Herbal Safety – Potential Drug Interaction and Side Effects

Tieraona Low Dog, M.D.

Founding Director Medicine Lodge Ranch

Chair: US Pharmacopeia Dietary Supplements Admissions Joint Standard Setting Sub-Committee

• Tieraona Low Dog, MD has the following to disclose: • Consultant: Healthy Lifestyle Brands • Consultant: Food State • Consultant: Vitamin Shoppe

• This talk will not discuss off-label and/or investigational use of pharmaceuticals or devices not yet approved by the FDA.

Participants will be able to:

1. Discuss the strength and limitations of in-vitro studies for determining herb-drug interactions. 2. Participants will be able to describe safety considerations for the use of botanical products in special populations: pediatrics, pregnancy/breastfeeding, liver/renal insufficiency, elders 3. Participants will be able to identify key pharmacokinetic and pharmacodynamic interactions for commonly used botanicals and how to reduce the risk of adverse effects in clinical practice. 4. Participants will be able to describe the legal/ethical implications of selling botanical products in their medical office.

Copyright © Integrative Medicine Concept, LLC. All Rights Reserved. "Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease...”

Sir William Osler (1849-1919)

• Same dose does not produce the same concentration of effect in each person: • Genetic variation • Drug-drug interactions • Drug-food interactions • Drug-supplement interactions (e.g., competitive inhibition) • Drug-disease interaction (altered GI, renal and/or hepatic function) • Pregnancy • Children • Body weight

• Pharmacokinetics, what the body does to do the drug (i.e., involved with drug absorption, distribution, metabolism, or excretion). • Pharmacodynamic, what the drug does to the body, (i.e., occur when drugs/supplements act at the same or interrelated receptor sites, resulting in additive, synergistic, or antagonistic effects of each drug at the target receptor).l • An interaction can be both pharmacokinetic and pharmacodynamic. • For the most part, pharmacodynamic interactions involving drugs and herbal products are difficult to predict. But this is why you will often see that valerian (an herb that has mild sedative effects) is contraindicated with benzodiazepines or other sedating drugs. (Think to yourself, how the herb/supplement/or drug will be impacting a given organ or system.)

• Bioavailability – how much of the drug gets into the circulation. • Clearance – how the drug is excreted by the body. • Metabolism - this is where most interactions take place. Something impacts the bioavailability and/or the clearance of the drug. The most important enzymes involved in drug metabolism are cytochrome P450. • Inhibitors of an enzyme: increase drug concentration • Berberine and paroxetine are strong inhibitors of CYP2D6 • Inducers of an enzyme: decrease concentration of drug by increasing metabolism • St John’s Wort and carbamazepine are inducers of CYP3A4 • ProDrugs – some drugs must be ‘activated’ by CYP enzymes. • Tamoxifen is metabolized by CYP2D6 to endoxifen, it’s active form. Co-administration of strong inhibitor of CYP2D6 decreases effectiveness.

Copyright © Integrative Medicine Concept, LLC. All Rights Reserved. •CYP enzymes are found throughout the human body, but for the purpose of drug metabolism, the CYP enzymes located in the liver and gastrointestinal tract are most relevant. •As drug enters the GI tract, CYPs in gut may metabolize a drug and change its form. Enzymes in gut affect the amount of drug that leaves the GI tract and moves into the liver. •CYP enzymes in liver can further transform the drug, which eventually is bound to proteins, moves on to be distributed into various tissues based upon the polarity and affinity of the metabolites, is excreted by the liver, or otherwise transformed for excretion by different means. •P450s play a role in the concentration of the parent drug and its drug metabolites based on the specific drug, the extent of its transformation, and the amount of enzyme available at the site of metabolism.

Alyssa A. Sprouse, and Richard B. van Breemen Drug Metab Dispos 2016;44:162-171

Copyright © Integrative Medicine Concept, LLC. All Rights Reserved. Inhibition of drug transporters responsible for uptake would reduce the absorption of therapeutic agents possibly lowering their efficacy, whereas induction of drug transporters might cause toxicity due to enhanced blood levels.

