements that are physically when a product is promoted to increase or usual.’’ Under section 403(a)(1) of the separate on the same panel is through these types of effects, the claim act, a food is misbranded if its labeling the use of a symbol such as an asterisk. encourages the consumer to exceed the is false or misleading in any particular. Symbols have been used within labeled directions for use to gain more Thus, the omission of a material fact nutrition labeling since its inception in of the desired effects (Ref. 25). For from the label or labeling would 1973 and have proven to be an effective example, if a product is promoted for misbrand a product. These statutory way of relating labeling information to energy, the consumer is encouraged to provisions, combined with section explanatory footnotes. For example, take more to gain greater energy. 701(a) of the act, authorize FDA to issue asterisks have been used adjacent to Many of the AER’s received by the a regulation designed to ensure that names of vitamins and minerals present agency were associated with dietary persons using ephedrine alkaloid- at very low levels to refer the consumer supplements containing ephedrine containing dietary supplements will to a footnote stating ‘‘Contains less than Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30699

2 percent of the Daily Value (formerly two times the required size of the net amphetamine whose use results in the U.S. Recommended Daily quantity of contents statement, in which destruction of serotonin-producing Allowance).’’ FDA is unaware of any case the accompanying information can neurons that play a direct role in data indicating consumer difficulties be no less than one-half the type size of regulating aggression, mood, sexual with such use of symbols. The use of the information modified, but no activity, and tolerance to pain (Ref. 16). symbols would also help differentiate smaller than one-sixteenth of an inch Many products claiming to be herbal between the label statements to which (see e.g., § 101.13(g) (1) and (i)(2)). The alternatives to MDMA bear claims on the disclaimer is referring and the other agency also has long held that one- their label or in the labeling that label claims to which the disclaimer sixteenth of an inch is the minimum highlight these mood-or mind-altering does not apply (e.g., authorized health type size for disclaimer statements, effects. claims or nutrient content claims). unless the package complies with Such street drug alternative claims do The agency points out that the § 101.2(c)(5) (see e.g., § 101.13(g)(1) and not fall within the scope of the claims proposed requirements for the (i)(2)). One-sixteenth of an inch is that Congress intended to permit on the disclaimer also extend to labeling: There specified in § 101.2(c) as the minimum labels or in the labeling of dietary are potentially many vehicles (e.g., type size for most other mandatory supplements. The Dietary Supplement placards, pamphlets, catalogs, books) information on the principal display Health and Education Act of 1994 (the that would have to bear the disclaimer. panel or information panel, e.g., DSHEA) added section 201(ff) to the act The agency is concerned that the designation of ingredients, name and (21 U.S.C. 321(ff)), which provides, in disclaimer be prominent in these forms place of business, and quantitative part, that the term dietary supplement of labeling. Even with the flexibility of information for relative claims. means a product ‘‘intended to the use of an asterisk to tie the claim Consequently, the agency tentatively supplement the diet’’ that bears or and the disclaimer to a single claim, the concludes that the minimum type size contains one or more dietary disclaimer could be obscured in pages for such information should be one- ingredients. While Congress did not of text of a package insert, pamphlet, or sixteenth of an inch. elaborate in the legislative history on book if it did not appear on the same Accordingly, FDA is proposing to what it intended the phrase ‘‘intended page or panel (i.e., in the same field of provide for the disclaimer, as outlined to supplement the diet’’ to mean, many vision) as the claim itself. Because of the above, in § 111.100(f)(2). If FDA adopts of the congressional findings set forth in variety of possibilities for the § 111.100(f)(2), the labeling of a dietary the DSHEA suggest that Congress presentation of the disclaimer, the supplement that contains ephedrine intended dietary supplements to agency tentatively concludes that for alkaloids and that purports to be, or that augment the diet to promote health and labeling, as for labels, it is important is represented as, useful for short-term reduce the risk of disease. that the disclaimer appear within the effects, such as increased energy, In using the term ‘‘diet’’ in section same field of vision, that is, on each increased mental concentration, or 201(ff) of the act, Congress did not package panel or page where a claim is enhanced well-being, would be define this term in either the act or the made. misleading, and thus misbranded, if it legislative history. The term ‘‘diet’’ is Section 403(f) of the act requires does not include the disclaimer set out defined in Webster’s Dictionary as ‘‘an mandatory label or labeling information in § 111.100(f)(1). organism’s usual food and drink’’ (Ref. to be prominently placed on the label The agency recognizes that most of 200). Dorland’s Medical Dictionary with such conspicuousness (compared the claims that will require the use of defines ‘‘diet’’ as ‘‘the customary with other words, statements, designs, the disclaimer, if this proposal is allowance of food and drink taken by or devices, in the labeling) as to render adopted, will be statements that are any person from day-to-day, particularly it likely to be read and understood by made subject to section 403(r)(6) of the one especially planned to meet specific the ordinary individual under act. That provision also requires that a requirements of the individual, and customary conditions of use. In other disclaimer accompany the statements. including or excluding certain items of instances where information must In the Federal Register of December 28, food’’ (Ref. 201). These definitions appear in a prominent and conspicuous 1995 (60 FR 67176), FDA proposed suggest that the diet is composed of manner on the product label, FDA has requirements for the disclaimer that is usual food and drink that may be proposed that the information be ‘‘in required to accompany statements made designed to meet specific nutritional easily legible print or type in distinct under section 403(r)(6) of the act. FDA requirements. Under section 201(ff) of contrast to other printed or graphic requests comments on how best to place the act, dietary supplements are food matter’’ (e.g., § 101.13(d)(2)). Therefore, the disclaimer proposed in this except for purposes of section 201(g) of to be consistent with previous actions document in conjunction with the the act and thus may be part of, or and to ensure that the information is disclaimer required under section augment, the diet. These common sense presented in a way that makes it likely 403(r)(6) of the act on the label or in definitions for the term ‘‘diet’’ do not to be read, FDA tentatively concludes labeling of dietary supplements so that encompass alternatives to illicit street that the information be presented in both disclaimers will be read and drugs. easily legible print or type in distinct understood by consumers. Products promoted to be an contrast to other printed or graphic c. Claims that suggest that the product alternative to or substitute for an illicit matter. is intended to be used as a substitute for street drug are intended to be used for FDA has long held that accompanying an illicit street drug. FDA is aware that recreational purposes to effect information should be in a size some ephedrine alkaloid-containing psychological states (e.g., to ‘‘get high’’ reasonably related to that of the products are being promoted as or to promote feelings of euphoria). information it modifies (e.g., alternatives or substitutes for such illicit Illicit street drugs are not food or drink §§ 101.22(i)(2) and 102.5(b)(2)(ii)). More street drugs as MDMA (4-methyl-2, and thus, cannot supplement the diet. In recently, this relative prominence has dimethoxyamphetamine), a addition, use of products claiming to be been expressed as a size no less than methamphetamine analogue. MDMA is alternatives to illicit street drugs does that required by § 101.105(i) for the net also known as ‘‘ecstasy,’’ ‘‘XTC,’’ and not promote health or reduce the risk of quantity of contents statement, except ‘‘X.’’ The precursor of MDMA is MDA disease, the intended use for dietary where the size of the claim is less than (3,4 methylene dioxyamphetamine), an supplements suggested in the 30700 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules congressional findings listed in the observed (Ref. 149a). Although these inhibitor or any other prescription drug. DSHEA. In fact, serious adverse events, AER’s are not sufficient to support a Discontinue use and consult your health including cardiac arrhythmia that lower per serving limit, they do provide care professional if dizziness, nausea, resulted in death, are associated with cause for concern for lower per serving sleeplessness, tremors, nervousness, the use and abuse of products promoted levels. To reduce the potential for headache, heart palpitations or tingling for use as an alternative to MDMA (see adverse events to occur at these lower sensations occur. NOT INTENDED FOR ARMS No. 10862 in Ref. 149a). per serving levels, FDA tentatively SALE TO OR USE BY PERSONS Because alternatives to illicit street concludes that a warning statement on UNDER THE AGE OF 18. KEEP OUT drugs are not intended to be used to the labels of dietary supplements OF REACH OF CHILDREN. DO NOT supplement the diet, products that containing ephedrine alkaloids is EXCEED RECOMMENDED DOSE. purport to be or that are represented, necessary, in conjunction with dietary FDA has carefully considered either expressly or implicitly, for use as ingredient limitations and other proposing adoption of the statement an alternative to a street drug are not requirements proposed in this suggested by industry. While the agency dietary supplements within the meaning document, to protect the public health. considers the industry suggestion to be of section 201(ff) of the act. Therefore, FDA is therefore proposing in a good starting point, FDA tentatively manufacturers, packers, and distributors § 111.100(g) to require that a specific concludes that some changes are cannot take advantage of the exemption warning statement appear on the labels necessary in the statement if it is to for structure function claims from the of dietary supplements containing fulfill its purpose of fairly warning drug definition in section 403(r)(6) of ephedrine alkaloids. FDA’s authority to consumers about the special risks the act. Because these products are require label warning statements on attendant to use of dietary supplements intended to be used to affect the dietary supplement products derives that contain ephedrine alkaloids. structure and function of the body, they from sections 201(n), 403(a)(1), and b. Tentative conclusions. The dietary are drugs within the meaning of section 701(a) of the act. These statutory supplement industry suggested that the 201(g)(1)(C) of the act. provisions authorize FDA to issue a warning statement begin with the term ‘‘caution.’’ FDA, however, questions 7. Warning Label Statements regulation designed to ensure that persons using dietary supplements will whether this term is adequate to convey Several members of the Working receive information that is material with the severity of the harm that can result Group and of the Food Advisory respect to consequences that may result from the use of the product. Because use Committee recommended that specific from the use of a product under its of ephedrine alkaloid-containing dietary information be conveyed in a warning labeled conditions. supplements has the potential to cause or cautionary statement for ephedrine a. Caution statement suggested by serious injury to certain subgroups of alkaloid-containing dietary supplements industry. Several dietary supplement the population, the agency tentatively (Refs. 25 and 27). Persons having certain industry trade groups met with FDA on concludes that the use of the term diseases or taking specific medications November 30, 1995, and suggested that ‘‘WARNING’’ is warranted. The term known to interact with ephedrine dietary supplements containing ‘‘WARNING’’ is commonly used to alkaloids are at risk of suffering adverse ephedrine alkaloids bear a specific denote danger, and, therefore, the use of events with the use of dietary warning statement (Ref. 199). this term will communicate to supplements containing ephedrine Representatives from the National consumers the harm that could result to alkaloids. Generally, use of ephedrine Nutritional Foods Association (NNFA), the special populations that are the alkaloids at any intake level by these the American Herbal Products subject of the warning. persons is contraindicated (Refs. 10 Association (AHPA), the The dietary supplement industry through 12, and 55). For these persons, Nonprescription Drug Manufacturers suggested that the statement include the a warning label statement can be a Association (NDMA), and the Utah instruction ‘‘Seek advice from a health useful means of alerting them to Natural Products Alliance (UNPA) care provider if you are pregnant or potential consequences that can result (hereinafter referred to as the dietary nursing or if you are at risk or are being from the use of the product. Table 5 supplement industry 2) recommended treated for high blood pressure, heart or identifies groups that are at risk if they the following statement: thyroid disease, diabetes, difficulty in use ephedrine alkaloids. In addition, CAUTION: Taking more than the urination due to prostate enlargement.’’ many consumers who are unaware that recommended amount will not Several members of the Working Group they are sensitive to the effects of necessarily increase benefits. Begin use and of the Food Advisory Committee ephedrine alkaloids may not recognize with one-half or less the recommended recommended that a warning statement the significance of early warning signs dose to assess your tolerance. (If direct consumers who have certain and symptoms as potential indicators of Pertinent) Please note: This product diseases or conditions that increase the more serious side effects (e.g., dizziness contains caffeine and should not be risk of adverse events not to use the or severe headache may be early taken by those wishing to eliminate product or to see a health care provider symptoms of hypertension or stroke). caffeine from their diet. Seek advice prior to using the product (Refs. 25 and Under these circumstances, a warning from a health care practitioner if you are 27). The feeling of these members was statement could provide information on pregnant or nursing or if you are at risk that a health care provider could assess what actions the consumer should take or are being treated for high blood the potential risks for the individual if certain symptoms occur. pressure, heart, thyroid or psychiatric consumer if he or she uses the product. FDA concurs with this portion of the FDA has received several AER’s, some disease, diabetes, depression, seizure industry’s labeling recommendation. As clinically significant, that were disorder, stroke or difficulty in discussed in section II.C. of this associated with the use of dietary urination due to prostate enlargement. document, based on the scientific supplements containing ephedrine Consult your health care professional literature and the known physiological alkaloids at levels below the level before use if you are taking an MAO proposed in § 111.100(a)(1) where signs and pharmacologic effects of ephedrine and symptoms including high blood 2 FDA is using this shorthand for convenience. It alkaloids, an individual who is pregnant pressure, chest pain, increased heart does not intend to imply that these groups represent or nursing, has high blood pressure, rate, severe headache, and nausea were the entire dietary supplement industry. heart or thyroid disease, or difficulty in Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30701 urination because of prostate associated with prostate enlargement or containing products at all. Several enlargement has an increased risk for only seen in men. Published case members of the Working Group and of experiencing serious adverse effects reports and AER’s received by the the Food Advisory Committee with the use of ephedrine alkaloids. agency document the finding that recommended that the warning However, FDA also tentatively finds urinary retention following the use of statement advise consumers not to use that the warning statement should be ephedrine alkaloid-containing products the dietary supplements containing broadened to address other individuals can occur in both females and males, ephedrine alkaloids if they are taking who may place themselves at particular including young boys without any these types of drugs (Refs. 25 and 27). risk if they consume the product. The history of prostate enlargement (see Because the use of MAOI drugs in relevant scientific literature, case ARMS No. 10298 and 11164 in Ref. combination with ephedrine alkaloids reports and AER’s suggest that persons 149a and Refs. 102, 103, 123, and 124). results in blood pressure elevations and suffering from depression or other Use of ephedrine alkaloids by persons increases the risk of serious psychiatric conditions, glaucoma, or suffering from depression or other consequences (e.g., stroke and heart seizure disorders are also at increased psychiatric conditions increases the risk attack), FDA is proposing to warn risk of experiencing an adverse event if for the occurrence of serious adverse against use of ephedrine alkaloid- they consume ephedrine alkaloid- events, including psychosis and mania containing products in this containing products. (Refs. 81 through 96, 98, 99, 109, and circumstance (Refs. 10 through 12, 39, Use of ephedrine alkaloids during 220). Because ephedrine can cause an 41, and 55). Because persons remain at pregnancy or while nursing can cause increase in intraocular pressure (i.e., risk while the MAOI drug remains in adverse effects in the fetus or the infant. pressure inside the eyeball), use of the body, FDA tentatively concludes Ephedrine alkaloids can cross the ephedrine alkaloids by persons with that consumers need to be informed that placental wall and can be absorbed by glaucoma will worsen this disease, it may take up to 2 weeks for the MAOI the fetus when taken by a pregnant which over time, can result in blindness drug to clear the body (Refs. 203 and woman (Refs. 10 through 12 and 55). (Refs. 39 and 41). Finally, persons with 204). Similarly, ephedrine is excreted in the seizure disorders who use ephedrine Because MAOI drugs increase the breast milk and can be consumed by the alkaloids have an increased risk for effects of sympathomimetic agents, and nursing infant. The fetus, infants, and experiencing a seizure (Refs. 63, 65, and consequently will increase the children are sensitive to the effects of 80). Because the nature of the risks frequency and severity of adverse ephedrine alkaloids and thus are more associated with the use of ephedrine effects, persons taking such drugs likely to experience adverse events alkaloids for persons who have the should be given as much information as (Refs. 39 and 41). diseases and health-related conditions possible. The agency is concerned that Use of ephedrine alkaloids by persons listed above, it is important that these some patients may not be fully informed with high blood pressure can result in consumers be advised to consult a about MAOI drugs, may not fully blood pressure elevations or loss of health care provider before using understand or remember all the adequate medical control of ephedrine alkaloid-containing dietary information given to them, or with the hypertension (Ref. 64) which increases supplements. passage of time, may forget or lose the risk of serious consequences (e.g., With regard to the statement in information that has been provided. stroke and heart attack) (Refs. 62 and industry’s suggested statement ‘‘if you Thus, the warning statement needs to be 70). Because ephedrine alkaloids also are at risk or are being treated for high as informative as possible. interfere with the regulation of serum blood pressure * * *,’’ the agency Rather than include general language, potassium levels (Refs. 53 through 55), considers it unlikely that consumers such as ‘‘any prescription drug’’ in the individuals with heart disease who use will be able to adequately evaluate their warning statement, FDA tentatively ephedrine alkaloids are at greater risk of risk for developing the conditions listed finds that it is important to identify cardiac dysrhythmias (i.e., abnormal in this statement. Most of these specific types of prescription and OTC heart rhythms) (Refs. 18 and 56), conditions are not self-diagnoseable. In drugs that contain ingredients that in myocardial ischemia (i.e., inadequate addition, individuals who have a combination with ephedrine alkaloids circulation of blood and oxygen to the disease or condition listed in this are known or expected to increase the heart muscle), and infarction (i.e., death statement, but who are not currently likelihood, frequency, or severity of or damage of heart cells, also called being treated, may believe that they are adverse effects. Therefore, FDA heart attack) (Refs. 57 through 61). not at risk of experiencing an adverse tentatively concludes that consumers With respect to thyroid disease, event. Consequently, the agency need to be warned not to use ephedrine individuals with hyperthyroidism tentatively concludes that the warning alkaloid-containing dietary supplement (resulting from increased secretion of statement needs to include an in combination with specific drugs, thyroid hormone) show increased instruction to consult a health care such as drugs for depression, sensitivity to adrenergic agents, such as provider before using an ephedrine psychiatric or emotional conditions ephedrine alkaloids, which can result in alkaloid-containing dietary supplement. (Refs. 10 through 12, 55, and 205); drugs thyroid storm with dire consequences The dietary supplement industry for Parkinson’s disease (Ref. 55); (e.g., cardiac dysrhythmias, congestive statement only instructs the consumer methyldopa (Ref. 206); or any product heart failure, coma, and death) (Refs. 39, to consult his or her health care containing ephedrine, pseudoephedrine, 41, 55, and 202). professional before use if he or she is or phenylpropanolamine (ingredients For persons with diabetes, use of taking an MAOI or any other often found in allergy, asthma, cough/ sympathomimetics can result in an prescription drug. FDA tentatively cold and weight control products) (Refs. increase in blood sugar and loss of concludes that this statement should be 180 and 207 through 209). diabetic control (Refs. 29, 41, and 51). broader because of the need for FDA tentatively finds that the drug In addition, ephedrine can cause professional help in assessing the risks methyldopa needs to be identified on constriction of the urinary bladder of ephedrine alkaloid intake with a the label. It increases the pressor results sphincter and ultimately lead to dysuria range of conditions. of sympathomimetic agents, such as (increased, painful, or difficulty in However, people using MAOI drugs ephedrine alkaloids, resulting in urination). This condition is not only should not use ephedrine alkaloid- hypertension (Ref. 206). FDA has 30702 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules reached a similar tentative judgment symptoms occur. A health care because the instruction for the with respect to ephedrine, professional will be able to evaluate the consumer not to exceed the pseudoephedrine, and significance of the signs and symptoms, recommended serving eliminates the phenylpropanolamine because each of determine the risks of more serious need for the ‘‘Taking more than these substances, in combination with adverse events occurring, and prescribe recommended * * *’’ statement. an ephedrine alkaloid-containing any treatment that may be necessary. The dietary supplement industry dietary supplement, could lead to an The effects, such as tremor, suggested that the statement advise the additive effect and consequently sleeplessness, and tingling sensations, consumer to: ‘‘Begin use with one-half increase the risk of serious adverse that are included in the instruction or less the recommended dose to assess events. While many consumers may not suggested by the industry are not your tolerance.’’ The agency addressed be familiar with the term ‘‘ephedrine,’’ usually clinically serious and will likely limiting the levels of ephedrine ‘‘pseudoephedrine,’’ or cease once the product use is alkaloids contained in dietary ‘‘phenylpropanolamine,’’ they may be discontinued (Refs. 210). For these supplements in proposed § 111.100 aware of the type of product being taken reasons, FDA tentatively concludes that (a)(1) and (b). In addition, because of for a specific condition or ailment, e.g., the statement needs to include the label space constraints, the agency is allergy, asthma, cough/cold, and weight instruction to ‘‘Stop use and call a trying to keep the warning statement as control products. health care professional immediately if short as possible. Therefore, FDA The agency recognizes that because of dizziness, severe headache, rapid or tentatively concludes that there is no the large number of drugs for irregular heart beat, chest pain, reason to require inclusion of this depression, psychiatric or emotional shortness of breath, nausea, noticeable information. conditions, and Parkinson’s disease that changes in behavior, or loss of The dietary supplement industry are contraindicated for use with consciousness occur.’’ recommended the following in a caution ephedrine alkaloids and the limited The dietary supplement industry statement, if appropriate for the amount of space on the labels of dietary suggested that the statement include a product: ‘‘This product contains supplements, not all of them can be direction for the consumer not to exceed caffeine and should not be taken by listed on the label. However, the the recommended dose. Members of the those wishing to eliminate caffeine from conditions for which the consumer is Working Group and of the Food their diet.’’ The Food Advisory taking the drug can be identified, using Advisory Committee recommended that Committee also suggested that other less label space. If consumers are unsure the warning statement include a stimulants with their source, such as whether their drug may interact with direction for the consumer not to exceed caffeine from Kola nut, be identified on the ephedrine alkaloids, they should be the recommended serving or dose (Refs. the label of a dietary supplement cautioned to check with their health 25 and 27). containing ephedrine alkaloids. care professional before using the The agency concurs with the However, the agency is proposing to dietary supplement. industry’s suggestion. FDA tentatively The dietary supplement industry finds that this type of statement is prohibit stimulant substances in suggested that the statement include the necessary to provide information combination with ephedrine alkaloids instruction ‘‘Discontinue use and instructing the user not to consume the in dietary supplements. Therefore, FDA consult your health care professional if product excessively. Excessive tentatively concludes that there is no dizziness, nausea, sleeplessness, consumption of ephedrine alkaloids is reason to require the inclusion of such tremors, nervousness, headache, heart associated with adverse events, a statement. palpitations or tingling sensations including heart attack, stroke, seizure, The dietary supplement industry occur.’’ Several members of the Working and death. Therefore, the statement is a recommended that the direction ‘‘Not Group and of the Food Advisory material fact about the consequences of for use by persons under the age of 18’’ Committee also recommended that any use of the product. However, FDA has be included in the warning statement. warning statement include information used the term ‘‘serving’’ rather than Several members of the Working Group on what actions the consumer should ‘‘dose,’’ because the agency considers and of the Food Advisory Committee take if certain symptoms occur (Refs. 25 the term ‘‘serving’’ to be more suggested that the warning statement and 27). appropriate for use on a food label. include a direction that the product is Signs and symptoms, such as The dietary supplement industry not intended for use by persons under dizziness, severe headache, rapid or suggested that the statement include the the age of 18. The agency has received irregular heart beat, chest pain, instruction that ‘‘Taking more than the limited reports of adolescents abusing or shortness of breath, nausea, recommended amount will not misusing ephedrine alkaloid-containing sleeplessness, noticeable changes in necessarily increase benefits.’’ dietary supplements. Moreover, the behavior, or loss of consciousness are Similarly, the Working Group suggested agency has stated elsewhere in this often early warning signs of serious that the warning statement contain the document that claims implying illness or injury, including heart attack, instruction that ‘‘Larger quantities may usefulness of these products as stroke, or seizure. It is important that not be more effective.’’ The agency is alternatives to illicit street drugs render the consumer stop using the product if not aware of any data or other the product an unauthorized drug. FDA these signs or symptoms occur because information that establishes that there considers that removal of alternative continued use of the product may are benefits from the use of dietary street drug claims from the labeling of aggravate the adverse effects. The supplements containing ephedrine dietary supplements will significantly agency tentatively finds that the terms alkaloids. Therefore, the agency would reduce or eliminate the appeal of these ‘‘stop’’ and ‘‘call’’ should be used for be concerned about requiring a products to adolescents and therefore is ‘‘discontinue’’ and ‘‘consult,’’ statement on the label that implies a not proposing to require that this respectively, because they are more judgment (that the product has benefits) direction be included in the warning. simple and direct terms. that the agency has not made. While However, the agency requests comments The proposed warning statement some questions can be raised in this on whether the direction ‘‘not for instructs the consumer to call a health regard under section 403(r)(6) of the act, persons under the age of 18’’ should be care professional if any of the listed the agency considers them to be moot included. Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30703

