Dietary Supplements: Assessing the Benefits and Risks in Hospitalized Patients.Patrick McDonnell, Pharm.D., FASHPProfessor of Clinical PharmacyTemple University School of Pharmacy

What federal law states that herbal and dietary supplements must be tested for safety and efficacy before coming to market?A) Federal Food, Drug and Cosmetic Act of 1938B) Dietary Supplement Health & Education Act of 1994

(DSHEA)C) Food and Drug Act of 1906D) None of the Above

Dangers to public health with dietary supplements include:A) Risk of adulteration due to lax regular of manufacturing

standardizationB) Us of these supplements may compromise, delay or even

supplant treatment with therapies of proven efficacy for potentially serious medical conditions

C) Certain populations such as the elderly, pregnant women, and patients with chronic disease states can be defined as “at risk” and therefore may be harmed by certain dietary supplements

D) All of the above

Which of the following dietary supplements pose a danger to public health as they are purposely and frequently adulterated?A) Supplements that are touted as diet aids/weight lossB) Supplements that are touted for male sexual performanceC) Supplement that promote good joint healthD) Both A & B

Significant hepatic induction drug interactions have been seen with?A) St. John’s wortB) Green teaC) Red yeast riceD) Gingko biloba

Objectives Define the term “dietary supplement” & review current US

regulatory practices Recognize potential and actual safety issues with dietary

supplements Demonstrate the evidence of the benefits of select dietary

supplements in patient care Recognize the importance of including dietary supplements

as part of the medicine reconciliation process

Phytomedicine Oldest form of health care Plants used in almost every culture Egyptian Papyrus---Rx pad Olive oil, castor oil, myrrh, aloe, garlic, opium, coriander, anise,

saffron, lotus flowers, linseed, juniper, henbane, colchicum, cedarWHO: 119 phytomedicines still used in modern medicine 20% of all prescription drugs were derived from plant sources Numerous non-prescription medications still contain one of

more natural products as an ingredient

Convention Medications with Plant OriginsAtropa belladonna: atropinePapaver somniferum: codeineColchicum autumnale: colchicineDigitalis purpurea: digoxinEphedra sinica: ephedraRauwolfia serpentine: reserpineSalix purpurea: salicylic acidDatura stramonium: scopolamineTaxus brevifolia: paclitaxelCatharanthus roseus: vincristine

Herbal & Dietary Supplement Statistics 2016 Survey: 40 million adults use herbal and dietary

supplements 25% of patients who seek medical attention for a serious

medical problem are already using dietary supplements However 70% do not directly disclose this use to their physicians

40% of patients used dietary supplements on a regular basis Only 4.5% of these supplements are sold in pharmacies Sales: $20 billion annually in the United States

http://www.cdc.gov/nchs/data/databriefs/db61.htm

Herbal & Dietary Supplements Statistics

Herbal & Dietary Supplements Statistics

Herbal & Dietary Supplements Statistics

Dangers to Public Health Some dietary supplements are just inherently unsafe when

ingested orally Lax regulation of dietary supplement manufacturing = risks of

adulteration Lax regulation of dietary supplement manufacturing = risk of no

ingredient Use of dietary supplements may compromise, delay, or supplant

treatment with therapies of proven efficacy Dangers to special at risk populations $$$ spent on dietary supplements without unsubstantiated value

ASHP statement on the use of dietary supplements. AJHP 2004; 61:1707-11.