Drug Portal vein

CYP Liver Absorption

Efflux CYP CYP Bioavailability PgP CYP CYP CYP

CYP CYP Metabolism CYP

To feces Gut wall Metabolism

Most common protein responsible for transport is P-glycoprotein (PgP). PgP found in intestine (limits drug absorption), liver (enhances excretion in bile), kidney (enhances excretion in urine), blood brain barrier (keeps drugs from entering CNS).

• In addition to first-pass hepatic metabolism, absorption after oral administration is a factor determining the bioavailability of a compound. • Low absorption might explain why many clinical trials of natural products have shown no drug interactions although interactions were predicted during preclinical studies. • P-glycoprotein is responsible for decreased drug accumulation in multidrug-resistant cells and sometimes mediates the development of resistance to anticancer drugs.

• Piperine (PIP) has been found to inhibit P-gp • Single oral dose of fexofenadine given to 12 healthy volunteers during the control phase and after the treatment phase. • Piperine 20 mg once daily was given during the treatment phase (10 days). • Piperine significantly increased the area under the curve for FEX. • Practitioners should be aware of this interaction with other drugs that are p-glycoprotein substrates. Bedada SK, et al. Eur J Clin Pharmacol 2017 • Piperine is often included at significant levels in Mar;73(3):343-349 turmeric products to enhance absorption.

Aliskiren (Tekturna) Estradiol (Climara, Estrace, etc) Ambrisentan (Letairis) Etoposide (Toposar) Apixaban (Eliquis) Everolimus (Afinitor) Atorvastatin (Lipitor) Ezetimibe (Zetia) Boceprevir (Victrelis) Fexofenadine (Allegra) Bromocriptine (Cycloset, Parlodel) Carbamazepine (Tegretol) Fluvastatin (Lescol) Carvedilol (Coreg) Fosamprenavir (Lexiva) Cimetidine (Tagamet) Grazoprevir (Zepatier) Colchicine (Colcrys, Mitigare) Imatinib (Gleevec) Cyclosporine (Neoral, Gengraf, Sandimmune) Indinavir (Crixivan) Dabigatran (Pradaxa) Itraconazole (Sporanox) Daclatasvir (Daklinza) Ivermectin (Stromectol) Dasabuvir (Viekira Pak) Lapatinib (Tykerb) Dexamethasone (Decadron) Ledipasvir (Harvoni) Digoxin (Lanoxin) Linagliptin (Tradjenta) Diltiazem (Cardizem) Loperamide (Imodium) Domperidone Losartan (Cozaar) Doxorubicin (Adriamycin) Lovastatin (Mevacor) Edoxaban (Savaysa) Maraviroc (Selzentry) Elbasvir (Zepatier) Methylprednisolone (Solu-Medrol) Empagliflozin (Jardiance) Erythromycin Methotrexate Morphine (MS Contin)

Nelfinavir (Viracept) Silodosin (Rapaflo) Nilotinib (Tasigna) Simvastatin (Zocor) Ombitasvir (Viekira Pak) Sirolimus (Rapamune) Paclitaxel (Taxol) Sitagliptin (Januvia) Paliperidone (Invega) Sofosbuvir (Sovaldi) Tacrolimus (Prograf) Paritaprevir (Viekira Pak) Ticagrelor (Brilinta) Phenytoin (Dilantin) Telaprevir (Incivek) Posaconazole (Noxafil) Tetracycline Pravastatin (Pravachol) Tipranavir (Aptivus) Prazosin (Minipress) Tolvaptan (Samsca) Quinidine Topotecan (Hycamtin) Ranitidine (Zantac) Vecuronium Ranolazine (Ranexa) Velpatasvir (Epclusa) Ritonavir (Norvir) Verapamil (Calan) Verelan (Verapamil) Rivaroxaban (Xarelto) Vinblastine Saquinavir (Invirase) Vincristine (Vincasar) Saxagliptin (Onglyza)

• Pharmacogenomics is the study of how genes affect a person’s response to drugs. This field combines pharmacology and genomics to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. • It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects. • Genetics vary based upon age and sex. • Most clinical studies indicate women metabolize drugs more quickly than men, particularly for substrates of CYP3A4.