The industry group’s statement warning statement proposed below may supplements containing ephedrine included the instruction ‘‘Keep out of need to be modified. alkaloids so that consumers are given reach of children.’’ Children show In an effort to promote uniformity in adequate notice of the information increased sensitivity to the effects of labeling, FDA is proposing to require contained in the warning. While the sympathomimetic agents compared to that the warning statement appear on risks associated with the use of dietary adults (Refs. 39 and 41) and are, the labels of ephedrine alkaloid- supplements containing ephedrine therefore, at increased risk for containing dietary supplements in the alkaloids are serious, the agency is not experiencing adverse events from the exact manner presented in proposed proposing to require that the warning use of ephedrine alkaloids. The agency § 111.100(g)(1), except when the label statement for dietary supplements has limited data and information that disclaimer proposed in § 111.100(f) containing ephedrine alkaloids appear dietary supplements containing appears on the same label panel as the on the principal display panel. The ephedrine alkaloids are being given to, warning statement, in which case the agency recognizes that, because of the or are associated with accidental instruction ‘‘Do not exceed length of the required warning overdosage by, children. FDA requests recommended serving’’ would not have statement, in many cases it may be comment, particularly data, on whether to appear in the warning statement. impracticable for the warning statement this statement is necessary to alert However, the agency recognizes that to appear on the principal display panel consumers to the fact that ephedrine other ingredients that may be used in without interfering with the placement alkaloid-containing dietary supplements ephedrine alkaloid-containing dietary of other information that is required to should not be made available to supplements may have consequences of appear on that panel. children. use that need to be disclosed on the The requirement in the act for c. The agency’s proposal. Based on label. The agency requests comments on prominent display means that the FDA’s authority under sections 201(n), how to allow for warning statements for warning statement must be presented on 403(a)(1), and 701(a) of the act, the other ingredients in conjunction with the label or labeling in a manner that agency proposes to require the ephedrine alkaloid warning renders it as readily observable and manufacturers to include the warning statement on the label of dietary likely to be read. In this regard, the statement set out in § 111.100(g)(1) in supplements. In addition, the agency agency’s experience with the graphic the labeling of their ephedrine alkaloid- solicits comments on the format of the requirements for the new nutrition label containing products. The agency warning statement to improve its clarity has been that a box around required (e.g., should the statement be set out in tentatively finds that the warning label information greatly increases the bullets). statement is necessary to disclose prominence of the information placed d. Placement of warning statement on inside the box. Moreover, focus group material facts about the consequences of label. The agency intends to provide an discussions regarding warning labels using the product, and that it will help approach to the placement of the show that messages put in a boxed area to reduce the risk that some individuals warning label statement to give help consumers to distinguish the will experience an adverse event from manufacturers flexibility to design their using this type of product. own label warning formats, while message from other information as well The agency solicits comments on all ensuring that consumers are given as draw attention to it (Ref. 210a). aspects of the warning statement, adequate notice of the information Therefore, FDA is proposing to require including data to support any specific contained in the warning. in § 111.100(g)(3) that the warning instruction. The agency also solicits Section 403(f) of the act requires that statement for ephedrine alkaloid- comments on approaches to shorten or information appearing on the label or containing dietary supplements be simplify the warning statement. Because labeling be prominently placed and separated from other information by a substances contained in ingredients appear with such conspicuousness (as box. If FDA adopts these regulations, (e.g., ephedrine alkaloids contained in compared with other words, statements, manufacturers will have the flexibility Ephedra) are not required to be listed in designs, or devices, in the labeling) as to design their own label and warning the ingredient list on the label of dietary to render it likely to be read by the label format subject to § 111.100(g)(3). supplements, the agency is concerned ordinary individual under customary Section 201(k) of the act defines the that consumers and health care conditions of use. In the agency’s term ‘‘label’’ as ‘‘a display of written, providers may not be aware that rulemaking that mandated warning printed, or graphic matter upon the ephedrine alkaloids are contained in the statements on certain protein products, immediate container of any article’’ and product and thus may not necessarily the agency decided not to mandate further states a requirement that ‘‘any recognize the seriousness of the specific requirements for type size and word, statement, or other information symptoms listed in the statement, when other format elements. However, the appear on the label shall not be they occur. FDA requests comments on agency did require that the warning considered to be complied with unless whether the warning statement should statement appear ‘‘prominently and such word, statement, or other disclose that ephedrine alkaloids are conspicuously on the principal display information also appears on the outside contained in the product. In addition, panel of the package label’’ (§ 101.17). In container or wrapper, if any there be, of the agency is concerned that some addressing the placement of the label the retail package of such AER’s suggest that a pattern of starting warning, the agency noted that the article * * *.’’ Thus, if FDA adopts its and stopping use of dietary supplements seriousness and nature of the risks proposal to require that a warning containing ephedrine alkaloids may associated with the use of protein statement appear on the label of increase an individual’s susceptibility to products in very low calorie diets was ephedrine alkaloid-containing dietary experiencing adverse events. FDA sufficient to require placement of the supplements, the warning statement requests comments on whether the warning statement on the principal would also have to appear on the retail warning statement should disclose the display panel (§ 101.17). package of such a product, if that possibility of increasing the risk of FDA tentatively concludes that the package is not the immediate container. adverse events by a pattern of stopping warning statement that it is proposing FDA requests comments on these and starting use. Based on the must appear prominently and proposed requirements for placement of comments received by FDA, the conspicuously on the label of dietary the warning statement. 30704 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