February 2015: “Cease & Desist” Courtesy of NY Attorney General Ginko Biloba: No ginko biloba DNA identified, but allium, rice,

spruce, and asparagacae. No other plant DNA St. John’s Wort: Negative for the DNA of St John’s Wort –

and all found allium, rice, and a houseplant Ginseng: No ginseng DNA but only rice, wheat, and other

plants. Echinacea: No echninacea DNA but from other plants found Sent to major retailers: GNC, Target, Walmart, Walgreen’s

http://www.nytimes.com/interactive/2015/02/02/health/herbal_supplement_letters.html

Regulation History 1906 Food and Drug Act Prohibited shipment of “adulterated” or ‘misbranded” drugs

across state lines Sherley Amendment of 1912 No false labeling claims

Federal Food, Drug and Cosmetic Act of 1938 Drugs must be tested for SAFETY before marketing

Kefauver-Harris Amendment of 1962 Marketed drugs must be proven to be safe AND effective “DRUGS” marketed before 1938 were exempt from this law Estimate for confirming the safety and efficacy of a drug: $250 million

1994 Dietary Supplement Health and Education Act (DSHEA)Established the first legal definition of a “dietary supplement”Restructured regulations on how supplements can be manufactured, sold and promotedLIMITED FDA authority on safety and efficacy

DSHEA: Definition of a Dietary SupplementA product intended to supplement the diet that

bears or contains one or more of the following dietary ingredients: a vitamin, mineral, amino acid, herb, or other botanical Intended for ingestion in the form of a capsule,

powder, soft gel, or gel capNot represented as a conventional food or as a

sole item of a meal or the diethttps://ods.od.nih.gov/About/DSHEA_Wording.aspx#sec1

Summary of DSHEAHerbal medicines and natural substances are

not classified as “drugs”Herbal products may be produced without the

assurance of compliance standards (Good Manufacturing Practices)NOT regulated by the FDAHowever, safety burden of the FDA, NOT on the

manufacturershttps://ods.od.nih.gov/About/DSHEA_Wording.aspx#sec1

The Loophole“This product is not intended to diagnose, treat, cure or prevent any disease”

DSHEA ClaimsProduct may affect the structure or function of the

body, as long as there is no claim of effectiveness for the prevention or treatment of a specific disease.And providing that there is a disclaimer informing

the user that the FDA has not evaluated the agentMany products “suggest” they can treat disease--

Labeled primarily to promote use and not necessarily to inform the patient.

ASHP Statement of the Use of Dietary Supplements Require that dietary supplements undergo FDA approval for

evidence of safety and efficacyMandate FDA-approved dietary supplement labeling Safe use instructions Standardized formats Potential for interactions Cautions for special populations

Require and enforce GMPs Require FDA-established standards for identity, strength,

purity and quality Establish an adverse event reporting system specifically for

dietary supplements

ASHP statement on the use of dietary supplements. AJHP 2004; 61:1707-11.

Benefits of Supplements??? Historical data—time and tried “folk remedies”Manufacturers need not conduct trials to prove efficacy under

DSHEA If proven to treat a disease, they can loose their status as a

supplement and become a “drug”. Nor do they need to conduct trials to prove safety or provide

mandatory post-marketing safety data Clinical evidence Meta-analysis Randomized controlled trials in the US sometimes conducted by

National Institutes of Health

Benefits: Trial Data Glucosamine and Chondroitin for joint pain/osteoarthiritis Chondroitin superior to placebo; similar to celocoxib Reginster JY, etal. Pharmaceutical grade chondrotin sulfate is as effective as celecoxib and superior to placebo in

symptomatic knee ostearthritis. Ann Rheum Dis 2017; 0:1-7. doi:10.1136

GAIT Trial: NIH sponsored at cost of $12.5 million 1538 patients to receive placebo or celocoxib or glucosamine or chondroitin or combination of

glucosamine/chondroitin Results: glucosamine/chondroitin either alone or in combination were found to be no different than placebo

reducing patient in knee by 20%. Preplanned subgroup analysis of 354 patient with baseline moderate to severe pain revealed a higher response with combination glucosamine/chondroitin vs. placebo (79.2% vs. 54.3% p = 0.002)

http://www.nejm.org/doi/ref/10.1056/NEJMoa052771#t=references

Beneficial data seen with: Ginger for nausea and vomiting Morning sickness in pregnant women Chemotherapy induced nausea and vomiting