Copyright © Integrative Medicine Concept, LLC. All Rights Reserved. Fraction of clinically used drugs metabolized by P450 isoforms and factors influencing variability. A total of 248 drug metabolism pathways with known CYP involvement were analyzed. Each metabolic pathway was only counted once for the major contributing CYP isoform. Important variability factors are indicated by bold type with possible directions of influence indicated (↑, increased activity; ↓, decreased activity; ↑↓, increased and decreased activity). Factors of controversial significance are shown in parentheses.

From: Ulrich M. Zanger, Matthias Schwab. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & Therapeutics, Volume 138, Issue 1, 2013, 103–141

• CYP3A4, CYP3A5, and CYP3A7, the CYP3A subfamily is the most abundant group of P450 enzymes in the human liver. • CYP3A enzymes are responsible for the metabolism of approximately 70% of all drugs. • Note: A simple way to distinguish inducer from inhibitor is to remember that when an inhibitor of an enzyme is added, the serum concentration of the drug or substrate metabolized by the enzyme will increase. An inducer will decrease the serum concentration of drugs or substrates metabolized by the enzyme. • Goldenseal is an inhibitor of CYP3A4, drug level would increase. • St. John’s wort is an inducer of CYP3A4, drug level decreases.

Macrolide Antibiotics: HIV Antivirals: PDE-5 Inhibitors: Clarithromycin (Biaxin) Erythromycin Indinavir (Crixivan) Sildenafil (Viagra) Telithromycin Ritonavir (Norvir) Tadalafil (Cialis) (NOT azithromycin) Saquinavir (Invirase) Vardenafil (Levitra) Nevirapine (Viramune) Anti-Arrhythmics: Others: Quinidine (Quinidex) Calcium Channel Blockers: Alfentanyl (Alfenta) Amlodipine (Norvasc) Aripiprazole (Abilify) Benzodiazepines: Boceprevir (Victrelis) Alprazolam (Xanax) Diltiazem (Cardizem) Buspirone (Buspar) Diazepam (Valium) Felodipine (Plendil) Midazolam (Versed) Nifedipine (Adalat) Carbamazepine (eg, Tegretol) Triazolam (Halcion) Nisoldipine (Sular) Cisapride (Propulsid) Ethinyl Estradiol Nitrendipine (Baypress) Immune Modulators: Imatinib (Gleevec) Verapamil (Calan) Cyclosporine (Neoral) Haloperidol (Haldol) Tacrolimus (Prograf) Pimozide (Orap) Sirolimus (Rapamune) HMG CoA Reductase Inhibitors: Quinine Atorvastatin (Lipitor) Antihistamines: Tamoxifen (Nolvadex) Lovastatin (Mevacor) Astemizole (Hismanal) Telaprevir (Incivek) Simvastatin (Zocor) Chlorpheniramine Trazadone NOT pravastatin or rosuvastatin Vincristine (Oncovin)

Strong Inhibitors of CYP 3A4, 5, 7: Inducers of CYP 3A4, 5, 7 Black pepper (20 mg or more piperine) Carbamazepine Goldenseal, Oregon Grape root, Barberry, Coptis Efavirenz Berberine Nevirapine Indinavir Phenobarbital Nelfinavir Ritonavir Phenytoin Clarithromycin Pioglitazone Itraconazole Rifabutin Ketoconazole Rifampin Nefazodone St. John’s wort Moderate Inhibitors: Troglitazone Erythromycin Grapefruit juice Schisandra Verapamil Diltiazem

• 7-14% of population has slow acting form; 7% super-fast form. • CYP2D6*2x2 – ultra metabolizers convert codeine to active metabolite morphine, more rapidly and completely than others – can experience overdose on typical dose • 35% are carriers of a non-functional CYP2D6 allele, elevating the risk of adverse drug reactions when taking multiple drugs. • CYP2D6 is responsible for activating prodrug codeine and other opioids into active forms. The analgesic activity of these drugs are therefore reduced or absent in poor metabolizers of CYP2D6. • Women who are PM may not effectively convert prodrug tamoxifen to active metabolites – question if this has an effect on outcomes.