In addition to this proposed applicable to humans, or whose results of ephedrine alkaloids in dietary regulation, the agency has issued establish intake-response curves for supplements because the therapeutic proposed and final rules on dietary ephedrine alkaloids in dietary use of ephedrine alkaloids has supplements, including premarket supplements and that could be used to traditionally not involved the same notification procedures for new dietary establish a level of ephedrine alkaloids conditions, the same populations, or the ingredients (61 FR 50774, September 27, that are safe for consumers to use in same purposes as those under which 1996) and label warning statements and dietary supplements. The intake- dietary supplements are used (Ref. 25). unit dose packaging requirements for response relationships between The agency considered the iron containing dietary supplements (62 ephedrine alkaloids and their effects in applicability of OTC drug data and FR 2218, January 15, 1997). The agency humans are unknown for both botanical tentatively concluded that these data, has proposed to codify each of the sources and marketed dietary which involve use in a restricted proposed and final regulations in supplement products containing population (physician-diagnosed mild different parts of the Code of Federal ephedrine alkaloids. Moreover, because asthmatics) under limited directions for Regulations. The agency believes that it there are consumers who may be use (i.e., not to exceed 12.5 to 25 mg would be easier for consumers as well sensitive to the effects of ephedrine every 4 hours, not to exceed 150 mg in as for the dietary supplement industry alkaloids because of a variety of factors 24 hours) and with warnings and to find and use regulations for dietary that are not readily identifiable or contraindications for use, has no supplements if they were consolidated predictable, a margin of safety based on application here. The determination of into one part of the CFR. Accordingly, classical toxicological principles likely safety for drugs is based on a weighing FDA is proposing to revise part 111 to cannot be determined. For these of the proven benefits of the use of the consolidate the regulations for dietary reasons, the agency tentatively finds product against the risks. This approach supplements. FDA is proposing to that the use of a classical toxicological may not be used with foods under change the title of part 111 from approach to determine a safe level of section 402(a) of the act. The only ‘‘Current Good Manufacturing Practice ephedrine alkaloids in dietary question for food use under this section for Dietary Supplements’’ to ‘‘Dietary supplements is not a usable approach. is whether it will cause harm or not. Supplements.’’ This is necessary to Several members of the Food While the concept of ‘‘unreasonable reflect that other regulations for dietary Advisory Committee recommended that risk’’ as stated in section 402(f)(1)(A) of supplements in addition to regulations FDA consider the risk associated with the act, may imply that some evaluation for current good manufacturing practice the use of dietary supplements of effects, including risks and benefits, will be contained in this part. FDA is containing ephedrine alkaloids in the is appropriate for dietary supplements, proposing to establish four subparts in context of any benefit that the consumer it is not necessary to reach that question part 111: Subpart A—General may receive from the use of these here, because, as stated above, there are Provisions, Subpart B—Current Good products (Ref. 25). In applying a risk-to- no demonstrated benefits for ephedrine Manufacturing Practice for Dietary benefit calculation, a certain amount of alkaloids. Moreover, the risks attendant Supplements, Subpart C—New Dietary risk may be accepted if there is a on consuming dietary supplements Ingredients, and Subpart D—Restricted meaningful benefit to be gained by the containing levels of ephedrine Dietary Ingredients. The labeling consumer (Ref. 25). However, the Food permitted in oral bronchodilator drugs provisions for dietary supplements will Advisory Committee members were (12.5 to 25 mg ephedrine per dose) are continue to be placed in 21 CFR part unable to identify a benefit for manifest. 101. ephedrine alkaloids in terms of In addition, there is no basis for supplementing the diet (Ref. 25). extrapolating from data from a subgroup D. Other Approaches Considered by the Moreover, risk-benefit analysis is of the population, diagnosed asthmatics, Agency something that is done under the act for who may be less sensitive to the effects In choosing the proposed approach to drugs, not food. of ephedrine (Ref. 25) than the general limit the risks presented by ephedrine Several members of the Working population, to the general population, alkaloids in dietary supplements, the Group suggested that any limitations on among which a significant number of agency considered, but rejected, several the level of ephedrine alkaloids in people are known or suspected of being other approaches. Because the act does dietary supplements be based on the use very sensitive to ephedrine. not allow premarket review authority of pharmaceutical ephedrine in OTC Finally, the agency finds it for dietary supplements, FDA has no oral bronchodilator drugs and the use of inappropriate to extrapolate data from data and information to establish Ephedra in traditional herbal medicine the use of OTC ephedrine-containing conditions of use that will ensure the (Ref. 27). Other members of the Working drugs because dietary supplements safe use of ephedrine alkaloid- Group and several members of the Food contain a mixture of several ephedrine containing dietary supplements. Advisory Committee found difficulty in alkaloids and a variety of other Therefore, the only viable approach extrapolating from OTC drug data ingredients, including vitamins, available to FDA is one in which the because the products, the populations minerals, other botanicals, and other agency prohibits levels of a substance using the products, and intended use of physiological and pharmacologically in, or conditions of use for, a dietary the products are dissimilar (Ref. 25). In active substances, while OTC drugs supplement that it can prove may addition, the latter members were contain only a single ephedrine render the product injurious to health or concerned about the potential for alkaloid. The presence of other alkaloids that present a significant or adverse events to occur, particularly in and substances in dietary supplements unreasonable risk of illness and injury populations sensitive to the effects of may act to increase the likelihood, under the conditions of use suggested or ephedrine alkaloids, if therapeutic frequency, and severity of adverse recommended in the labeling or under levels of ephedrine are used in dietary events from the use of these products. ordinary conditions of use. supplements (Ref. 25). Several members In fact, clinical studies show that The agency is unaware of any of the Food Advisory Committee were adverse events are more likely to occur classical toxicological studies whose also concerned about using data from when ephedrine is combined with other results identify ‘‘no adverse effect the use of Ephedra in traditional herbal substances, such as caffeine. Therefore, levels’’ for ephedrine alkaloids directly therapies to support the safety of the use the fact that pharmaceutical ephedrine Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30705 has been approved by FDA for an OTC competition, or jobs, or if it raises novel 6. Take proposed action, but do not use does not provide assurance of safety legal or policy issues. If a rule has a require warning statement. for the use of ephedrine alkaloids in significant economic impact on a 7. Require warning statements only. dietary supplements. substantial number of small entities, the C. Benefits and Costs The agency considered the Regulatory Flexibility Act requires applicability of traditional use of agencies to analyze regulatory options 1. Option 1—Take No Action botanical sources of ephedrine alkaloids that would minimize the economic By convention, the option of taking no in establishing dietary ingredient levels impact of that rule on small entities. action is the baseline in comparison for ephedrine alkaloids in dietary FDA finds that this proposed rule is with which the costs and benefits of the supplements. A history of long usage of an economically significant rule as other options are determined. Therefore, a medicinal herb in traditional therapies defined by Executive Order 12866, and neither additional costs nor benefits are does not provide an assurance of safety finds under the Regulatory Flexibility associated with taking no action. for a component of a dietary supplement Act that this proposed rule will have a Although no regulatory costs or benefits because these conditions of use are so significant impact on a substantial are generated if no regulatory action is different. The history of use of Ephedra number of small entities. Finally, FDA, taken, preventable adverse events will in traditional Asian medicine primarily in conjunction with the Administrator continue to occur if no regulatory action for the treatment or relief of respiratory of the Office of Information and is taken. The number of such adverse symptoms provides insufficient Regulatory Affairs (OIRA) of the Office events is expected to increase over time assurance that ephedrine alkaloids will of Management and Budget (OMB), because the marketplace for these types not present a significant or an finds that this proposed rule is a major of products has been increasing rapidly unreasonable risk of injury to rule for the purposes of congressional since the 1994 passage of the DSHEA, consumers who use dietary supplement review (Pub. L. 104–121). products containing ephedrine alkaloids and the number of AER’s associated to supplement the diet. Not only are A. Market Failure with use of these products has also been dietary supplements marketed for The market failure addressed by this increasing sharply over the last few different uses than the traditional use of regulation is that some consumers may years (Figure 1). Ephedra, most dietary supplements are not have sufficient information on the 2. Option 2—Take No Regulatory marketed in a form that is different than health risks associated with dietary Action, but Generate Additional the form in which it has been supplements containing ephedrine Information on Which To Base a Future traditionally used, e.g., as a alkaloids to make informed choices Regulatory Action concentrated extract in capsules and concerning the consumption of these tablets, in the presence of other products, despite the presence of FDA has the option of taking no substances rather than the raw botanical warning labels of various types on many regulatory action but generating in a tea. of these products. Ordinarily, additional information on which to base FDA is not aware of any systematic consumers would be expected to seek future regulatory action on this issue. collection of data related to adverse out and pay for the level of information The benefit of generating additional effects occurring in individuals treated they consider appropriate with respect information is a reduction in the with Ephedra in traditional medicine. to consumption decisions. However, the substantial uncertainty concerning the However, several reference texts list level of information currently utilized specific nature of the relationship of the precautions and contraindications for by consumers with respect to these adverse events associated with dietary the use of the botanical Ephedra in products may be less than optimal supplements containing ephedrine traditional medicine preparations (Refs. because of consumer perceptions that alkaloids and, possibly, a more precisely 6, 14, and 146). Thus, FDA tentatively products marketed as foods or derived targeted regulation. A more precisely concludes that use of ephedrine from botanical sources are inherently targeted regulation could imply potency alkaloids in traditional Asian medicine safe, and the cost of generating evidence limits either higher or lower than the does not provide the basis on which to to evaluate the safety of these products proposed potency limits, and either establish a safe level of use of ephedrine may be quite high. In addition, the onset more or fewer ingredient and labeling alkaloids in dietary supplements. of the adverse health events associated restrictions than those proposed. The cost of generating additional IV. Analysis of Impacts with these products is frequently quite unexpected or occurs without information is the cost of whatever FDA has examined the impacts of the identifiable risk factors, and consumers activity is undertaken to generate the proposed rule under Executive Order may have little or no opportunity to additional information and the health 12866 and the Regulatory Flexibility Act adapt their behavior based on cost of any adverse events to these (5 U.S.C. 601–612). Executive Order experience with the risks of these products that would occur if regulatory 12866 directs agencies to assess all costs products prior to suffering a severe action were delayed but that would not and benefits of available regulatory adverse event. occur if regulatory action were not alternatives and, when regulation is delayed. necessary, to select the regulatory B. Regulatory Options 3. Option 3—Take Proposed Action approach that maximizes net benefits FDA has the following primary (including potential economic, options: a. Benefits. The benefit of the environmental, public health and safety, 1. Take no action. proposed action is a potential reduction and other advantages; distributive 2. Take no regulatory action, but in the number or severity of adverse impacts; and equity). Executive Order generate additional information on events associated with dietary 12866 classifies a rule as significant if which to base a future regulatory action. supplements containing ephedrine it meets any one of a number of 3. Take proposed action. alkaloids. The proposed rule consists of specified conditions, including having 4. Take proposed action, but with a the following four actions: (1) Per day an annual effect on the economy of $100 higher potency limit. and per serving potency limits on total million or adversely affecting in a 5. Ban dietary supplements that ephedrine alkaloids (TEA), (2) material way a sector of the economy, contain ephedrine alkaloids. restrictions on caffeine and other 30706 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules stimulants, (3) mandatory warning all ephedrine alkaloids from these breakfast cereals were reported to have statement, and (4) labeling restrictions. products. First, the functional effect, as increased approximately 40 percent To estimate the benefits of these perceived by consumers, of removing all (Ref. 213). The effect of eliminating actions, a percentage decrease in the ephedrine alkaloids from a product is label claims on dietary supplements current number of adverse events probably greater than the perceived containing ephedrine alkaloids will associated with dietary supplements functional effect of removing some of probably be smaller because the claims containing ephedrine alkaloids will be the ephedrine alkaloids and removing involved are more general, and because estimated for each regulatory action some ingredients that interact with other sources of information on the listed above. The estimated effects of all those ephedrine alkaloids. Second, if purported effects of ephedrine alkaloids proposed actions will then be combined only some firms remove ephedrine are readily available or have been used to obtain a total reduction in the alkaloids from their products, relatively recently enough that consumers are expected annual number of adverse close substitutes will exist for the prior familiar with them. events. This percentage reduction will formulations of those products because However, approximately 10 percent of then be applied to an estimate of the other firms might not remove ephedrine the AER’s involved supplements labeled current number of such adverse events alkaloids from their products. However, as alternatives to street drugs. Assuming to obtain an estimated number of if all firms make the same changes in that consumers of these products will adverse events avoided per year. The their products, then relatively close not purchase these products if they are estimate of the current number of substitutes will not exist for the prior not labeled as alternatives to street adverse events will be based on, but not formulations of those products. drugs, the labeling restriction will identical to, the current number of Therefore, the proposed potency limits reduce expected adverse events by at relevant AER’s because of uncertainty and other ingredient restrictions are least 10 percent. Therefore, the over a number of issues including, for estimated to reduce the number of proposed restriction on label claims will example, the degree to which the people consuming these products by probably reduce the number of people relevant adverse events are reported. between 0 to 33 percent. The effect of consuming these products by between These sources of uncertainty will be the potency limits on the probability of 10 percent and 40 percent. discussed in greater detail later. an adverse event for those who continue In addition to these consumption Each of the proposed actions may to consume these products will be effects, the proposed potency limits and affect the number of adverse events by addressed later in this section. ingredient restrictions will probably reducing the number of people who The proposed warning statement is also decrease the likelihood that those consume the relevant products or by also likely to reduce the number of who continue to consume these modifying their use of these products in people consuming these products products will suffer an adverse event. a manner that reduces the risk of an because a few of the relevant products FDA is not aware of clinical adverse effect. In addition, the potency do not currently have warning information, particularly evidence from limits and ingredient restrictions may statements, and because, in some cases, well-designed and conducted human affect the number of adverse events by the proposed warning statement is more studies on the relationship between reducing the probability that those who comprehensive, more focused, and more intakes of ephedrine alkaloids from consume these products will suffer an strongly worded than existing warning botanicals and the probability of an adverse event. Each of these effects will statements. The only information adverse event. One method of be considered in turn, beginning with available on the effect of warning approaching the estimation of the health the effect of the proposed actions on the statements on sales concerns diet soft benefits of reduced exposure to number of people who consume these drinks containing saccharin. Following ephedrine alkaloids is to consider the products. the introduction of warning statements proportion of adverse event reports that The proposed potency limits and relating to saccharin, annual sales of involve products with TEA levels other ingredient restrictions may affect diet soft drinks containing saccharin greater than that allowed under the the number of people consuming these were reported to be 15 percent below proposed potency limits. FDA was able products because they may affect the what they would otherwise have been to obtain information on the actual value placed by consumers on the use (Ref. 212). The effect of the proposed exposures associated with adverse of these products. Some information on warning statement for dietary events for 13 products that provided the likely effect of the proposed potency supplements containing ephedrine intakes of less than 20 mg TEA per limits on the consumption of these alkaloids will probably be smaller than reported use by multiplying the products comes from a report from one the effect of the saccharin warning label consumer’s reported use level against an firm that marketed an ephedrine on diet soft drinks because most such FDA product analysis result. These alkaloid-free substitute for a supplement supplements already have some type of reports provided information on the that previously contained ephedrine warning statement. Therefore, the lower end of the range of estimated alkaloids. The sales of the substitute proposed warning statement will intakes by consumers. Among these 13 product were reportedly approximately probably reduce the number of people reports of adverse events associated 33 percent lower than the sales of the consuming these products by 0 to 15 with intakes of less than 20 mg, 9 ephedrine alkaloid-containing product percent. involved consumer intakes of between 8 (Ref. 211). In the absence of more The proposed label claim restrictions mg and 20 mg/per serving. This specific information, it is reasonable to are also likely to reduce the number of approach suggests that the proposed suppose that a given reduction in sales people consuming these products by potency limit might reduce the expected is associated with a proportionate making the marketing of these products number of adverse events by at least 80 reduction in the number of people more difficult. The only information percent, although the actual reduction is consuming these products. available on the potential effects of label probably higher because the 13 reports It would not be reasonable to suppose claims on sales concerns ready-to-eat did not include the many adverse event the proposed potency limits and other breakfast cereals. Following an reports that occurred at intakes above 20 ingredient restrictions would have a advertising campaign relating bran mg TEA per serving. On the other hand, greater effect on the sales of these consumption to a reduced risk of the actual reduction might also be lower products than complete elimination of developing cancer, sales of high bran because the 13 reports did not include Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30707 all adverse event reports that occurred somewhat lower because the impact probably between 27 and 90 percent. at intakes below 20 mg TEA per serving. may depend on the levels of stimulants Within this range, FDA believes the This approach to estimating the and ephedrine alkaloids involved, and most likely value is around 80 percent impact of the proposed potency limits the levels of stimulants and ephedrine and, therefore, tentatively assumes that assumes that the probability of an alkaloids found in dietary supplements 80 percent of the reported adverse adverse event is related to intakes of may be lower than the levels used in the events are actually related to the TEA. If the probability of an adverse study on which this estimate is based. consumption of dietary supplements. event is not related to TEA intake, then In order to address this possibility, the FDA requests comments on this the potency limits may result in little or restrictions on stimulants will be assumption. no reduction in the expected number of assumed to reduce the expected number The second issue is the uncertainty adverse event reports. For example, if of adverse reactions by 25 percent. that all 600 AER’s involved products individual sensitivities to ephedrine In order to use the estimated risk that actually contained ephedrine alkaloids are the major underlying factor reductions discussed above to derive an alkaloids. Confirmation of the presence in the reported adverse events, then it expected reduction in the number of of ephedrine alkaloids in problem is possible that there may be no ‘‘safe’’ adverse events, the current number of products is not available in all cases. intake for these persons. Based on this adverse events must be estimated. There The likelihood of the presence of information, all that can be said are a number of issues involved in ephedrine alkaloids is based on the concerning the proposed potency limits estimating the current number of labeling of the products involved, FDA’s is that they may reduce the expected adverse events based on the number of own market survey (including number of adverse events by between 0 reported adverse events. laboratory analysis of 125 marketed to 80 percent. The first issue is that the data base of products), and the similarity of the The restriction on other stimulants, over 600 AER’s includes all reports reported adverse events to the known including caffeine, should also reduce thought to be related to the effects of ephedrine alkaloids. The the probability of an adverse event. consumption of ephedrine alkaloid- proportion of reported adverse events Combinations of ephedrine alkaloids containing dietary supplements, even associated with dietary supplements and caffeine, at sufficiently high doses, though the nature of the available that involve supplements containing are associated with an increased evidence did not allow specific cause ephedrine alkaloids is probably between probability of an adverse event. For and effect determinations for the 25 and 90 percent. Within this range, example, one study found that 60 majority of individual reports. FDA, FDA believes the most likely value is percent of the study subjects had an therefore, used additional information around 80 percent and, therefore, adverse reaction to a combination of 20 to provide assurance that the patterns of tentatively assumes that 80 percent of mg ephedrine and 200 mg caffeine, signs and symptoms associated with the the reported adverse events associated while only 44 percent had an adverse ephedrine alkaloid-containing dietary with consumption of dietary reaction to 20 mg ephedrine alone (Ref. supplements were likely due to the supplements involve supplements that 105). Thus, in this study, the presence presence of ephedrine alkaloids in these contain ephedrine. FDA requests of 200 mg caffeine appears to have products. One approach to addressing comments on this assumption. increased the probability of an adverse this issue is to examine the evidence for The third issue is that the actual event from consumption of 20 mg positive dechallenge and rechallenge number of adverse events is likely to ephedrine by about 50 percent. when product use is discontinued and differ from the reported number of Comparable information is not available reinitiated, respectively. The adverse events because all adverse on the effect of combinations of relationship of the reported adverse events are probably not reported. This ephedrine and caffeine at lower levels of events to the consumption of dietary issue is particularly important with either ephedrine or caffeine. Similarly, supplements categorized as containing respect to passive reporting systems that no information is available on the effect ephedrine alkaloids has been rely on the voluntary submission of of other stimulants or other ephedrine corroborated by dechallenge in about 27 data, such as the system used to gather alkaloids. percent of the AER’s. Positive the AER’s relevant to this issue. An informal review of 217 adverse rechallenge was reported in about 4 Typical reporting rates for passive event reports featuring dietary percent of the AER’s. The majority of reporting systems addressed to adverse supplements suspected of containing AER’s, however, lacked sufficient events associated with drugs are ephedrine alkaloids found that 99 information to evaluate the presence or generally assumed to be on the order of reports featured products for which absence of dechallenge or rechallenge 10 percent. Reporting rates are higher labeled ingredient information was effects. Therefore, the number of cases than usual if the potential health risks available. Of those reports, 70 percent in which dechallenge alone or in associated with a particular substance involved products labeled as containing combination with rechallenge was tried are widely publicized, if the adverse a source of caffeine. The levels of but did not occur is not available; nor events are considered to be otherwise caffeine and ephedrine alkaloids in is there information on whether unusual, and if reports are gathered these products is not known. Assuming dechallenge and rechallenge would from a variety of sources. On the other that these adverse event reports are have occurred in the large number of hand, reporting rates would be lower typical of all relevant adverse event reports which lack such information. It than usual if consumers and physicians reports and that 50 percent of the is possible that all cases might have assume that dietary supplements are reported adverse events to products been associated with positive incapable of producing adverse events labeled as containing caffeine may have dechallenge and rechallenge results if because they are not drugs or because been due to the presence of caffeine in such information were available. On the they are ‘‘natural.’’ In order to conjunction with ephedrine alkaloids, other hand, a certain number of false incorporate this uncertainty, the the restriction on stimulants is reports might also be expected. The reporting rate for the relevant adverse estimated to reduce the expected proportion of reported adverse events events is assumed to be 10 percent. number of adverse events by up to 35 actually related to the consumption of Based on the current number of percent. However, the impact of the dietary supplements suspected of reported adverse events and the proposed stimulant restrictions may be containing ephedrine alkaloids is assumptions discussed above 30708 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules concerning the relationship between the myocardial infarctions, dysrhythmias, most likely values for the relevant number of reported adverse events and strokes, and cardiomyopathies. ‘‘Serious assumptions. The fourth column is the the underlying number of adverse NS’’ refers to serious nervous system estimated reduction in adverse events events, the expected annual number of events, including seizures, loss of from all proposed actions, given as a adverse events involving these products consciousness, vestibular events, and range from low to high. These estimated is approximately 1,100 cases. Applying psychiatric events. ‘‘Less clinically reductions are based on adding the the risk reductions discussed previously significant’’ events may include certain effects of the proposed actions as for the proposed actions implies a types of dermatological events and summarized in Table 7. The low end of reduction in the health risks from these gastrointestinal events. The second this range represents a 35 percent products such that the expected number column is the average annual number of reduction in the estimated annual of adverse events involving these AER’s from January 1993 to June 1996. adverse events and the high end products will be reduced by between Because the sales of these products is represents a 100 percent reduction. The approximately 400 cases and 1,100 increasing rapidly, and the reports of estimates have been rounded to the cases per year. Based on published adverse events are also increasing nearest ten. The fifth column is the estimates of the value consumers might rapidly (see Figure 1), FDA believes that value of reducing the risk of particular place on reducing the risk of the general this is a conservative estimate of adverse events such that one expected types of adverse events involved, these benefits. The 3-year average has been adverse event is avoided per year across benefits are valued at between $240 used rather than the growth trend the at-risk population, in thousands of million and $670 million per year (Ref. because extrapolating short-term growth dollars. The sixth column is the 215). trends into the future can result in large estimated value of the annual risk Table 6 summarizes these results. The errors. The third column is the reductions for the various adverse first column is the type of adverse event. estimated average annual number of events in millions of dollars, given as a ‘‘Serious CVS’’ refers to serious adverse events over this time period range from low to high, rounded to the cardiovascular system events, including based on what FDA believes are the nearest million.