St. John’s wort for mild to moderate depression

Reports of Adulteration

Type of Adulterant Examples

Botanicals Aristolochia, digitalis, colchicum, rauwolfia, belladonna

Microorganisms Bacterial endotoxins: E. coli, Salmonella, Shigella, Pseudomonas; Staphylococcus aureus entero-exotoxins

Pesticides Chlorine, organic phosphates

Toxic Metal Lead, cadmium, arsenic, mercury

Drugs Steroids, warfarin, NSAIDs, sildenafil, fenfluramine, benzodiazepines, sibutramine

“Cleanse Thyself”A 26 year old female was admitted to the hospital with a decreased heart rate and heart block after taking a plantain-containing laxative called Chomper, of the “Cleanse Thyself Line”, Aris and Shine Company from Mt. Shasta, CA. The product was contaminated with woolly foxglove (digitalis).

Scheinost ME: Digoxin toxicity in a 26 year old woman taking a herbal dietary supplement. J Am Osteopath Assoc. 2001 Aug; 101(8): 444-6.

Adulteration: Not so Accidental X-ROCK 3 Day Pill For Men and Z-ROCK: Recall –

Undeclared Drug Ingredient: 7-24-12Mojo Nights and Mojo Nights for Her: Recall -

Undeclared Drug Ingredient: 9-12-12 ACTRA-Sx 500 Capsules by Body Basics Inc.: Recall -

Undeclared Drug Ingredient : 9-18-12 Libigrow, Libigrow XXXtreme, Blue Diamond, Blue

Diamond Platinum, Mojo Nights, Mojo Nights Supreme, And Casanova: Recall - Undeclared Ingredients: 12-18-12 Super Power: Recall - Undeclared Ingredient: 1-24-13

Tainted Sexual Enhancement Products

Tainted Sexual Enhancement Products For more medication health fraud topics, please see

our Medication Health Fraud page. FDA has identified an emerging trend where over-the-counter products,

frequently represented as dietary supplements, contain hidden active ingredients that could be harmful. Consumers may unknowingly take products laced with varying quantities of approved prescription drug ingredients, controlled substances, and untested and unstudied pharmaceutically active ingredients. These deceptive products can harm you! Hidden ingredients are increasingly becoming a problem in products promoted for sexual enhancement.

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/MedicationHealthFraud/ucm234539.htm

Weight Loss Products In 2010. sibutramine, an oral anorexiant was removed from the US

market due to cardiovascular risks Deaths were reported with its use 10-31-2012 FDA Safety Alert Classic Zi Xiu Tang Bee Pollen Capsules And Ultimate Formula Capsules by

Zi Xiu Tang Success: Recall - Undeclared Sibutramine 8-17-2015 FDA Safety Alert Blue Square Market Issues Update to Voluntary Nationwide Recall

of Kaboom Action Strips and Lida Daidaihua Due to the Presence of Undeclared Sulfoaildenafil, Sibutramine and Phenolphthalein LiDa DaiDaiHua was found to contain sibutramine and phenolphthalein.

Sibutramine is an appetite suppressant that was withdrawn from the U.S. market in October 2010 due to increased risk of heart attacks and strokes. Phenolphthalein is an ingredient previously used in over-the-counter laxatives, but because of concerns of carcinogenicity, it is not currently approved for marketing in the United States

The Story of Ephedra & the FDAUsed forweight lossstimulant-- “energy”; “increased concentration”enhance athletic performance

Ephedra

Total of 140 adverse reactions reported to the FDA from June 1997 through March 1999 Adults from 18-45 Cardiac--tachyarrhythmias, hypertension, cardiac arrest &

AMI, sudden death CNS--TIA’s, stroke, seizure Ten deaths 15% permanent medical damage FDA Banned Ephedra

Shekelle PG, Hardy ML, Morton SC, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. 2003:289:1537-45.

