Adverse Events Associated with Ephedrine-Containing Products -- Texas, December 1993-September 1995

During December 1993-September 1995, the Bureau of Food and Drug Safety, Texas Department of Health (TDH), received approximately 500 reports of adverse events in persons who consumed dietary supplement products containing ephedrine and associated alkaloids (pseudoephedrine, norephedrine, and N-methyl ephedrine). This total included reports by individuals and reports identified by the Bureau of Epidemiology, TDH, in a review of records from the six centers of the Texas Poison Center Network. Reported adverse events ranged in severity from tremor and headache to death in eight ephedrine users and included reports of stroke, myocardial infarction, chest pain, seizures, insomnia, nausea and vomiting, fatigue, and dizziness. Seven of the eight reported fatalities were attributed to myocardial infarction or cerebrovascular accident. This report describes three patients in which the recommended dosage for the dietary supplements reportedly was not exceeded, summarizes results from ongoing investigations, and underscores the potential health risks associated with the use of products containing ephedrine. Case Reports Patient 1. In December 1993, a 44-year-old man died from acute coronary artery thrombosis approximately 3 weeks after beginning daily use of a dietary supplement containing ephedrine. He was an active swimmer and tennis player with no known cardiovascular risk factors. He received the dietary supplement from his family physician during a routine physical examination when he requested a substitute for his daily coffee and cocoa. He used the product as directed and eliminated his coffee and cocoa use. On December 18, 1993, after playing tennis and returning home, he sustained a cardiorespiratory arrest. An autopsy revealed an acute thrombus in the left anterior descending coronary artery. All other coronary lumina were patent, although calcified with focal narrowing to approximately 50%. Patient 2. In May 1995, a 35-year-old woman who was taking no other prescription or over-the-counter (OTC) medications began use of a dietary supplement containing ephedrine for weight loss. She used the supplement within the dosage recommended on the label for approximately 30 days, discontinued use of the supplement while on a 1-week vacation, then resumed the usual dosage when she returned on June 24, 1995. On June 25, while sleeping, she had acute onset of symptoms including anterior chest pain that radiated to her left shoulder and arm, numbness of the left arm and hand, diaphoresis, and shortness of breath. She was taken to the hospital and her pain remitted after she was treated with nitroglycerin and morphine. Although an electrocardiogram and cardiac enzymes indicated an acute myocardial infarct, cardiac catheterization indicated normal cardiac function and normal coronary arteries. She had no history of cardiovascular risk factors. She was discharged with a diagnosis of acute myocardial infarction secondary to cardiac spasm and was advised to discontinue use of the dietary supplement that contained ephedrine. Since discontinuing use of the product, she has had no additional cardiac-related symptoms. Patient 3. On August 17, 1995, a 38-year-old woman with no history of seizures experienced two petit mal seizures beginning at 11 p.m. She experienced two additional petit mal seizures the following morning, and that afternoon had onset of a generalized tonic-clonic seizure lasting approximately 2 minutes, during which she required respiratory assistance. On August 17, she had taken two tablets of an ephedrine-containing dietary supplement at 10 a.m. and two more 5 hours later as directed on the product label. She denied use of other drugs except oral contraceptives. During August 19-22, she experienced five additional episodes of unresponsiveness while sitting or standing; while waiting in the office of a neurologist, she sustained an additional generalized seizure witnessed by the neurologist and staff. She was hospitalized for monitoring, treated with antiseizure medication, and diagnosed with new onset of tonic-clonic seizures with complex partial seizures. Other possible causes of seizures were excluded. She was discharged and was advised to avoid any medications or products that contained ephedrine, pseudoephedrine, or related drugs. Since discontinuing use of the product, she has had no additional seizures. Ongoing Investigations

TDH also has received reports of persons who had acute onset of palpitations and fainting after using ephedrine-containing products marketed as "beyond smart drugs" for "euphoric stimulation, highly increased energy levels, tingly skin sensations, enhanced sensory processing, increased sexual sensations, and mood elevations." Although these substances have been sold without warnings or contraindications on the information labels, one label indicated that the product "acts on the same basis as MDMA (3,4-methylenedioxy-methamphetamine, "ecstasy") triggering similar but not identical physical reactions in the body." TDH investigators purchased a product labeled "no side effects" that also listed wild Chinese ginseng as the only ingredient. Laboratory analysis indicated that a single tablet contained 45 mg ephedrine and 20 mg caffeine; the label on this product instructed users to take five tablets, representing a total ephedrine dosage of approximately 11 times the usual recommended OTC dosage of bronchodilator products, which contain 12.5 mg-25.0 mg of ephedrine per dose.

Ephedrine-containing products usually are marketed and labeled for weight loss, energy, "pep," performance enhancement, or body building or as a substitute for illicit drugs such as MDMA. They are commonly labeled as "natural" or "herbal" and use common names for herbs as the source of active ingredients (ma huang, Chinese ephedra, and Sida cordifolia -- another plant source with small amounts of ephedrine alkaloids). An additional 400 reports of adverse events involved OTC drug products containing ephedrine that were labeled as required for use as bronchodilators but marketed in a manner to imply their effectiveness for weight loss and as stimulants.

Since September 1995, the Texas Poison Control Network has received approximately 300 additional reports of adverse events in persons consuming products containing ephedrine. These reports are being investigated by TDH.

Reported by: DM Perrotta, PhD, Bur of Epidemiology; G Coody, C Culmo, Bur of Food and Drug Safety; Texas Poison Center Network, Texas Dept of Health. Clinical Research and Review Staff, Center for Food Safety and Applied Nutrition, Food and Drug Administration. Environmental Hazards Epidemiology Section, Health Studies Br, Div of Environmental Hazards and Health Effects, National Center for Environmental Health, CDC.

