life sciences research office “evaluating adverse event reporting systems for dietary...

Life Sciences Research Office“Evaluating Adverse Event Reporting

Systems for Dietary Supplements” Bethesda, MD January 30-31, 2003

Considerations for botanical supplements and

an overview of ephedra

Steven Dentali, Ph.D. VP for Scientific and Technical Affairs American Herbal Products Association

American Herbal Products Association 2

Today’s Talk

An Overview of Ephedra– What it is, Does, and Regulatory Review– Scientific Reviews and Studies

Review of DSHEA– Prior to and Findings of

Special Case of Botanicals– Identification and Characterization– Extracts and Standardization


American Herbal Products Association

The National Trade Association and Voice of the Herbal Products Industry

The American Herbal Products Association exists to serve its members by promoting the responsible commerce of products which contain herbs and which are used to enhance health and quality of life.


American Herbal Products Association

Founded in 1983, the American Herbal Products Association represents the manufacturers, growers, suppliers and retailers of herbal supplement products

AHPA published Herbs of Commerce and wrote Botanical Safety Handbook

HerbMed® searchable database. www.ahpa.org.


What ephedra is … a generic name with forty species. ...standardized common name for ma huang

(pharmacopeial term designating the dried stem of Tsao-ma-huang, Mu-tsei-ma-huang, San-ma-huang, and Chung-ma-huang or Ephedra sinica Stapf, E. equisetina Bunge, E. distachya L., and E. intermedia Schrenk & Meyer, respectively (Hsu et al. 1986).

… the original source of the alkaloid ephedrine reportedly first isolated from E. equisetina in 1887 by Nagi.


What ephedra is One of the oldest herbs in Chinese

medicine, used extensively > 5,000 yrs Chen & Schmidt described

pharmacodynamic characteristics of ephedrine in 1924. Value as a circulatory stimulant in surgical shock and bronchodilator in asthma.

Traditional dosages of 3-9 g per day, equivalent to as much as 75-225 mg per day of ephedrine alkaloids.


What ephedra is Products generally contain 8-24 mg

ephedrine alkaloids per dose. Formulated using extracts containing 6% or 8% ephedrine alkaloids.

Methods of quantification of ephedrine alkaloids: (primarily the first two) ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine, and methylpseudoephedrine are being validated.

PPA not present (racemic mixture) Ephedrine usually predominates.


What it does

Indirect sympathomimetic adrenergics.

Orally active causing bronchial dilation. CNS stimulant & vasopressor effects.

Anorectic and thermogenic effects.


Regulatory Review October 11-12, 1995 Special Working Group of the

Food Advisory Committee of FDA on Foods Containing Ephedrine Alkaloids was Convened.– Considered significance and extent of serious adverse

events reported in a passive reporting system RECOMMENDATIONS

– Limit dosage of ephedrine alkaloids, per unit and per RDI– List ephedrine and caffeine content– List appropriate cautions and health risks, and statement

to discourage taking more than recommended dose– Not for under 18, during pregnancy, long term use, or with

certain diseases or disorders, or with certain drugs– Assure GMPs including identity and quantity of alkaloids– Develop appropriate analytical methods to control content– Conduct more laboratory and clinical research


Regulatory Review August 27-28, 1996, Full Food Advisory

Committee Meeting– Critical review of adverse event reports to

weed out non-applicables was not done– Some adverse events apparent with short

term use or long term low doses use– Approx. half of the panel recommended safe

dose for ephedrine in ds as zero– Calls for the repeal of DSHEA were heard– One ridiculed herbs, homeopathy, astrology


Regulatory Review June 4, 1997 Dietary Supplements

Containing Ephedrine Alkaloids Proposed Rule (62 FR 30677-30724)– 8 mg per serving, 24 mg per day– Prohibits use with stimulant ingredients and

claims requiring long term use (weight loss/body building)

– Requires “Do not use this product for more than 7 days. ”If short term effects are promoted such as increased energy, mental alertness, or well being then the label shall state: “Taking more than the recommenced serving may result in heart attack, stroke, seizure or death.”


Regulatory Review … and the following statement.