TABLE 6.ÐESTIMATED VALUE OF ANNUAL RISK REDUCTION FROM PROPOSED ACTIONS

Value of estimated risk Value of esti- Annual re- Estimated Reduction in reduction per mated risk Type of event ported annual estimated an- case reduction cases 1 cases 2 nual cases 3 ($ thou- ($ millions) 5 sands) 4

Death ...... 6 40 10±40 5,000 70±190 Serious CVS ...... 27 170 60±170 837 50±140 Serious NS ...... 29 190 70±190 1,483 100±280 Ab. liver function ...... 7 50 20±50 3 0 Other serious ...... 12 80 30±80 775 20±60 Less serious ...... 93 600 210±600 0.4 0

Total ...... 174 1,110 390±1,110 NA 240±670 1 Annual reported cases are based on the average number of adverse event reports per year between January 1993 and June 1996. Trends in the data were not extrapolated because of the short timeframe involved. 2 Estimated annual cases are based on the following assumptions: (1) 80 percent of the reported adverse events involving the consumption of dietary supplements suspected of containing ephedrine alkaloids are actually related to the consumption of dietary supplements, (2) 80 percent of the supplements involved in the reported adverse events that are related to the consumption of supplements actually contain ephedrine alkaloids, and (3) 10 percent of adverse events to the dietary supplements containing ephedrine alkaloids are reported. Thus, the estimated number of annual cases is 0.8 × 0.8 × 10 times the number of annual reported cases. Considerable uncertainty exists with respect to the validity of the assumptions on which this estimate is based and the actual number of annual cases may be higher or lower than the estimate. 3 The low end of the range of the reduction in estimated annual cases represents a 35 percent reduction in estimated annual cases. The high end of this range represents a 100 percent reduction in estimated annual cases. The 35 percent and 100 percent estimates are based on adding up the estimated effects of the proposed actions, as indicated in Table 7. 4 The value of the risk reduction per case is based on published estimates of the value consumers place on reducing the risk of the general types of adverse events involved (Ref. 215). 5 The value of the estimated risk reduction is based on multiplying the risk reduction per case times the reduction in the estimated annual cases.

TABLE 7.ÐCOMBINED EFFECT OF PROPOSED ACTIONS

Estimated reduction in ad- Proposed action verse events (in percent)

Actions reducing consumption of supplements containing ephedrine alkaloids: Potency limits and ingredient restrictions ...... 0±33 Warning statement ...... 0±15 Label claim restrictions ...... 10±40 Combined effect ...... 10±88 Actions reducing probability of adverse event given consumption: Potency limits ...... 0±80 Ingredient restrictions ...... 25 Combined effect ...... 25±100 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30709

TABLE 7.ÐCOMBINED EFFECT OF PROPOSED ACTIONSÐContinued

Estimated reduction in ad- Proposed action verse events (in percent)