Bitter orange or Citrus aurantium

Incidence of Herbal and Dietary Supplement Interactions Interaction between dietary supplements and conventional

drugs: unknown incidence No body of reliable information currently available to draw

upon to assess the scope of the problem Lack of evidence Under-reporting Unrecognized interaction No mechanism explained of the interaction, therefore theoretical

or hypothesized.

Some facts on dietary supplements and interactions Does an interaction always equate to an adverse drug event? Patient variables can lead to less harm or more harm from

the interactions Variability in preparation of supplements are non-

standardized Believe it or not, different enzymes of cytochrome p450 can be

affected on this preparation. PK and PD interactions do exist

St. John’s WortSt. John’s Wort is widely

used to treat mild to moderate depression.Studies have show that it

is efficacious for this indicationNumerous PK and PD

interactions with St. John’s Wort

St. John’s Wort: Inducer of Cytochrome P450 CYP 1A2 CYP 2C19 CYP 2C8 CYP 2C9 CYP 2E1 CYP 3A4

St. John’s Wort Interactions Cyclosporine Reports in 1999 and 2000 of significant drug interactions

resulting in organ rejection with the induction of cyclosporine in patient’s taking St. John’s Wort

Protease Inhibitors St. John’s Wort causes a marked reduction in the serum levels of

indinavir, ritonavir and other protease inhibitors

St. John’s Wort Interactions Oral Contraceptives Treatment failure reported when taken with hormonal

contraceptives (ethinyl estradiol) again through induction of CYP 3A4

Nifedipine/Verapamil: decrease bioavailability of these agents leading to suboptimal cardiovascular effects Methadone: induces metabolism and reports of treatment failure

and withdrawal symptoms Tacrolimus: decreased levels Warfarin: decreased INR by affecting both isomers which are

metabolized by CYP 3A4 and 2C9 Azole antifungals: Decreased efficacy again through 3A4

induction and/or 2C9

Pharmacodynamic Interactions with St. John’s Wort Serotonin Syndrome Photosensitivity

Advising about herbsQuality Efficacy Safety Advice

Present AND Present AND Present Recommend

Uncertain OR Uncertain Or Uncertain Caution

Absent OR Ineffective OR Unsafe Discourage

Health Care Professional’s Role-Patient Information

All botanicals should be purchased from reliable sourcesBotanicals should be dated. Discard if over one

year old.Excessive dosages of dietary supplements should

be avoidedAny undesirable effects from these products

should be reported and the product discontinuedREPORT TO MEDWATCH

Health Care Professional’s Role--Patient InformationBotanicals should generally NOT be used for

serious health conditions without the advice and supervision of a qualified health care professionalQuestion patients about herbals in a non-

judgmental wayBe wary of potential drug interactionsConcern now arising with anesthesia--generally

d/c herbal medicines 2 weeks prior to elective surgery

Questions?

What federal law states that herbal and dietary supplements must be tested for safety and efficacy before coming to market?A) Federal Food, Drug and Cosmetic Act of 1938B) Dietary Supplement Health & Education Act of 1994

(DSHEA)C) Food and Drug Act of 1906D) None of the Above

Dangers to public health with dietary supplements include:A) Risk of adulteration due to lax regular of manufacturing

standardizationB) Us of these supplements may compromise, delay or even

supplant treatment with therapies of proven efficacy for potentially serious medical conditions

C) Certain populations such as the elderly, pregnant women, and patients with chronic disease states can be defined as “at risk” and therefore may be harmed by certain dietary supplements

D) All of the above

Which of the following dietary supplements pose a danger to public health as they are purposely and frequently adulterated?A) Supplements that are touted as diet aids/weight lossB) Supplements that are touted for male sexual performanceC) Supplement that promote good joint healthD) Both A & B

Significant hepatic induction drug interactions have been seen with?A) St. John’s wortB) Green teaC) Red yeast riceD) Gingko biloba