WARNING: If you are pregnant or nursing, or if you have heart disease, thyroid disease, diabetes, high blood pressure, depression or other psychiatric condition, glaucoma, difficulty in urinating, prostate enlargement, or seizure disorder consult a health care provider before using this product. Do not use if you are using monoamine oxidase inhibitors (MAOI) or for 2 weeks after stopping a MAOI drug; certain drugs for depression, psychiatric or emotional conditions; drugs for Parkinson's disease; methyldopa; or any product containing ephedrine, pseudoephedrine or phenylpropanolamine (ingredients found in allergy, asthma, cough/cold and weight control products). Stop use and call a health care professional immediately if dizziness, severe headache, rapid and/or irregular heart beat, chest pain, shortness of breath, nausea, noticeable changes in behavior, or loss of consciousness occur. Do not exceed recommended serving.


AHPA Code of Ethics March 1994 (revised March 2001) Ephedra Trade Recommendations

– Warning statement– Serving limits per dose and per day– Use of standard common name (HOC)– NO added synthetic alkaloids– *List amounts of ephedrines and caffeine– *NO legal high or “legal” illicit drug claims– (*added since 1994)


AHPA’s Cautionary WARNING. Not intended for use by anyone under the age of

18. Do not use this product if you are pregnant or nursing. Consult a health care professional before using this product if you have heart disease, thyroid disease, diabetes, high blood pressure, depression or other psychiatric conditions, glaucoma, difficulty in urinating, prostate enlargement, or seizure disorder, if you inhibitor (MAOI) or any other prescription drug, or you are using an over-the-counter drug containing ephedrine, pseudoephedrine or phenylpropanolamine (ingredients found in certain allergy, asthma, cough/cold and weight control products).

Exceeding recommended serving will not improve results and may cause serious adverse health effects.

Discontinue use and call a health care professional immediately if you experience rapid heartbeat, dizziness, severe headache, shortness of breath, or other similar symptoms.


GAO Report House Committee on Science request August 4, 1999, Dietary Supplements:

Uncertainties in Analyses Underlying FDA's PR on Ephedrine Alkaloids.

Concerns about reported adverse events in supporting proposed dosing level and duration of use limit.

April 3, 2000, withdrawal of Proposed Rule limits on level and duration.


More Info Needed August 8-9, 2000 Public Meeting

– Department of Health and Human Services' Office on Women's Health

December 2000 Cantox Report– Formal risk assessment (nutrient based)

St. Luke’s Hospital/Columbia Study– Boozer CN et al. An herbal spl containing

Ma Huang-Guarana for weight loss: a randomized, double-blind trial. Int J Obes Relat Metab Disord 2001 25:316-24.


More Info Needed Haller and Benowitz AER Review

– Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000 343:1833-8.

Mayo Clinic AER Review– Samenuk D et al. Adverse cardiovascular

events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc 2002 77:12-6.


More Info Needed Greenway Literature Review

– Greenway FL. The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent. Obes Rev 2001 Aug;2(3):199-21.

Harvard/Columbia Study– Boozer CN et al. Herbal ephedra/caffeine

for weight loss: a 6-month randomized safety and efficacy trial. International Journal of Obesity (2002) 26:593–604


More Info Needed Phenylpropanolamine Data Review

– Morgenstern LB et al. Use of Ephedra-containing products and risk for hemorrhagic stroke. Neurology 2003 60:132-5

RAND Corporation Report– HHS funded comprehensive review of the

existing science on ephedrine alkaloids– NIH to use information to guide expanded

research effort to better understand the safety of ephedrine alkaloids.


Prior to DSHEA 1972 FDA Proposed to Regulate

Vitamins and Minerals as Drugs 1976 Rogers-Proxmire Amendment

Exempted Drug Status by Potency 1990 Nutrition Labeling and

Education Act (NLEA) – Award winning nutrition facts box

Food Additive Provisions Used to Remove Dietary Supplements


Prior to DSHEA June 18, 1993 ANPR-Dykstra Report

– rules on safety levels for vitamins/minerals– regulating amino acids as drugs– food additive/drug status for some herbs

Problems of the day included:– no claims, dosage, cautions, warnings allowed– no third party literature– proof of safety-manufacturer’s burden– food or not food? If not food then what is it?– uncertain and inconsistent enforcement


DSHEA: Findings Improving Citizen Health - Top National Priority Preventative Health Measures (diet, lifestyle,

and use of supplements) Can Reduce Chronic Disease and Health Care Costs

Consumers are Increasingly Relying on Alternative Health Methods

Almost 50% of Americans Take Supplements Consumers Should Be Empowered to Make

Choices Based on Data from Scientific Studies of Health Benefits from Dietary Supplements