Combined effect of all proposed actions ...... 35±100

b. Costs. The primary social costs of FDA has previously estimated the cost Dose Packaging Requirements’’ that the proposed actions are the compliance of relabeling all dietary supplements in published in the Federal Register of costs, which include the one-time costs the economic impact analysis for the January 15, 1997 (62 FR 2218), this associated with relabeling and proposal on nutrition labeling of dietary estimate was revised to 29,000. If 200 reformulating the affected supplements supplements that was published in the dietary supplements contain ephedrine and the recurring costs associated with Federal Register of December 28, 1995 alkaloids, then about 1 percent of the testing for the level of ephedrine (60 FR 67184) (the December 1995 estimated total number of dietary alkaloids in conjunction with future proposal). Total discounted labeling supplements contain ephedrine product reformulations or changes in costs based on an 18 month compliance alkaloids and the cost of changing the ingredients, and the value of the utility period were estimated to be between labels on dietary supplements losses to any consumers who do not $52 and $85 million. This cost included containing ephedrine alkaloids would value the reformulated supplements as recurring testing or analytical costs be about 1 percent of the costs estimated highly as supplements currently found based on testing the nutrient content of for changing the labels on all dietary on the market. This cost must be each product an average of once every supplements. considered somewhat paradoxical 5 years. Based on comments to the Another method of estimating the because the cause of this loss of value, December 1995 proposal, these proportion of dietary supplements that the reduction or removal of ephedrine estimates were revised in the economic contain ephedrine alkaloids is to use alkaloids, would also reduce or impact analysis of the final rule. The sales data. This method is complicated eliminate the risks associated with using revised estimate was $194 million, with by the fact that sales might not be these products. In addition, indirect $91 million of these costs occurring in evenly distributed across dietary social costs in the form of capital losses the first 18 months and the remainder supplements, implying that the and temporary unemployment may arise being a discounted sum of future proportion of dietary supplement sales from the distributive effects of the analytical costs. In order to use this accounted for by supplements that proposed action, which are discussed estimate as a basis for estimating contain ephedrine alkaloids may not be below. Some portion of the compliance labeling costs for the current proposal, the same as the proportion of dietary costs will be borne by manufacturers the previous estimate must be adjusted supplement products that contain and distributors of these products, and to account for the compliance period ephedrine alkaloids. some portion will be passed on to associated with this rule and the fact Ma huang and other ephedra products consumers of these products. Costs that not all dietary supplements contain have been reported to represent 3.5 borne by manufactures and distributors ephedrine alkaloids. percent of individual botanical sales in selected health food stores, while will be borne by the owners, The proposed effective date of any regulation based on this proposal will individual sales of products containing stockholders, and employees of those be 180 days after the date of publication single botanicals are estimated to make firms. of the final rule. If the nutritional up about 53 percent of total botanical In addition to the potential impact of labeling rule had a compliance period of supplement use (Ref. 3). Information is compliance costs, manufacturers and 180 days rather than 18 months, the not available on the proportion of distributors of the dietary supplements total estimated labeling costs would products with multiple botanical containing ephedrine alkaloids will be have been $334 million, with $286 ingredients that contain ephedrine adversely affected by the reduction in million of these costs occurring in the alkaloids. Botanical supplement retail consumption of these products caused first 6 months. sales have been estimated to have by the proposed actions. Also, Adjusting the previous estimate to accounted for approximately 26 percent manufacturers, distributors, and account for the fact that not all dietary of total dietary supplement retail sales importers of raw or bulk Ma huang and supplements contain ephedrine in 1995 (Ref. 217). However, this other affected ingredients may be alkaloids requires information on the estimate includes a number of product affected by these consumption effects. proportion of dietary supplements that categories under dietary supplements These effects are distributive effects contain ephedrine alkaloids. The market that would not be considered dietary rather than social costs because they do surveys identified 125 dietary supplements under the legal definition not involve the loss of productive supplements suspected of containing of a dietary supplement. After adjusting resources, and because a loss of ephedrine alkaloids. A public comment for the definition of dietary business in one sector of the economy submitted to the Special Working Group supplements, supplements containing is generally associated with an increase of the Food Advisory Committee botanicals accounted for approximately in business in competing sectors. suggested the number of such products 35 percent of dietary supplement retail However, as indicated above, social is at least 200 (Ref. 216). In the sales in 1995. The definition of dietary costs may be involved to the extent that December 1995 proposal, the total supplement used in this estimate otherwise productive capital investment number of dietary supplement products includes vitamins, minerals, and is lost and temporary unemployment is was estimated to be between 4,000 and botanical (including herbal) generated. In addition, distributive 25,000. In the final rule entitled ‘‘Iron- supplements. effects are obviously very significant to Containing Supplements and Drugs: If all supplements containing the affected parties. Label Warning Statements and Unit- ephedrine alkaloids are characterized as 30710 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules botanical supplements, this information will either have to be reformulated or consumer utility losses that may be suggests that between 1 and 17 percent removed from the market. The number associated with this action. However, if of dietary supplement use involves of dietary supplements containing substitute products could be identified, products that contain ephedrine ephedrine alkaloids has been estimated, then the absolute price difference alkaloids. If the proportion of dietary above, to be between 200 and 5,000. between the affected products and the supplement products containing Under this assumption, if all products substitute products would represent a ephedrine alkaloids reflects the were reformulated, the one-time cost of lower bound on consumer utility losses. proportion of dietary supplement sales reformulating the affected products No comparable argument is available for accounted for by products containing would be between $0.2 million and $25 the upper bound of the utility loss. ephedrine alkaloids, then between 1 and million. The recurring costs associated In addition to compliance costs and 17 percent of the total number of dietary with testing for ephedrine alkaloid utility losses, the proposed action will supplement products contain ephedrine levels in conjunction with future also generate distributive effects. The alkaloids, or between 200 and 5,000 product reformulations was addressed total reduction in the consumption of products. in the labeling costs. dietary supplements containing Based on the preceding information, Another cost associated with product ephedrine alkaloids from all proposed labeling costs for this proposal are reformulation is the cost of any actions including the potency limits, estimated to be between 1 and 17 inventory losses involving products ingredient restrictions, labeling percent of the costs previously produced prior to the publication of a restrictions, and mandatory warning estimated for changing the labels on all final rule based on this proposal that statement was estimated in the analysis dietary supplements, after adjusting cannot be sold by the date that final rule of the benefits of this option to be those costs for the length of the goes into effect. The proposed effective between 10 percent and 33 percent. compliance period. Thus, total date of any final rule on this issue is 180 Total annual sales of supplements discounted labeling costs for this days after publication of the final rule. containing Ma huang have been proposal are estimated to be between $3 FDA has no information on the amount estimated to be between $600 million million and $60 million, with between of inventory typically carried for these and $700 million (Ref. 219). Therefore, approximately $3 million and $50 products, but tentatively assumes that sales of these products may be reduced million of these costs occurring in the 180 days will provide sufficient time to by between $60 million and $230 first year and between a minimal utilize existing stock. million per year. Information is not amount and approximately $0.5 million In addition to the compliance costs available on the total annual sales of in every year after the first year. discussed above, the proposed action supplements containing sources of If the proposed 180 day compliance will also lead to utility losses for some ephedrine alkaloids other than Ma period for making the proposed label consumers because it removes products huang. changes coincided with some portion of with certain characteristics from the Countervailing effects may also take the 18-month compliance period of the marketplace. Theoretically, the value of place which may reduce the impact of final rule requiring nutritional labeling this utility loss is the difference in the these negative distributive effects on of dietary supplements, then some value consumers placed on the affected firms. For example, the portion of the combined labeling costs eliminated products and the value of the proposed rule may reduce the number of the two regulations would be products purchased in place of the of product liability lawsuits brought eliminated because some firms would eliminated products. Estimating this against manufacturers of dietary be able to make both labeling changes loss requires estimating demand curves supplements containing ephedrine during normally scheduled labeling for the eliminated products and for the alkaloids. FDA has insufficient changes. The degree of overlap of the products substituted for the eliminated information on the current incidence or compliance periods of these regulations products. cost of these lawsuits to estimate the depends on the date on which the final Identifying likely substitutes for effect of this reduction, if any, on the rule is published. If appropriate, this dietary supplements as currently negative distributive effects generated consideration will be addressed in the formulated is complicated by the fact by consumption changes. Of course, economic analyses of the final rule. that a wide range of effects are distributive effects that are negative Information is not available on the attributed to these supplements, for with respect to a given industry will be cost of reformulating the affected example, energy, weight loss, body positive with respect to some other products. Reformulation may simply building, and increased mental industry. involve reducing the amount of the concentration. However, little reliable Finally, social costs may be associated ingredient source of the ephedrine information is available on the actual with these distributive effects. For alkaloids and removing the restricted effects produced by these supplements. example, some portion of the value of ingredients. One method of approaching In addition, various other botanical the capital invested in the production of this issue is to consider the types of substances exist that might be used in these supplements may be lost and that personnel and the amount of effort that supplements to replace either some loss might not be offset by other effects, might be required for reformulation. A portion of the ephedrine alkaloids or the such as an augmentation to the value of reasonable assumption is that it might restricted ingredients and might the capital invested in the production of take a scientist from 1 to 4 weeks to produce effects that consumers may substitutes. However, FDA has develop an acceptable reformulation. In perceive to be similar to the effects that insufficient information to estimate the this case, the cost of reformulating a consumers attributed to these social costs that might be associated product would be between $1,000 and supplements as currently formulated. with these distributive effects. $5,000, based on median weekly Finally, FDA has insufficient Under these assumptions, the earnings data for 1994 and 50 percent information to estimate demand curves proposed action will generate total overhead (Ref. 218). for dietary supplements containing compliance costs of between $3 million Many dietary supplements containing ephedrine alkaloids or potential and $80 million, plus unquantifiable ephedrine alkaloids probably contain substitutes for these products. utility losses to consumers of these restricted ingredients or do not meet the Based on these considerations, FDA products. Between $3 million and $70 proposed potency limits on TEA and cannot place bounds on the value of the million of these costs will occur in the Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30711 first 6 months after publication of the of these products than the proposed have warning statements. Even with the final rule. In addition, the proposed potency limits. However, as indicated proposed potency limits and ingredient action will produce distributive effects above, FDA has insufficient information restrictions, some consumers may be at of between $60 million and $230 to estimate the effect of small changes high risk of suffering an adverse event million per year and social costs might in the potency limits on the from consuming these products because be associated with those distributive consumption effects produced by those of high individual sensitivity to these effects. Because the sales of these limits and cannot estimate the utility products, because of an increase in risk products are increasing rapidly, FDA losses associated with various potency associated with simultaneous believes that this is a conservative limits. consumption of drug products, or estimate of cost and distributive effects. because of an underlying health 5. Option 5—Ban Dietary Supplements Again, extrapolations have not been condition. Thus, the proposed warning That Contain Ephedrine Alkaloids made on the growth trend because statement is expected to have some extrapolating short-term trends into the Based on the framework used earlier, benefit independent of the other future can result in large errors. Costs banning dietary supplements that proposed requirements. Eliminating the and sales reductions of this magnitude contain ephedrine alkaloids would lead proposed mandatory warning statement may threaten the viability of many firms to a somewhat higher lower bound on will affect estimated labeling costs in this industry. If some of these firms estimated benefits. In particular, because, under this option, only those go out of business, temporary banning these products would reduce labels affected by the claims restrictions unemployment of labor and permanent the health risks from these products would have to be changed. However, the loss of capital resources may result. such that the expected number of vast majority of the affected products FDA has insufficient information to adverse events are reduced by between have labels that would be affected by estimate these costs. approximately 120 cases and 1,400 the claims restrictions. Among the cases per year. products in the market surveys, 94 4. Option 4—Take Proposed Action, but Banning dietary supplements that percent of the products investigated had With a Higher Potency Limit contain ephedrine alkaloids will not one or more claims that would be Another option is to take all proposed change the one time compliance costs restricted under this option. Thus, actions but adopt potency limits higher estimated under Option 3 because all labeling costs under this option will be than the proposed potency limits. For affected products were subject to only approximately 6 percent lower example, some trade associations reformulation and relabeling costs than the labeling costs estimated for representing the dietary supplement under Option 3. However, banning these Option 3. industry have previously expressed products would decrease access to these Finally, under the framework support for potency limits of 12 mg/ products by consumers who may developed earlier, this option will have serving and 50 mg/day TEA (Ref. 220). perceive benefits, thus substantially little effect on the other costs and With respect to benefits arising from increasing the potential utility losses to distributive effects estimated for the consumption effects (i.e., the likelihood consumers. With respect to distributive proposed action under Option 3 because of reducing the number or seriousness effects generated by consumption of the influence of the other factors of adverse events), FDA has some changes, the total reduction in the involved. information to estimate the effect of consumption of dietary supplements variations between the proposed that now contain ephedrine would 7. Option 7—Require Warning potency limits and higher potency probably be approximately 33 percent Statements Only limits on the consumption effects under this option, that is, at the high Estimating the benefit of eliminating associated with those limits. That is, of end of the range of 10 to 33 percent all proposed actions except the required the 13 reports of adverse events for estimated under Option 3. Therefore, warning statement involves a which exposure data for intakes less sales of these products would be controversial value judgment than 20 mg per serving were also reduced by between $200 million and concerning the evaluation of risks that available, 5 were in the range between $230 million per year. Costs and sales are voluntarily accepted in the presence 8 and 12 mg per serving intake. reductions of this magnitude may of the amount of information on those If consumption is sensitive to small threaten the viability of many of the risks provided on the proposed warning changes in the potency limits, then firms producing these products. statement. higher potency limits would reduce the However, countervailing distributive Under the assumption that any benefits resulting from consumption effects are also possible in that some adverse events that may occur due to effects because higher potency limits firms that currently produce dietary such behavior cannot represent net would presumably have a smaller effect supplements containing ephedrine social costs, warning statements will on the effects of these products than the alkaloids may also produce or be able to eliminate all net social costs associated proposed potency limits. Therefore, the produce substitute products. In that with these adverse events. This effect of raising the potency limits on case, those firms would avoid some or assumption is based on the notion that benefits arising from shifts in all of the costs associated with the proposed warning statement consumption will be to reduce those producing dietary supplements provides adequate information on the benefits below those generated under containing ephedrine alkaloids. risks of consuming these products and Option 3. the notion that if those consuming these Raising the proposed potency limits 6. Option 6—Take Proposed Action, but products have adequate information on will not affect the one-time compliance Do Not Require Warning Statement the risks involved, then their costs but might reduce utility losses to The purpose of the proposed warning consumption decisions reflect their consumers of these products and the statement is to focus existing warnings personal judgments concerning the distributive effects produced by more precisely on the health risks posed relative value of the benefits and risks consumption shifts. Again, these by these products, particularly in cases of consuming these products. changes may occur because higher where any use of these products may be If no existing warning statements potency limits might have a somewhat contraindicated, and to add warnings to provide adequate information while the smaller impact on the perceived benefits those products which do not already proposed warning statement will 30712 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules provide adequate information, then the percent of those firms classified as small generated by consumption shifts to social benefits of this option would be businesses. between $0 and $110 million per year. at least as great as the value of banning The proportion of dietary supplement Taking the proposed action without dietary supplements containing manufacturers producing products requiring the warning statement would ephedrine alkaloids. On the other hand, containing ephedrine alkaloids is slightly reduce compliance costs to if some existing warning statements unknown. The two market surveys between $3 million and $80 million, already provide adequate information, identified 85 manufacturers and with between $3 million and $70 then the benefits of this option would distributors of dietary supplements million of these costs occurring in the still be at least as great as the value of suspected of containing ephedrine first 6 months, but would not affect banning dietary supplements containing alkaloids. Assuming that the proportion distributive effects because of the other ephedrine alkaloids; however, the of these firms that are small businesses factors influencing those effects. Taking benefits of both options would be lower. is the same as the proportion of firms in the proposed action but raising the Under the assumption that any the dietary supplement industry that are proposed potency limit to the level adverse events that may occur due to small businesses, 95 percent of these suggested by a trade group representing such behavior represent social costs, firms, or approximately 80 firms, are the dietary supplement industry would eliminating all actions other than the small businesses. probably not significantly alter the proposed warning statement will Total compliance costs incurred by impact of this rule on small businesses. substantially reduce the benefits from small businesses will be virtually equal Finally, banning dietary supplements those estimated for Option 3. This to total compliance costs incurred by all containing ephedrine would not change assumption is based either on the notion businesses estimated earlier because the reformulation or relabeling costs and that the level of information provided vast majority of the firms affected by the would lead to distributive effects from on the proposed warning statement is proposed action are small businesses. consumption shifts in the range of $200 inadequate to ensure that consumers Relabeling, reformulation, and testing million to $230 million per year. This costs are fixed costs on a per product can make informed consumption action would have the greatest negative basis and will disproportionately affect decisions, or on the notion that public impact on small businesses. small businesses. Total compliance health risks require intervention even if costs of the proposed action were VI. Conclusions those risks are voluntarily undertaken in estimated to be between $3 million and The estimated benefits of Option 3, the presence of adequate information on $80 million, with between $3 million take the proposed action, are between the benefits and risks of the relevant and $70 million of these costs occurring $240 million and $670 million per year. activity. Under this assumption, this in the first 6 months after publication of The estimated quantifiable costs are option will reduce the health risks from the final rule. However, FDA has between approximately $3 and $70 these products such that the expected insufficient information to estimate the million in the first year, and between a number of adverse events will be portion of these costs that will be borne minimal amount and about $0.5 million reduced by between 0 cases and by the owners, stockholders, and in every year after the first year. Thus, approximately 210 cases per year. employees of these firms and the notwithstanding the considerable With respect to compliance costs, portion that will be passed on to uncertainty concerning the marginal eliminating all actions except the consumers of these products through effectiveness of the individual warning statement would eliminate the price increases. In addition, the requirements of the proposed rule, FDA costs associated with product proposed action will generate is confident that it would generate reformulation and consumer utility consumption shifts that were previously benefits that far exceed the quantifiable losses. estimated to produce negative costs. In addition to the quantifiable Finally, this option would distributive effects of between $60 costs, however, the proposed action will substantially reduce the distributive million and $230 million per year. also generate non-quantifiable utility effects of this action. Under this option, Countervailing distributive effects are losses for some consumers and the estimated total reduction in the also possible. For example, the distributive effects from consumption consumption of dietary supplements proposed rule may reduce the number shifts with an estimated value of containing ephedrine alkaloids would of product liability lawsuits brought between approximately $60 million and be between 0 and 15 percent. Therefore, against manufacturers of dietary $230 million per year, with possible sales of these products would be supplements containing ephedrine countervailing distributive effects from reduced by between $0 and $110 alkaloids. Based on reported annual a reduction of liability lawsuits. Social million per year. A reduction in sales of retail sales of between $600 million and costs might be associated with these this magnitude would threaten the $700 million for products containing Ma distributive effects. viability of fewer firms than the huang, these costs and distributive proposed action, as estimated under effects may be significant. VII. Environmental Impact Option 3. Most of the regulatory alternatives The agency has carefully considered discussed earlier would reduce the the potential environmental effects of V. Regulatory Flexibility Analysis impact of this rule on small businesses. this action. Based on the available In the economic impact analysis for The options of taking no action and information, FDA has concluded that the December 1995 proposal, FDA taking no action other than generating the action will not have a significant estimated the number of dietary additional information both reduce the impact on the human environment, and supplement manufacturers to be impact on small businesses to zero. that an environmental impact statement between 150 and 600, with the majority Requiring only warning statements is not required. The agency’s finding of of those firms being small businesses. would substantially reduce compliance no significant impact and the evidence Based on additional information, these costs to between $3 million and $60 supporting that finding, contained in an estimates were revised in the economic million, with between $3 million and environmental assessment, may be seen impact analysis of the final rule on $50 million of these costs occurring in in the Dockets Management Branch nutritional labeling. The revised the first 6 months, and also substantially (address above) between 9 a.m. and 4 estimate was 500 to 850 firms, with 95 reduce negative distributive effects p.m., Monday through Friday (Ref. 221). Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30713

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Harston, of Ephedrine/Caffeine Mixtures on Energy Appetite-suppressant Drugs in the Treatment ‘‘Fetal Tachycardia Associated with Maternal Expenditure and Glucose Metabolism in of Obesity,’’ Annals of Internal Medicine, Use of Pseudoephedrine, and Over-the- Humans,’’ International Journal of Obesity, 119:707–713, 1993. Counter Oral Decongestant,’’ Journal of the 17 Suppl 3:S73–7, 1993. 122. Beck, R. A., D. L. Mercado, S. M. American Board of Family Practice, 5:527– 109. Astrup, A., C. Lundsgaard, J. Madsen, Seguin, W. P. Andrade, and H. M. Cushner, 528, 1992. and N. J. Christensen, ‘‘Enhanced ‘‘Cardiovascular Effects of Pseudoephedrine 140. Nishikawa, T., H. J. Bruyere, E. F. Thermogenic Responsiveness During Chronic in Medically Controlled Hypertensive Gilbert, and Y. Takagi, ‘‘Potentiating Effects Ephedrine Treatment in Man,’’ American Patients,’’ Archives of Internal Medicine, of Caffeine on the Cardiovascular Journal of Clinical Nutrition, 42:83–94, 1985. 152:1242–1245, 1992. Teratogenicity of Ephedrine in Chick 110. Astrup, A., and S. Toubro, 123. Glidden, R. S., and F. J. DiBona, Embryos,’’ Toxicology Letters, 29:65–68, ‘‘Thermogenic, Metabolic, and ‘‘Urinary Retention Associated with 1985. Cardiovascular Responses to Ephedrine and Ephedrine,’’ Journal of Pediatrics, 90:1013– 141. Kanai, T., T. Nishikawa, A. Satoh, and Caffeine in Man,’’ International Journal of 1014, 1977. A. Kajita, ‘‘Cardiovascular Teratogenicity of Obesity, 17 Suppl 1:S41–S43, 1993. 124. Boston, L. N., ‘‘Dysuria Following Ephedrine in Rats,’’ Teratology, 34:469, 1986. 111. Astrup, A., S. Toubro, S. Cannon, P. Ephedrine Therapy,’’ Medical Times, lvi:94– 142. Nishikawa, T., H. J. Bruyere, Y. Hein, L. Breum, and J. Madsen, ‘‘Caffeine: A 95, 1928. Takagi, E. F. Gilbert, and H. Uno, Double-blind, Placebo-controlled Study of its 125. Swenson, R. D., T. A. Golper, and W. ‘‘Cardiovascular Teratogenicity of Ephedrine Thermogenic, Metabolic, and Cardiovascular M. Bennett, ‘‘Acute Renal Failure and in Chick Embryos,’’ Toxicology Letters, Effects in Healthy Volunteers,’’ American Rhabdomyolysis After Ingestion of 29:59–63, 1985. Journal of Clinical Nutrition, 51:759–767, Phenylpropanolamine-Containing Diet Pills,’’ 143. Matsuoka, R., E. F. Gilbert, H. Bruyers, 1990. Journal of the American Medical Association, J. M. Optiz, ‘‘An Aborted Human Fetus with 112. Astrup, A., S. Toubro, S. Cannon, P. 248:1216, 1982. Truncus Arteriosus Communis—Possible Hein, and J. Madsen, ‘‘Thermogenic 126. Sequeira, R. P., ‘‘Central Nervous Teratogenic Effect of Tedral,’’ Heart and Synergism Between Ephedrine and Caffeine System Stimulants and Anoretic Agents’’ In Vessels, 1:176–178, 1985. in Healthy Volunteers: A Double-Blind, ‘‘Side Effects of Drugs Annual 16,’’ edited by 144. Mortimer, E. A., ‘‘Drug Toxicity from Placebo-Controlled Study,’’ Metabolism, Dukes, M. N. G., and J. K. Aronson, Breast Milk? [letter],’’ Pediatrics, 60:780–781, 40:323–329, 1991. Amsterdam: Elsevier, 1–6, 1993. 1977. 30716 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