Editorial Note

Editorial Note: The three reports presented here and the approximately 500 reports of adverse events received by TDH underscore that use of dietary supplements containing ephedrine and related alkaloids can be associated with a spectrum of adverse health events. Although a cause-and-effect relation cannot be established for the three patients presented here, no other cause was found to explain their medical conditions, all of which are compatible with documented effects of ephedrine consumption. Ephedrine and associated alkaloids are structurally similar to the amphetamines (1) and, by stimulating adrenergic receptors, can increase arterial blood pressure through both peripheral vasoconstriction and cardiac stimulation. Adverse effects from ephedrine can be variable, and do not always depend on the dose consumed. Serious adverse effects of ephedrine and related alkaloids, such as acute cardiovascular and central nervous system stimulant effects, can occur in susceptible persons with use of low dosages. Other adverse effects associated with the use of ephedrine include palpitations, tachycardia, hypertension, coronary spasm, paranoid psychoses, convulsions, respiratory depression, coma, and death (2). Particularly when used in combinations with phenylpropanolamine (PPA) and caffeine, ephedrine has been associated with stroke secondary to intracranial hemorrhage, seizures, mania, and psychosis (3,4). Combinations of ephedrine and caffeine have been documented to have side effects substantially greater than those from the consumption of either compound alone or of a placebo (5-8).

In the United States, ephedrine, pseudoephedrine, and PPA have been marketed extensively for some OTC uses. For example, preparations containing ephedrine are marketed for oral use as a short-term, OTC bronchodilator for persons with mild asthma. The Food and Drug Administration (FDA) has proposed to remove oral ephedrine drug products from the OTC market based on their use in the production of illicit drugs and on their misuse and abuse as stimulants and for weight loss. * Pseudoephedrine, an ephedrine alkaloid contained in many OTC decongestant, cold, and allergy products, is associated with fewer cardiovascular and central nervous system stimulant effects than ephedrine. PPA, another ephedrine alkaloid, also is contained in OTC decongestant, cold, and allergy preparations and is marketed for use in the United States as a weight-control agent.

Dietary supplements can be marketed with no premarket safety evaluation by FDA. For dietary supplements that include an ingredient marketed in the United States before October 15, 1994 -- such as products containing sources of ephedrine alkaloids -- no FDA review is required. For dietary supplements that include an ingredient that was not marketed before October 15, 1994, manufacturers or distributors must submit a notice to FDA 75 days before marketing; however, the notice is not required to include objective evidence of safety, only an explanation of why there is a reasonable expectation that use of the supplement will be safe.

Because many of these products are marketed as "natural" or promoted as foods, consumers may assume incorrectly that the products are safe and without side effects. For example, the TDH investigation determined that, during medical evaluations, some patients did not report taking ephedrine-containing dietary supplements because they did not initially believe that a "natural" or "herbal" food supplement could be related to their illness. In addition, health-care providers or consumers may not have realized that ephedrine alkaloids and other stimulants were in the product because they were not included in the ingredient listing or because an unfamiliar name for the compound was used.

Because of misuse of and adverse reactions to products containing ephedrine, approximately 21 states have passed regulations stricter than federal regulations, including requiring that ephedrine drug and food products be made available by prescription only; moving ephedrine products to the schedules of controlled substances; and prohibiting weight loss, appetite control, or stimulant claims on the labels. Because of concerns about the safety of dietary supplements that contain sources of ephedrine alkaloids, a working group convened by FDA in October 1995 made several recommendations about potency limits and label warnings to promote safer use of these products. FDA has been evaluating these recommendations and, because of continuing concerns about the safety of these products, is convening a meeting of the Food Advisory Committee and the special working group on August 27-28, 1996, in Washington, D.C.

The findings in this report underscore the need for the general public and for health-care providers to be aware of potential health hazards associated with use of dietary supplements containing ephedrine and associated alkaloids. Health-care providers should question patients about their use of dietary supplements and herbal medications and report any adverse effects to dietary supplements, including those containing ephedrine and associated alkaloids, to FDA's MedWatch Program, telephone (800) 332-1088 ({800} FDA-1088). Consumers can report adverse events to the FDA Consumer Hotline, (800) 332-4010 ({800} FDA-4010).

References

1. Dollery C, ed. Ephedrine (hydrochloride). In: Therapeutic drugs. Vol 1. New York: Churchill Livingstone, 1991:E26-E29.

2. Pentel P. Toxicity of over-the-counter stimulants. JAMA 1984;252:1898-903.

3. Loizou LA, Hamilton JG, Tsementzis SA. Intracranial haemorrhage in association with pseudoephedrine overdose. J Neurol Neurosurg Psychiatry 1982;45:471-2.

4. Lake CR, Gallant S, Masson E, Miller P. Adverse drug effects attributed to phenylpropanolamine: a review of 142 case reports. Am J Med 1990;89:195-208.

5. Breum L, Pedersen JK, Ahlstrom F, Frimodt-Moller J. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity: a double-blind, multi-centre trial in general practice. International Journal of Obesity and Related Metabolic Disorders 1994;18:99-103.

6. Astrup A, Lundsgaard C, Madsen J, Christensen NJ. Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr 1985;42:83-94.

7. Astrup A, Toubro S. Thermogenic, metabolic, and cardiovascular responses to ephedrine and caffeine in man. International Journal of Obesity and Related Metabolic Disorders 1993;17 (suppl):S41-S43.

8. Astrup A, Toubro S, Cannon S, Hein P, Breum L, Madsen J. Caffeine: a double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers. Am J Clin Nutr 1990;51:759-67.

• 60 FR 38,643.

  
  

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