Federal Government Should Take Swift Action Against Unsafe or Adulterated Products


DSHEA: Findings Federal Gov Should Not Restrict or Slow the

Flow of Safe Products and Accurate Information

DS are Safe Within a Broad Range of Intake

Safety Problems with DS are Relatively Rare

Legislative Action That Protects Consumer’s Access to Safe Dietary Supplements is Necessary to Promote Wellness

Rational Federal Framework Must be Established to Supersede the Current ad hoc, Patchwork Regulatory Policy on DS


Dietary Supplement A product (not tobacco) intended to

supplement the diet: vitamin, mineral, herb or other botanical, amino acid, or concentrate, metabolite, constituent, extract, or combination of the above …intended for ingestion in form…not food or food replacement ….labeled as a dietary supplement and is not formerly a drug….


DSHEA Enacted Food Additive Exclusion Presumption of Safety Statements of Nutritional Support New Dietary Ingredients Unsafe GMPs to be Modeled After Foods

(Feb 6, 1997 ANPR of Dietary Supplement cGMPs from Industry Proposal submitted Nov 20, 1995)

June 18, 1993 ANPR Withdrawn Commission Labels Established Office of DS Established (ODS/NIH)


Special Case of Botanicals (AERs)

Closer to foods than most drugs – Complex mixtures derived from plants

Regulated as foods + DSHEA Identification of material is critical (‘97)

– digitalis with plantain from Europe– germander not skullcap in Belgium– aristolochia root for stephania root– Periploca sepium for eleuthero


The Hairy Baby Case Androgenized baby boy born to mother

taking “Siberian ginseng”– toxicity attributed to “Siberian ginseng”– silk vine (Periploca sepium) substituted for

eleuthero (Eleutherococcus senticosus)– 'Ci Wu Jia' (eleuthero) frequently confused

with Southern 'Wu Jia Pi' and 'Xiang Jia Pi' – Product actually labeled Panax ginseng root

Misidentification or Adulterations


Characterization for Publication (or AERs)

Study material needs explicit definition– Proper identification, collection– Plant part, method of extraction– Solvent, ratio of solvent to herb – Ratio of herb to finished extract– Percent native extract in total extract– Percent of identified markers– Manufacturer, part and lot numbers


Types of Extracts Wide spectrum extracts

– Exhaustive extracts, solvent nonspecific St. John’s wort, black cohosh Multiple groups of chemical constituents

Narrow spectrum extracts– Selective, solvent specific or purifications

Milk thistle, saw palmetto, green tea catechin

Intermediate extracts Ginkgo – 30% flavonols/terpenes, 70% other


Botanical Process Flow Chart

Lip id So lub les(d iscard)

Acids

Finished sem i-purified ExtractChem ically Define

Neutrals Bases

Acid/Base Extraction

W ater Soluble Constituents(Enriched B ioactiv ity)

H exane Extraction

Solub le M ateria l(T ota l C rude Extract)

R esidue(d iscard)

Acetone/W aterM aceration

F in ished Extract

S im ple Extract(Se lect So lvent)

C rude D ried Botan ica lSpecifica tions


Semi-Purified Extracts Prepared for a Specific Purpose

– Not a whole plant extract– Not a single isolated compound

Isolation of “Active” Fractions Ratio is Starting to Final (ex. 50:1)

– Ginkgo, silymarin, green tea catechins – Not a conc. of all possible extractables


Guidance Documents for the Manufacture and Sale of Botanical

Extracts

Retail Labeling – extract ratios/ranges Manufacture and Sale of Bulk Extracts

– Extract types and approaches, QA/QC Marker Compounds in Manufacturing

and Labeling of Botanical Products Standardization White Paper


How to Standardize

In order to produce a consistent product, controls must be implemented over both the raw material supply and the manufacturing process.

The ultimate purpose of each of these controls is to reduce variability in the composition of the raw material.


What to Standardize Good Agricultural Practices (material)

– Seed, growing, harvesting (wild), drying Good Manufacturing Practices (process)

– Powdering, extraction, granulation Safe and Effective Products

– Adequate specifications (expertise)

– Validated methods of analysis


Standardized Quality

Standardization requires a thorough description of the starting plant material and of the whole extraction process…It is more than the assay of an active principle or marker. “Standardization signifies the body of information and controls that are necessary to guarantee constancy of composition…”

– A. Bonati (1991) journal of ethnopharmacol., 32:195-197