145. Park, P. G., J. Merryman, M. Orloff, Center for Health Statistics, Series 10, No. Yohimbine and Atropine,’’ Journal of and H. M. Schuller, ‘‘Beta-Adrenergic 193, December 1995. Pharmacology and Experimental Mitogenic Signal Transduction in Peripheral 160. Table 22. Annual Average of Therapeutics, 248:57–61, 1989. Lung Adenocarcinoma: Implications for Impairments and Chronic Conditions 1990– 179. Folic Acid Proposed Rule (58 FR Individuals with Preexisting Chronic Lung 1992, to be published in Prevalence of 53269, October 14, 1993). Disease,’’ Cancer Research, 55:3504–3508, Selected Chronic Conditions: United States 180. ‘‘Nasal Decongestants,’’ Drug 1995. 1990–1992, National Center for Health Interaction Facts, Facts and Comparisons, 146. Hsu, H. Y., Y. P. Chen, S. J. Shen, C. Statistics, Vital and Health Statistics 10 [194] pp. 183i–184d, 1996. S. Hsu, C. C. Chen, and H. C. Chang, ‘‘7. 1995. 181. ‘‘Salicylates: Sallicyclic Acid Ephedrae Herba (Ephedra, Ma-Huang)’’ In 161. Diabetes Statistics, p. 1, NIH Derivatives,’’ Drug Interaction Facts, Facts ‘‘Oriental Materica Medica: A Concise Publication No. 96–3873, National Diabetes and Comparisons, pp. 248a–248d, 1996. Guide,’’ Long Beach, CA: Oriental Healing Information Clearinghouse, National Institute 182. Weiner, M., ‘‘White Willow’’ In Arts Institute, 52–53, 1986. of Diabetes and Digestive and Kidney ‘‘Weiner’s Herbal—The Guide to Herb 147. Blumenthal, M., and P. King, ‘‘A Diseases, NIH, PHS, DHHS, October 1995. Medicine,’’ Mill Valley, CA: A Quantum Review of the Botany, Chemistry, Medicinal 162. Number of U.S. Adults (in millions) Book, 260–261, 1990. Uses, Safety Concerns, and Legal Status of with Mental Disorders, 1990, National 183. Herbal Diuretics (Monograph). 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Disorders’’ In ‘‘Krause’s Food, Nutrition, & Longterm Smoking,’’ International Journal of 170. Unknown: Mate. IARC Monographs, Diet Therapy,’’ edited by Mahan, L. K., and Obesity, 17 Suppl 3:S112–4; discussion S115, Edition 51:pp. 273–287, 1996. S. Escott-Stump, Philadelphia: W.B. 1993. 171. Belliardo, F., A. Martelli, and M. G. Saunders, 451–488, 1996. 154. Pi-Sunyer, F. X., ‘‘Short-Term Medical Valle, HPLC Determination of Caffeine and 194. ‘‘Nutrition and Your Health: Dietary Benefits and Adverse Effects of Weight Loss,’’ Theophylline in Paullinia Cupana Kunth Guidelines for Americans,’’ U.S. Department Annals of Internal Medicine, 119:722–726, (guarana) and Cola spp. samples, Zeitschrift of Agriculture, DHHS, 1995. 1993. Fur Lebensmittel-Unterschung Und- 195. National Task Force on the Prevention 155. Landsberg, L., and D. R. Krieger, Forschung, 180:398–401, 1985. and Treatment of Obesity: Long-term ‘‘Obesity, Metabolism, and the Sympathetic 172. Herb Research Foundation: Herbal Pharmacotherapy in the Management of Nervous System,’’ American Journal of Stimulants Fact Sheet, 1995. Obesity, Journal of the American Medical Hypertension, 2:125S–132S, 1989. 173. Dulloo, A. G., ‘‘Ephedrine, Xanthines Association, 276:1907–1915, 1996. 156. Stokholm, K. H., L. Breum, and A. and Prostaglandin-inhibitors: Actions and 196. Levy, A. S., and A. W. Heaton, Astrup, ‘‘Cardiac Contractility, Central Interactions in the Stimulation of ‘‘Weight Control Practices of U.S. Adults Haemodynamics and Blood Pressure Thermogenesis,’’ International Journal of Trying to Lose Weight,’’ Annals of Internal Regulation During Semistarvation,’’ Clinical Obesity, 17 Suppl 1:S35-S40, 1993. Medicine, 116:661–666, 1992. Physiology, 11:513–523, 1991. 174. Dulloo, A. G., J. Seydoux, and L. 197. Lowenthal, D. T., and Y. Karni, ‘‘The 157. Association of Analytical Chemists Girardier, ‘‘Potentiation of the Thermogenic Nutritional Needs of Athletes’’ In ‘‘Total (AOAC) Official Method 980.35 Ephedrine in Antiobesity Effects of Ephedrine by Dietary Nutrition. The Only Guide You’ll Ever Solid Dosage Drugs: Spectrophotometric Methylxanthines: Adenosine Antagonism or Need,’’ edited by Herbert, V., G. J. Subak- Method. In ‘‘Official Methods of Analysis,’’ Phosphodiesterase Inhibition?,’’ Metabolism, Sharpe, and T. S. Kasdan, New York: St. edited by AOAC International, Arlington, 41:1233–1241, 1992. Martin’s Press, 403–421, 1996. 197a. Salemi, VA: AOAC International, 9–10, 1995. 175. Astrup, A., S. Toubro, N. J. J., and J. T. O’Donnell, ‘‘Performance 158. Fact Book Fiscal Year 1995, Chapter Christensen, and F. Quaade, ‘‘Pharmacology Enhancing Drug Use in Athletes,’’ Journal of 2 Program Overview, pp. 9, 27–28, National of Thermogenic Drugs,’’ American Journal of Pharmacy Practice, IX, 5:386–395, 1996. Heart, Lung and Blood Institutes, National Clinical Nutrition, 55:246S–248S, 1992. 198. Cybergenics, Phase I, Anabolic Muscle Institutes of Health (NIH), Public Health 176. Yohimbe (Monograph), The Lawrence Building Cycle, distributed by L&S Research Service (PHS), DHHS, March 1996. Review of Natural Products, Facts and Corp., 1990. 159. Table 62. Number of Selected Comparisons, pp. 1–2, May 1993. 199. Memorandum of November 30, 1995 Reported Chronic Conditions, by Age: United 177. ‘‘Agents for Impotence, Yohimbine Industry Meeting, Executive Secretary, States, 1994, Current Estimates From the HCl,’’ Drug Interaction Facts, Facts and January 4, 1997. National Health Interview Survey, 1994, Vital Comparisons, p. 731m, 1996. 200. ‘‘Webster’s New Riverside University and Health Statistics, from the Centers for 178. Wilkerson, R. D., ‘‘Cardiovascular Dictionary,’’ edited by Soukhanov, A. H., and Disease Control and Prevention/National Effects of Cocaine: Enhancement by K. Ellis, The Riverside Publishing Co., 1984. Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30717

201. Dorland’s Illustrated Medical adverse events in an adverse event category PART 111ÐRESTRICTIONS FOR Dictionary, Philadelphia, W. B. Saunders, that are of the type for which values are SUBSTANCES USED IN DIETARY 1988. reported. The dollar figures were converted SUPPLEMENTS 202. Wilson, B. E., and W. N. Hobbs, ‘‘Case to 1996 dollars based on the relative Report: Pseudoephedrine-Associated Thyroid consumer price indices for 1988 and 1996.) Subpart AÐGeneral ProvisionsÐ Storm: Thyroid Hormone-Catecholamine 216. Submission by D. Jones, Information [Reserved] Interactions,’’ American Journal of the Relevant to the Assessment of the Safety of Medical Sciences, 306:317–319, 1993. Subpart BÐCurrent Good 203. Elis, J., D. R. Laurence, H. Mattie, and Dietary Supplements Containing Ephedrine B. N. C. Prichard, ‘‘Modification by Alkaloids, FDA Advisory Committee on Food Manufacturing Practice for Dietary Monoamine Oxidase Inhibitors of the Effect Products Containing Ephedrine Alkaloids, Supplements of Some Sympathomimetics on Blood pp. 1–20, October 9, 1995. § 111.50 Packaging of iron-containing Pressure,’’ British Medical Journal, 2:75–78, 217. Nutrition Business Journal, vol. 1, No. dietary supplements. 1967. 1, pp. 1–5, August 1996. (a) The use of iron and iron salts as 204. Dawson, J. K., S. M. Earnshaw, and C. 218. Median Weekly Earning of Wage and iron sources in dietary supplements S. Graham, ‘‘Dangerous Monoamine Oxidase Salary Workers Who Usually Work Full Time Inhibitor Interactions Are Still Occurring in by Detailed (3-Digit Census Code) offered in solid oral dosage form (e.g., The 1990s,’’ Journal of Accident and Occupation and Sex, 1994 Annual Averages, tablets or capsules), and containing 30 Emergency Medicine, 12:49–51, 1995. milligrams or more of iron per dosage 205. Grahame-Smith, D. G., and J. K. U.S. Department of Labor, Bureau of Statistics. unit, is safe and in accordance with Aronson, ‘‘Drug Interactions’’ In ‘‘Oxford current good manufacturing practice Textbook of Clinical Pharmacology and Drug 219. Food Labeling and Nutrition News, Therapy,’’ Oxford: Oxford University Press, pp. 14–15, July 18, 1996. only when such supplements are 122–136, 1992. 220. Safe and Appropriate Marketing of packaged in unit-dose packaging. ‘‘Unit- 206. ‘‘Sympathomimetics—Methyldopa,’’ Ephedra-Containing Products, August 22, dose packaging’’ means a method of Drug Interaction Facts, Facts and 1996. packaging a product into a nonreusable Comparisons, p. 679, 1996. 221. Memorandum to Office of Special container designed to hold a single 207. ‘‘Bronchodilators: Nutritionals from Environmental Scientist, dosage unit intended for administration Sympathomimetics,’’ Drug Interaction Facts, re: Agency Action on Ephedra Alkaloids in directly from that container, irrespective Facts and Comparisons, pp. 173a–173h, Dietary Supplements, December 20, 1996. of whether the recommended dose is 1996. one or more than one of these units. The 208. ‘‘Nonprescription Diet Aids: List of Subjects in 21 CFR Part 111 term ‘‘dosage unit’’ means the Phenylpropanolamine HCl,’’ Drug Interaction Facts, Facts and Comparisons, pp. 240b–241, individual physical unit of the product Drugs, Packaging and containers, (e.g., tablets or capsules). Iron- 1996. Incorporation by reference, Labeling. 209. ‘‘Anorexiants,’’ Drug Interaction containing dietary supplements that are Facts, Facts and Comparisons, pp. 236–239, Therefore, under the Federal Food, subject to this regulation are also subject 1996. Drug, and Cosmetic Act and under to child-resistant special packaging 210. Lefkowitz, R. J., B. B. Hoffman, and P. authority delegated to the Commissioner requirements codified in 16 CFR parts Taylor, ‘‘Neurohumoral Transmission: The of Food and Drugs, it is proposed that 1700, 1701, and 1702. Autonomic and Somatic Motor Nervous (b)(1) Dietary supplements offered in 21 CFR part 111 be revised as follows: Systems’’ In ‘‘Goodman and Gilman’s The solid oral dosage form (e.g., tablets or Pharmacological Basis of Therapeutics,’’ capsules), and containing 30 milligrams edited by Gilman, A. G., T. W. Rall, A. S. PART 111ÐRESTRICTIONS FOR Nies, and P. Taylor, New York: McGraw-Hill, SUBSTANCES USED IN DIETARY or more of iron per dosage unit, are Inc., 84–121, 1990. SUPPLEMENTS exempt from the provisions of 210a. Proposed Warning Labels for Iron- paragraph (a) of this section until Containing Products; FDA Report on Subpart AÐGeneral ProvisionsÐ January 15, 1998, if the sole source of Consumer Research; Availability (60 F.R. [Reserved] iron in the dietary supplement is 27321, May 23, 1995). carbonyl iron that meets the 211. FDC Reports, pp. 11–12, September Subpart BÐCurrent Good Manufacturing Practice for Dietary Supplements specifications of § 184.1375 of this 16, 1996. chapter. 212 Schucker, R., R. Stokes, M. Stewart, Sec. (2) If the temporary exemption is not and D. Henderson, ‘‘The Impact of the 111.50 Packaging for iron-containing extended or made permanent, such Saccharin Warning Label on the Sales of Diet dietary supplements. Soft Drinks in Supermarkets,’’ Journal of dietary supplements shall be in Public Policy and Marketing, 2:46–56, 1983. Subpart CÐNew Dietary IngredientsÐ compliance with the provisions of 213. Freimuth, V., S. Hammond, and J. [Reserved] paragraph (a) of this section on or before Stein, ‘‘Health Advertising: Prevention for July 15, 1998. Profit,’’ American Journal of Public Health, Subpart DÐRestricted Dietary Ingredients 78:557–561, 1988. 111.100 Dietary supplements that contain Subpart CÐNew Dietary IngredientsÐ 214. Scott, H., and S. Rosenbaum, ‘‘Rhode ephedrine alkaloids. [Reserved] Island Physician’s Recognition and Reporting Authority: Secs. 201, 402, 403, 701 of the of Adverse Drug Reactions,’’ Rhode Island Federal Food, Drug, and Cosmetic Act (21 Subpart DÐRestricted Dietary Medical Journal, 70:311–316, 1987. U.S.C. 321, 342, 343, 371). Ingredients 215. Estimating the value of consumer’s loss from foods violating the FD&C Act, vol. § 111.100 Dietary supplements that II, Final Report, pp. G1-G40, September 1988. contain ephedrine alkaloids. (The valuation of particular adverse event The ephedrine alkaloids include categories is based on the values presented ephedrine, pseudoephedrine, for acute CNS and liver or kidney changes, chronic CNS system impairment, heart norpseudoephedrine, norephedrine, disease, and stroke. The reported values are methylephedrine, the averages of the values generated by the methylpseudoephedrine, and related three health indices presented and, where alkaloids. These substances are appropriate, weighted by the proportion of chemical stimulants contained in 30718 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules particular botanical products, including (c) The label of dietary supplements alkaloids shall bear the following those from the botanical species that contain ephedrine alkaloids shall warning: Ephedra sinica Stapf., Ephedra state ‘‘Do not use this product for more WARNING: If you are pregnant or equistestina Bunge, Ephedra intermedia than 7 days.’’ nursing, or if you have heart disease, var., tibetica Stapf., Ephedra distachya (d) No ingredient, or ingredient that thyroid disease, diabetes, high blood L., and Sida cordifolia or their extracts. contains a substance, that has a known pressure, depression or other (a)(1) Dietary supplements that stimulant effect (e.g., sources of caffeine, psychiatric condition, glaucoma, contain 8 milligrams (mg) or more of yohimbine) may be included in a difficulty in urinating, prostate ephedrine alkaloids (the total of dietary supplement that contains enlargement, or seizure disorder consult ephedrine, pseudoephedrine, ephedrine alkaloids. a health care provider before using this norpseudoephedrine, norephedrine, (e) No dietary supplement that product. Do not use if you are using methylephedrine, contains ephedrine alkaloids may monoamine oxidase inhibitors (MAOI) purport to be, or be represented as, methylpseudoephedrine, and related or for 2 weeks after stopping a MAOI either expressly or implicitly, for use for alkaloids) per single serving shall be drug; certain drugs for depression, long-term effects, such as weight loss or deemed to be adulterated under sections psychiatric or emotional conditions; body building. 402(a)(1) and 402(f)(1)(A) of the Federal drugs for Parkinson’s disease; Food, Drug, and Cosmetic Act. (f)(1) The label or labeling for dietary supplements that contain ephedrine methyldopa; or any product containing (2) The Food and Drug alkaloids that purport to be or are ephedrine, pseudoephedrine or Administration will use high represented, either expressly or phenylpropanolamine (ingredients performance liquid chromatography implicitly, to be used for short-term found in allergy, asthma, cough/cold (HPLC) to determine the level of effects, such as increased energy, and weight control products). Stop use ephedrine alkaloids in a dietary increased mental concentration or and call a health care professional supplement as specified in its enhanced well-being, shall state immediately if dizziness, severe Laboratory Information Bulletin (LIB) ‘‘Taking more than the recommended headache, rapid and/or irregular heart No. 4053, which is incorporated by serving may cause heart attack, stroke, beat, chest pain, shortness of breath, reference in accordance with 5 U.S.C. seizure, or death.’’ nausea, noticeable changes in behavior, 552(a) and 1 CFR part 51. Copies may (2) This information shall appear on or loss of consciousness occur. Do not be obtained from the Director, Office of the same label panel or same page of exceed recommended serving. Constituent Operations, Industry labeling as the claim and shall be (2) The phrase ‘‘Do not exceed Activities Staff (HFS–565), Center for connected to the claim by use of an recommended serving’’ is not required Food Safety and Applied Nutrition, asterisk. This information shall appear to appear in the warning statement Food and Drug Administration, 200 C in easily legible print or type, in distinct when the disclaimer required in St. SW., rm. 5827, Washington, DC contrast to other printed or graphic paragraph (f)(1) of this section appears 20204, or may be examined at the matter, and in a type size no less than on the same label panel as the warning Center for Food Safety and Applied is required by § 101.105(i) of this statement. Nutrition’s Library, Food and Drug chapter for the net quantity of contents (3) The warning statement required by Administration, 200 C St. SW., rm. statement, except where the size of the paragraph (g)(1) of this section shall 3321, Washington, DC, or at the Office claim is less than two times the required appear prominently and conspicuously of the Federal Register, 800 North size of the net quantity of contents on the product label and shall be set off Capitol St. NW., suite 700, Washington, statement, in which case the in a box by use of hairlines. DC. information shall be no less than one- (b) The labeling of dietary half the size of the claim, but no smaller Dated: April 22, 1997. supplements that contain ephedrine than one-sixteenth of an inch. Where Michael A. Friedman, alkaloids shall not suggest or the label or labeling contains multiple Deputy Commissioner for Operations. recommend conditions of use that claims, the information shall appear Donna E. Shalala, would result in an intake of 8 mg or once on each label panel or on each Secretary of Health and Human Services. more ephedrine alkaloids within a 6- page of labeling. Note: The following Appendix will not hour period or a total daily intake of 24 (g)(1) The labeling of any dietary appear in the annual Code of Federal mg or more of ephedrine alkaloids. supplement that contains ephedrine Regulations.

Appendix—AER’s Associated With Ephedrine Alkaloid-Containing Dietary Supplements

ARMS No. Product manufacturer Clinical summary

9101 ...... Thermojetics Herbal Tablets-GreenÐ 33 yo F used product (bid, ?dose) in 11/93 until 1st week in 1/94, when she started Herbalife International. having dizzy spells that progressed to involve numbness of L arm & forehead, weakness of both legs, SOB, and shaky feelings. 1/30/94 seen in ER for dizziness & tachycardia, Dx labyrinthitis, Tx Valium, d/c on Antivert. 2/2/94 episodes wors- ened, including dizziness, severe tachycardia, and SOB. She was transported to hospital & admitted w/extensive w/u (CAT, XR echo, doppler, halter, labs). D/c on 2/8 on Tenormin and Ativan w/Dx of SVT. Normal PE in 10/93. No h/o allergies or CV disease. Mother (insomnia) & husband (blood in stool) using product w/various SSx. Sister took product w/o problems. 9316 ...... E'OLA AMP II Pro DropsÐE'OLA Bio- 23 yo F hospitalized w/ cardiac arrest, CPR, then ICU. Dx inferolat MI. CK > 2000 genics, Inc. (MB+), EKG: sinus tachy & ↑ST inf leads; angio: lacerated coronary (partial dissec- tion) & hematoma at bifurcation of circumflex artery. Used AMP II 3-4 drops in bev- erage night before arrest, also noted to be using other `diet pills' (?dose/durations). Drug screen negative, doing well off product. Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30719

ARMS No. Product manufacturer Clinical summary

9552 ...... Nature's Nutrition Formula OneÐAffiliated 35 yo F good health, no risk factors for CAD used product 04/94Ð05/94 (30 days) for Consultants Inter./Alliance U.S.A. Inc. WL&E, as much as 1±2 caps bid 30 days. She stopped for a week but resumed again at 3 caps qd. On 6/25/94, developed acute onset of throbbing, ant. CP at rest, w/ pain radiation to the left shoulder, numbness of left arm & hand, diaphoresis and SOB. The pain persisted, and she was taken to the ER. The pain decreased with subl nitro and was completely relieved with morphine and nitro. On admission, BP: 140/100, EKG: minor ST depressions V1, V2, and minor ST ele- vation in INF leads, elevated cardiac enzymes. Dx: Acute non-Q wave MI probably secondary to coronary spasm. Cardiac cath 6/27/94 LV angiogram very mild pos- terior basilar hypokinesis, normal LV function w/ good ejection fraction. Normal coronary arteries. Discharged after 4 days on Cardizem, aspirin, nitro prn, & f/u for a limited stress test. 9747 ...... Ripped FuelÐTwin Laboratories, Inc ...... 40 yo F reported by physician to suffer a grand mal seizure after using product for 3 days (2 bid) as directed. Her husband stated she stopped breathing and he had to administer mouth to mouth resuscitation. She was on no medication and had no personal nor family history of seizures. She had no symptoms until she felt dizzy immediately before her seizure. CT headÐno abnormalities. 9751 ...... Slim NRGÐMomentum Marketing ...... 28 yo F (weighing 95 lb) reported by MD. Used product, 1 tid for 6 months for weight loss (30 lb). Stopped product abruptly, became despondent over 10 days ending w/ attempted suicideÐgunshot wound to chest. No other products used. Past mental history negative for mental illness, use of drugs/alcohol. Drug/ETOH screen neg. Tx: w/antidepressants. Positive dechallenge. 9754 ...... Shape-FastÐShaperite Concepts Ltd ...... 44 yo F reported by physician's assistant to be taking product (400 mg bid) when she developed heat stroke, chest and back pain, hyperthermia and tachycardia while exercising. 9818 ...... Power TrimÐEnrich International ...... 43 yo M who used product (details not given) over a 6 wk period and lost 30 lb., developed new onset insomnia and atrial fibrillation. Seen by health care provider and given Lanoxin, hospitalized next day when light headedness developed. Extensive w/u (EKG, CXR, echo-cardiogram, smac, myocardial enzymes), compatible with AF. Dx: ``new onset atrial fibrillation, possibly due to the stimulant effect of his dietary supplement.'' Tx: Lanoxin, Betapace, Verapamil, and Coumadin. 9864 ...... Nature's NutritionÐFormula OneÐAffili- 44 yo M, active swimmer and tennis player, with no known cardiovascular risks as ated Consultants Intl/Alliance U.S.A. documented by medical history, originally obtained a sample of product during a routine physical from his health care provider when he requested some substitute for his daily coffee and cocoa use. He used this product as directed, and was able to eliminate his afternoon coffee/cocoa use. On 12/18/93 (∼3 weeks after starting product), after playing his routine weekly game of tennis, he came home, laid down and was found dead about noon. Resuscitative efforts were unsuccessful. Autopsy revealed an acute thrombus, 1.5 cm from the origin of the left anterior descending coronary artery, resulting in occlusion. All lumina were otherwise patent, although calcification of the coronary arteries resulting in focal narrowing to about 50 percent was noted. A drug screen performed at the time of autopsy was reportedly negative for amines. 10009 ...... MetaboLift ThermogenicÐTwin Labora- 35 yo M w/acute MI (inferoapical). Took product (two capsules at noon and 3 cap- tories, Inc. sules at 4:30 PM) Worked out 5:30 PMÐ6:30 PM and developed chest pain around 7:30 PM. Consumer admitted, treated w/TPA, subsequent cardiac catheterization demonstrated normal coronaries. CPK elevated, EKG diagnostic for MI. 10026 ...... Formula OneÐAffiliated Consultants Intl./ 48 yo F took product (3 caps qd) for 6±7 months when developed weakness, Alliance U.S.A. syncopal episode, increased BP, increased HR, tightness in chest. Seen in ER w/ EKG which showed nonspecific STT wave abnormality, and increased cardiac enzymes. BP±120/99. Saw MD next day, complained of right sided weakness and speech difficulty. Meds: antihypertensives, hormones. Dx: ``conversion reaction'', thought to be stress related. Sxs improved over next month. MD later told about use of product, which he states could aggravate nervousness. 10063 ...... Super Diet MaxÐKAL, Inc ...... 22 yo F had been using product several months at 1 tab bid for WL. On day of adverse event she had taken 2 caps (1 q AM, 1 q PM), and experienced increased BP, pounding heart, n/v, lasting 1.5±2 hr. Event abated after product discontinued. Saw health care provider. Started on Prozac 2 wks prior to adverse event. 10088 ...... Nature's Sunshine SN±X 100 VegitabsÐ 38 yo F took product for 4 days and developed syncope, blood pressure = 180/110. Nature's Sunshine. Seen in ER with severe HA, nausea, diaphoresis. The consumer had been seen every 3±4 months for 5 years prior to this event and no history of high blood pressure. After stopping the product her blood pressure returned to normal. 10275 ...... Nature's Nutrition Formula OneÐAffiliated 63 yo F reports using product for 3 weeks at recommended dose, never used maxi- Consultants International/Alliance U.S.A. mum recommended dose, when she developed hives. The next day she had difficulty walking across room, difficulty breathing and swallowing, and vomited. She suffered ventricular fibrillation, a small non Q-wave infarct by enzymes criteria and was hospitalized 5 days where evaluation (cardiac catheterization, electrophysiology study) failed to find any sort of heart problem or heart disease to explain her arrest. She has chronic obstructive pulmonary disease secondary to cigarette smoking. Previous to arrest no medicine and only vitamin and occasional aspirin. 30720 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

ARMS No. Product manufacturer Clinical summary

10437 ...... Thermojetics Herbal TabletsÐBeige, 55 yo F reports grand mal seizure after 3 days on product per directions. No signifi- Thermojetics Herbal TabletsÐGreen, cant past history, normal CT and EEG. No meds or other dietary supplement prod- Formula 1, Formula 2, Formula 3Ð ucts. Herbalife International. 10862 ...... Ultimate XphoriaÐAlternative Health Re- 20 yo M took 8 tabs @ ∼4 pm (directions: Take 4 tablets, on an empty stomach; do search. not exceed 4 tablets in 24 hours). Within ∼30 minutes, complained of being hot, w/ sweating & HA. Found dead by friends ∼8 hr later. Coroner's report notes toxic levels of ephedrines. 10919 ...... Power TrimÐEnriched International ...... 49 yo F used Power Trim, 3 capsules three times daily for 3 weeks for weight loss. She developed weakness, dizziness, nausea, vomiting, and palpitations and went to the ER where she was found to have vertigo, serous otitis media bilaterally, hypertension (150/102) and elevated liver enzymes. The consumer reports stopping the product and her blood pressure has returned to normal without any medical treatment. She has no history of high blood pressure. 10943 ...... Multi DSÐ(1) Omnitrim Tea & (2) Omni 37 yo F used for 1 week, Omnitrim Tea, 2 teaspoons three times per day, and Omni 4ÐOmnitrition International, Inc. 4 (a vitamin) one daily, both as directed, for weight loss. She stopped due to the development of shakes, sweats, dizziness, racing heart, and loss of hearing in R ear. Symptoms abated after stopping product. No other products in use and no significant medical history. 10946 ...... Multi DSÐ(1) ThermoChrome 5000, (2) 42 yo F used Thermochrome 5000, 1 capsule twice daily for 3 days for weight loss. Isotonic Vitamin B12, & (3) Isotonic She was also taking B12 and an antioxidant supplement. She developed a rash OPC3 (1) Health Power Products Inc./ over her entire body and stopped all three products. She restarted the Market America; (2) & (3)ÐLabels un- Thermochrome 5000 after 3 days and 3 days after that, on a visit to her doctor for available. a nonproductive cough and congestion, was found to be hypertensive (170/114). She has no history of hypertension and was seen by her gynecologist 1 week before starting the Thermochrome with a normal blood pressure (120/78). 10957 ...... E'Ola Amp II Pro DropsÐE'OLA Bio- 34 yo F used E'Ola AMP II Pro Drops according to label directions, off and on over a genics, Inc. 2 year period for weight loss. She developed ``triple vision'' which lasted a few mo- ments and recurred 3 days later accompanied by vertigo. She was initially seen in an ER, where examination and CT were normal and she was diagnosed with dehydration. She spent 3 days in bed with severe vertigo, nausea, and vomiting. She was unable to reach out and pick up a drinking glass. An MRI showed multiple bi- lateral cerebellar infarcts. No source of embolization was identified. Cardiovascular, autoimmune, and coagulopathy workups were unremarkable. 10960 ...... Blast and BurnÐVita Labs Inc ...... 16 yo F used Blast and Burn as directed on the package for several weeks for performance as a high school athlete. Within the first week of use she was taken to the ER with a racing heart. She had several similar episodes. She couldn't afford to buy a second bottle of the product and noticed her symptoms resolved once she stopped using the product. 10974 ...... ShapeFastÐShaperite Concepts Ltd ...... 19 yo F took Shaperite, one before each meal, three times per day (1¤2 of recommended amount) for 1 month, for weight loss. Her family witnessed seizure activity at mealtime and took her to the ER. CT and EEG were normal. Neurologist's evaluation found no other risk factors for seizure. No other products used, no significant past history noted. 10977 ...... Emphora EcstasyÐLabel unavailable ...... 18 yo F took Emphora Ecstasy, 4 pills at once, to get high. About 2 hours later she noted dizziness, racing heart and felt she would pass out if she stood up. She was unable to sleep for most of that night. The next morning she passed out in the shower, injuring her neck and back. She went to the ER where the only abnormality noted was a low potassium of 3.1 meq/L (normal 3.6±5.2). She has had dizziness in the past but no previous loss of consciousness. The product was not used again and her symptoms resolved. 10989 ...... Herbal EcstasyÐLabel unavailable ...... 18 yo F used Herbal Ecstasy, 5 pills at once, one time as directed to get high at a Lolapalooza concert. She felt ``numb, weird'' and fell backwards. She was unable to sleep for 3 nights in a row. Over the next 8 months, she had difficulty sleeping, re- fused to leave the house unless her parents insisted and did not attend college as planned in the fall. She has been diagnosed with panic attacks and depression and is currently under psychiatric treatment. She has also been diagnosed with a ``weak heart valve.'' 10990 ...... Tri-ChromaleaneÐAchievers Unlimited ..... 58 yo M used Tri-Chromaleane, 3 pills once daily for 6 weeks for weight loss. He developed memory problems. He couldn't remember his son's middle name, his office phone number or how to get home from a local store. He would start work and be unable to remember why he had started the task or what to do next. He stopped the product and his symptoms resolved over the next 2 weeks. At the same time he had been participating in a clinical trial of Proscar for the prevention of prostate cancer and does not know whether he had been taking Proscar or placebo. The Proscar study coordinator reported that it was unlikely that the consumer's complaints were related to Proscar. Of note, he never had prostate cancer. Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30721

ARMS No. Product manufacturer Clinical summary

10991 ...... Tri-ChromaleaneÐAchievers Unlimited ..... 54 yo F used Tri-Chromaleane, at less than the recommended amount, once daily for a number of weeks. She was under treatment for hypertension and was told by the distributor that the product would lower her blood pressure. After starting the product her blood pressure increased and her doctor added a second medication and her blood pressure improved. She was unable to pass an insurance physical due to her inadequately controlled high blood pressure. She stopped the Tri- Chromaleane and her blood pressure has improved to the point that her doctor is planning to stop the second blood pressure medication to see if she can be controlled on a single medication (as she was before using the Tri-Chromaleane). 11050 ...... ThermoChrome 5000ÐHealth Power 63 yo F took 2±3 pills bid, for 2 months for weight loss. She was taking Lescol for Products. hypercholesterolemia, Zantac for esophageal reflux and Vasotec for hypertension. She developed worsening of her hypertension (174/93) and episodes of palpitations. She sought medical assistance from a neighbor who is a physician after an especially severe episode of palpitations. After stopping products BP normalized (140/80) and palpitations resolved. 11062 ...... Power TrimÐEnrich International ...... 42 yo F used 2±3 caps before meals tid as directed for 3 months for weight loss. She was taken to hospital by ambulance after family members found her seizing. She had another seizure while being examined by neurologist. She complained of increased headaches and slow thinking in the days preceding her stroke and was taking penicillin for a dental abscess. CT and MRI showed a small R-sided intracerebral hemorrhage. MRI and angiography revealed no evidence of any vascular abnormality. She was treated with Dilantin. 11065 ...... Thermo SlimÐWeight Loss Specialist ...... 23 yo F used product, 1 tab before meals 3 times per day with The Accelerator Guarana, 1 tab before AM and noon meals, for 8 days. On the 9th day she forgot to take her noontime dose. At first she thought she might be going into withdrawal, took another dose and vomited shortly afterwards. She was taken to the ER with complaints of a racing heart, dizziness, numbness of face and arms, and disorientation. The doctor advised her to stop the products and over the next week her symptoms resolved. 11078 ...... Formula One with Quick StartÐAlliance 36 yo F used Formula One for 2 yrs, stopped that product and then took Quick Start U.S.A. 2 caps which she used once. The next morning she experienced grand mal seizures. She was taking 2 iron tablets, Ionamin 30 (a dietary supplement) and B12 liquid; also had switched to the night shift. CT, MRI, and EEG were normal. 11081 ...... Herbal EcstacyÐLabel unavailable ...... M used Herbal Ecstacy, 10 pills once, to get high. He states he became ``psycho,'' very active, developed a ``bad mood'' and assaulted a friend. His symptoms resolved and he did not try the product again. 11105 ...... Trim EasyÐTeamUp International Inc ...... 31 yo F used Trim Easy for about 1 year for weight loss. She originally used 2 capsules three times daily for 1 month and then increased to 3 capsules three times daily (9 total). The directions advised beginning at 2 capsules three times per day and increasing if tolerated to 3 capsules three times per day, the maximum recommended dose. At times she would forget one of the 3 doses and double up the next time she took the product (6 capsules at once). She continued to take a total of 9 capsules this way daily for about 3 months and then decreased to a total of 6 capsules taken all at once each day for about 8 months. She developed dizzy spells which increased over 1 month's time to twice daily and eventually suffered a strokeÐan intracerebral hemorrhage with Lft hemiparesis and aphasia. CT and MRI documented the bleed, showing midline shift. Cerebral angiogram did not show any additional abnormality such as an arteriovenous malformation. 11106 ...... Therma SlimÐGreat American Products ... 47 yo F used 1 pill at breakfast and 1 at lunch for 2 months. She developed profuse sweating, trembling and HTN, and menstrual bleeding which lasted 6 wks. She was treated first with Megesterol and then with Premarin and Provera, by gynecologist. It was also noted that her BP had risen from 110/70 (3/18/96) to 156/98 (4/10/96). She complained to radio station where she originally heard about product and received a letter telling her side effects she was experiencing were normal and would quickly subside. 4/11/96ÐConsumer contacted her HMO after seeing broadcast on ephedra and was advised to stop using product. 6/1/96ÐThis consumer later suffered a pontine stroke and requires an endotracheal tube and feeding tube for long-term ventilatory and nutritional support, respectively. Estrogen use was implicated as a possible contributing factor by health care provider. 11107 ...... Diet FuelÐTwin Laboratories, Inc ...... 42 yo M used Diet Fuel, 3 pills daily for 9 months. He became dizzy, nauseated, developed left sided chest pain, passed out in a meeting. Paramedics noted his pulse to be in the 30's and he was hospitalized. After cardiology evaluation and electrophysiologic studies it was concluded that the consumer had an abnormal vasodepressor response to tilt plus catecholamine administration and was placed on Tenormin. The consumer reports a similar episode many years prior and as a young man treated with Dilantin for what was diagnosed as epilepsy. 11109 ...... Unspecified E'OLA productÐE'OLA Bio- 46 yo F used two E'OLA products, an energy product, 2 drops twice daily, and a me- genics, Inc. tabolism booster, 4±5 drops twice daily, both for 11¤2 weeks, for energy and weight loss. She developed a heart rate of 200 beats per minute and sought medical attention. Medical records describe evaluation for recurrent paroxysmal palpitations for 20 years. No mention of the use of E'Ola products. Blood pressure, pulse, EKG, echocardiogram, exercise stress test failed to reveal an underlying cardiac disorder. 30722 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

ARMS No. Product manufacturer Clinical summary

11112 ...... Thinner JizerÐQuiet Storm ...... 34 yo F used Thinner Jizer 1 pill for 1 day, 1 pill twice daily, then 2 pills in AM and 1 pill in PM, increasing as directed. After 3 days on the highest amount (2 pills AM and 1 pill PM) she developed jitters and was advised by the distributor to cut back the dose as this response was normal. She used 1 pill AM and 1 pill PM for an additional 3 days when she developed acute visual changes in her right eye lasting 25 minutes. She sought medical care and was advised that her symptoms were likely due to vascular spasm, possibly related to her use of ephedra. She stopped the product, took aspirin for 1 week and has had no further episodes of acute visual changes. She was taking no other products and has no significant prior history. 11114 ...... Herbal EcstacyÐLabel unavailable ...... 16 yo M used Herbal Ecstacy, 2 pills one time. Half an hour later he found himself driving down the wrong side of a road and didn't realize it until he saw a car head- ed towards him. He described feeling ``a major rush, tingly, hyper.'' He denies taking other products including drugs, alcohol, or street-type drugs at the time. He oc- casionally uses ginkgo biloba, but had not taken any that day. 11131 ...... Multi DSÐ(1) Herbal Ecstacy & (2) Nir- 20 yo M used Herbal Ecstacy, 5 pills one time as directed, for recreational purposes. vanaÐ(1) Global World Media & (2) He also took 6 Nirvana pills one time (directions recommend 7 pills) also for rec- Label unavailable. reational purposes. He went to a club and began to feel dizzy, lightheaded and nauseous. He noted stomach cramps, thirst, and a ``real bad headache.'' His symptoms forced him to leave the dance floor, feeling he was going to pass out. He fell on his knees, started ``seeing things'' and felt his seeing and hearing were dis- torted. He noted shortness of breath, sleeplessness, and hives. His symptoms resolved by the next day. He denies alcohol, other drug or product use that night. 11134 ...... Multi DSÐ(1) Ripped Fuel, (2) The Ulti- 23 yo M college student who used multiple dietary supplements for approximately 2 mate Whey Designer Protein, (3) Super years with observed daily use during the year prior to being found dead at home by Amino 2000, (4) Super Once-A-Day his sister. There was no previous medical history and no evidence of trauma or Timed Release Multiple Vitamins and substance abuse. Toxicology screens were negative for alcohol, barbiturates, co- Chelated MineralsÐ(1) Twin Labora- caine, methamphetamine, morphine, and salicylate but indicated the presence of tories, Inc. (2) Next Nutrition Inc. (3) Ulti- ephedrine alkaloids in the urine. The Medical Examiner's reports states the cause mate Nutrition Products Inc. (4) Quest of death as, ``patchy necrosis associated with ephedrine toxicity from protein drink Vitamins LTD. containing ma huang extract.'' Review of health examination reports from the Uni- versity Health Service indicate the consumer was in excellent health with normal weight, height, blood pressure, and laboratory measurements. 11137 ...... Natural TrimÐStarlight International ...... 39 yo F used product for 6.5 months, 1 thermogenic pill, 1 vitamin and 1 booster pill at 10 AM, and 1 thermogenic pill at 4 PM, as directed. While on antibiotics for a sore throat, she developed upset stomach and stopped the products. She became shaky, weak, and exhausted, and felt as if she were about to pass out if she tilted her head. She was diagnosed with hyperthyroidism. She also reports her supplier has stopped selling the product as the seller has suffered seizures. 11140 ...... Power TrimÐEnrich International ...... 59 yo F used Power Trim and later Power Prime and has had a total of 3 vertigo attacks: 2/96, 4/96, and the third at an unspecified time. She has been to the ER and seen her physician. 11144 ...... MetaboliftÐTwin Laboratories, Inc...... 28 yo M used Metabolift for 10 months, 1 cap 1±2 times daily for energy. While visiting a rental property with his father's truck, his father had found him bloody, walking away from the garage, and responding inappropriately. He has transient retro- grade amnesia. In the emergency room his blood pressure was 168/90, and pulse was 116. CT head EKG were normal. He was diagnosed with syncope and a closed head injury. The next week the consumer had an EEG, echocardiogram, and MRI of the headÐall normal. His neurologist stated ``most likely he had a seizure secondary to the ephedrine'' from the health food substance he was taking. He was advised to avoid the product and dispose of it. He was on no other medication, has no significant past medical history and has never had problems with dizziness or passing out. 11180 ...... Nature's Nutrition Formula OneÐAlliance 41 yo F used Nature's Nutrition Formula One (Alliance) 1±2 pills in AM and 1±2 pills U.S.A. Inc. PM for about 6 months for energy. One morning she took 2 pills, skipped breakfast and drank a diet Pepsi. Soon after she developed hives while visiting a nursing home and was given benadryl tablets. Two hours after taking the Formula One she was found unconscious in a stairwell by nursing personnel who described seizure activity. She was taken to an ER where the evaluation including EEG and CT scan was normal. She has not used the product again and has had no further episodes. 11181 ...... Multi DSÐ(1) Ripped Fuel & (2) Unspec- 19 yo M used Ripped Fuel 2 pills 2±3 times daily, according to label directions, for 2 ified chromium picolinate with caffeine days for weight-loss and body-building. He was found by family members on the productÐ(1) Twin Laboratories, Inc., (2) morning of the third day, in his bed with seizure activity and afterward complained GNC. of dizziness and a headache. He was taken to the ER and given IV Dilantin. CT and MRI were normal and EEG was nonparoxysmal. He had also been taking chromium picolinate, 1 pill daily as directed for 3±4 months; Phosphagen, 1 tea- spoon with meals, three times per day as directed for 3±4 months; and B2G vanadyl sulfate, 2 capsules with meals, three times per day, as directed for 1 month at the time of the event. Based upon the test results and history of use of the Ripped Fuel, his neurologist felt the patient did not need to be treated with Dilantin. The neurologist advised the patient to stop use of all ``over-the-counter medications''. The patient suffered a second witnessed seizure 1 month later and was started on Dilantin. His past history is significant for a concussion as a child with a normal CT at the time. Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30723

ARMS No. Product manufacturer Clinical summary

11215 ...... Multi DSÐRipped Fuel and Ripped 24 yo M used Ripped Fuel, 2 tablets three times daily for 2 years and Ripped Force, ForceÐLabel unavailable. 1 bottle daily for 2 months. He used both products for body building. He went on vacation, stopped the products and within 3 days experienced 2 grand mal seizures. The second seizure was witnessed by the ambulance crew while en route to the ER. MRI of head and EEG were both reportedly normal. He was also using `vanadyl', creatine, and amino acids as part of his body building regimen. He de- nied use of recreational drugs, medications, or other products. 11248 ...... (1) Formula One, (2) Equilizer, (3) Protein 37 yo M used products 2 yr (and had used other products containing ephedrine prior Plus Chromium Picolinate, (4) Fast to use of Formula One). (Formula One use: 1±2 cap mid AM & PM, per label in- StartÐ(1) Alliance U.S.A., Inc, (2), (3), structions). Also known to consume large amount of diet cola. Experienced appar- (4) Equinox Intl. ent sudden cardiac arrest, with no details known surrounding death. Coroner's report notes: cardiomegaly w/mild LVH, focal interstitial fibrosis & mild medial hypertrophy. PMH: neg for HTN. Tox screen noted pseudoephedrine in urine. 11249 ...... Victory Turbo PumpÐJoe Wider Nutrition 20 yo M took product for 3 months (once or twice per week), experienced grand mal seizure. Neg. past history and family history for seizure disorders. He was treated with Dilantin. 11286 ...... Breathe Easy Herbal TeaÐTraditional 36 yo F used Breathe Easy Herbal Tea on one occasion at less than recommended Medicinals. dose. She steeped tea for 1 minute and drank 1¤3 cup instead of steeping tea for 5 min as indicated on the instructions. She used product along with 2 Advil to relieve cold/congestion symptoms. Approximately 15 min after drinking tea she experienced rapid, pounding heartbeat. Following advice of friend who is a nurse, she drank large amounts of water in effort to ``flush tea out of her system.'' She felt so bad she could hardly get out of bed, but did not seek medical care secondary to anxiety about hospitals. Symptoms resolved completely within 5 hours. Routine medical visit approx 1 month after event was unremarkable. Past medical history is significant for occasional palpitations. Consumer's husband used product on several occasions prior to event with no report of negative side effects. 11298 ...... (1) Fast Start-The Equilizer, (2) Nigh Time, 41 yo M used 3 herbal products as directed on labels in an attempt to lose weight. (3) Protein Plus, ChromemateÐEquinox He experienced a ``rush'', and blurred vision which influenced his ability to operate International. heavy equipment. On 5th day of using the product, his underwear was noted to be stained red. A physician visit confirmed hematuria, and noted BP of 136/102, and labs: SGPT 72, cholesterol 208, triglycerides 401. He stopped the product, with re- covery, including normalization of BP. 11401 ...... Ultra Energy NowÐPhoenix Health Prod- 42 yo M used Energy Now tablets on 2 separate occasions. He took 3 tablets as in- ucts. structed on label on both occasions. First occasion was without incident. 2 weeks later when he used product for second time, he experienced severe diaphoresis, blurred vision, SOB, lightheadedness, and pounding chest pain within 1 hour of taking product. Symptoms lasted approx 15 min and had resolved completely by the time he was seen in emergency room. He was admitted to hospital overnight for evaluation including EKG, CBC, & SMA±18 which was all within normal limits. Of note, he was not using any other products. History is significant only for positive tobacco history=1.5 pack of cigarettes per day. 11417 ...... Thermojetics Herbal TabletsÐGreenÐ 34 yo F died following diagnosis of primary pulmonary hypertension (PPH). Mother of Herbalife International. deceased found bottles of Herbalife Green & Beige tablets in home of the deceased. Duration and detail of use are unknown. Deceased appeared to be in excellent health until approx. 3 months prior to her death when she developed SOB & n/v while skiing in Colorado despite numerous previous ski trips in same location which were uneventful. She was diagnosed with ``high altitude sickness.'' Symp- toms persisted and she subsequently underwent cardiac catheterization 3 months after onset of sxs. Results of cath were apparently consistent with PPH and indicated that she would need heart/lung transplant in 3±5 years. She died 3 days later in August 94. Past medical history is significant only for hospital admission 1 year prior to death for CP, SOB, and possible pneumonia. 11441 ...... Ripped FuelÐTwin Laboratories, Inc ...... 27 yo M died secondary to injuries sustained in motor vehicle accident. Wife of deceased reports he had been taking Ripped Fuel 2 tabs bid as instructed on label for approx. 3 years prior to death. No autopsy was performed. Post mortem blood analysis indicate: 0.05 percent ethyl alcohol & 0.31 percent mg/L phentermine. Post mortem urine analysis: Positive for phentermine, negative for cocaine, opiates, benzodiazepine, cannabinoids. 11442 ...... Thermojetics Herbal TabletsÐGreenÐ 39 yo F used Herbalife Diet Plan which consisted of the following 5 products: For- Herbalife International. mula 1 Protein Drink Mix (2 tablespoon bid); Formula 2 Multivitamin-Mineral Tablet (1 tablet tid); Formula 3 Cell Activator Capsules (2 capsule bid); Herbal Beige Tab- let (1 tablet bid); Herbal Green Tablet (3 tablet bid) all taken as directed on label. No other products were being used at the time she developed the adverse events. 3±4 months after starting plan, she began experiencing blurred vision and headache. 2 weeks later she began experiencing dizziness, lightheadedness, slurred speech, and numbness on right side of her body. Evaluation by neurologist indicated patchy sensory deficit in right leg, most pronounced in foot. MRI of brain showed findings consistent with recent hemorrhage associated with cavernous malformation. Evaluation by internist indicated negative w/u for Lyme disease and no additional significant findings. Symptoms improved after consumer discontined use of products. 30724 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules

ARMS No. Product manufacturer Clinical summary

11619 ...... AMP II DropsÐE'OLA Bio-genics, Inc ...... 35 yo F used Liquithin & AMP II Pro (both 7 drops bid) and Citrin Trim (2 tablet/day) for 1 day and developed migraine headache which she typically experiences every month. She awoke at 3 AM on morning after using products with notable right sided facial weakness, CP, palpitations, right arm weakness and numbness, photophobia, and unsteady gait. She was seen by doctor and admitted to hospital. Symptoms improved during hospitalization which was uneventful. All test results were within normal limits except cerebral arteriogram findings which suggested mycotic aneurysmal change or possible changes secondary to an unusual drug induced vasculitis or collagen vascular disease. Discharge dxs included: right facial and arm weakness, cause uncertain; improving right eye irritation; resolving headache; resolved chest pain & palpitations with neg w/u; and history of right C5±6 cervical radiculopathy, carpal tunnel syndrome. Sxs continued to improve in month following discharge. History is significant for: Classical migraine headache associated with right jaw tingling; cardiac murmur with prior evaluation; allergy to iodine dye (tachycardia); and habit of drinking 1.5 quart of caffeinated soda daily.

Abbreviations Used in Clinical Summaries ETOH = ethanol PMH = past medical history in the Appendix F = female q = every abn = abnormal f/u = followup qd = everyday angio = angiography fxn = function R = right ant = anterior GPT = alanine aminotransferase SGPT = serum GPT AF = atrial fibrillation h/o = history of SOB = shortness of breath bid = twice a day HA = headache SSx = signs & symptoms BP = blood pressure HTN = hypertension ST/STT = ST–T waves CAD = coronary artery disease ICU = intensive care unit subl = sublingual Cap/caps = capsule(s) IEP = immunoelectrophoresis SVT = supraventricular tachycardia cath = catheterization inf = inferior tab(s) = tablet(s) CBC = complete blood count L = left or liter tach(y) = tachycardia CK (CPK) = creatine kinase LFT = left tid = 3 times a day cm = centimeter lb = pound tox = toxicological CP = chest pain LV = left ventricle TPA = tissue plasminogen activator CPR = cardiopulmonary resuscitation M = male Tx = treatment CT = computerized tomography MB+ = MB positive w/ = with CV = cardiovascular MD = medical doctor w/o = without CXR = chest X-ray meq = milliequivalents w/u = workup d/c = discontinue or discharge MI = myocardial infarction WL&E = weight loss & energy DTR = deep tendon reflexes min = minutes wnl = within normal limits Dx(s) = diagnosis(es) MRI = magnetic resonance imaging yo = years old EEG = electroencephalogram neg = negative yr = year EKG = echocardiogram nitro = nitroglycerin EMG = electromyography n/v = nausea and vomiting [FR Doc. 97–14393 Filed 6–2–97; 8:45 am] ER = emergency room PE = physical examination BILLING CODE 4160±01±P