Lash, et al. J Natl Cancer Inst 2011; 103(6):489-500 Thompson, et al. Breast Cancer Res Treat 2011; 125(1):279-87 Lammers, et al. Br J Cancer 2010; 103(6):765-71 Dahabreh, et al. PLoS Curr 2010; 2: RRN1176

Beta Blockers: Others: Carvedilol (Coreg) Aripiprazole (Abilify) Caution: S-metoprolol (Lopressor) Propafenone (Rythmol) Atomoxetine (Strattera) Berberine Bupropion Timolol Codeine Fluoxetine Antidepressants: Dextromethorphan (Robitussin, Amitriptyline Delsym) Paroxetine Clomipramine (Anafranil) Perhexilline Doxepin Desipramine (Norpramin) Quinidine Duloxetine (Cymbalta) Flecainide (Tambocor) Resveratrol (1 Fluoxetine (Prozac, Serafem) Mexiletine (Mexitil) gram/d or more) Imipramine (Tofranil) Paroxetine (Paxil) Ondansetron (Zofran) are strong Venlafaxine (Effexor) Oxycodone (Oyxcontin, etc) inhibitors of CYP2D6. Antipsychotics: Tamoxifen (Nolvadex) Haloperidol Risperidone (Risperdal) Tramadol (Ultram) Thioridazine (Mellaril) Venlafaxine (Effexor)

• CYP polymorphisms may account for high rates of side-effects or diminished efficacy of opioids in affected patients. • Oxycodone and tramadol, are metabolized mostly by CYP2D6, and buprenorphine is metabolized by CYP3A4.

• A reduction of ~20% in the metabolism of Prostran M, et al. Front Aging CYP2D6 substrates was observed in older Neurosci 2016; 8:144 population.

Prostran M, et al. Pharmacotherapy of Pain in the Older Population: The Place of Opioids. Front Aging Neurosci 2016; 8:144

• ~25% of P450 enzymes in the human liver • Defects in CYP2C19 are rare in Caucasians (2%–5%) but affect 12%– 23% of Asians • CYP2C19 – poor metabolizers have diminished response to clopidogrel (Plavix) • 18-23% of Japanese, 13% islanders of Vanuatu, 2-5% Caucasians • CYP2C19*17 – ultra rapid metabolizers • 18% Ethiopians & Swedes, 1.3% Japanese • CYP2C9 – poor metabolizers caution with celecoxib (Celebrex) • CYP2C9*2 or CYP2C9*3 alleles – increased risk of bleeding with warfarin • 6-12% European descent, 1-2% African Americans, 2-4% Asians

NSAIDs: Others: Diclofenac (Voltaren, Cataflam) Caution: Celecoxib (Celebrex) Ibuprofen (Motrin, Advil) Fluconazole is Naproxen (Aleve) Fluvastatin (Lescol) strong inhibitor Piroxicam (Feldene) Phenytoin (Dilantin) >80% decrease in clearance of these Torsemide (Demadex) Oral Hypoglycemics: drugs Tolbutamide Valproic acid (Depakote) Resveratrol (1 gram Glipizide (Glucotrol) Warfarin (Coumadin) or more/d) Glyburide (Micronase, Diabeta) moderate to strong Rosiglitazone (Avandia) Zafirlukast (Accolate) inhibitor

Angiotensin II Blockers: Losartan (Cozaar) Irbesartan (Avapro)

PPIs: Others: Esomeprazole (Nexium) Amitriptyline Caution: Lansoprazole (Prevacid) Carisoprodol (Soma) Fluconazole, Omeprazole (Prilosec) Citalopram (Celexa) Fluvoxamine Ticlodipine are Clomipramine (Anafranil) Pantoprazole (Protonix) all strong Clopidogrel (Plavix) inhibitors. Anti-epileptics: Cyclophosphamide (Cytoxan, etc) Resveratrol 1 gram Diazepam (Valium) Imipramine (Tofranil) moderate Labetalol (Trandate) inhibitors. Phenytoin (Dilantin) Proguanil (Malarone) Inducer: Phenobarbital St. John’s wort Voriconazole (Vfend)

Copyright © Integrative Medicine Concept, LLC. All Rights Reserved. • Half-life of drugs processed by hepatic CYP enzymes or via renal elimination is typically 50–75% longer in those older than 65 as compared to young adults. Ginsberg, et al. Environ Health Perspect. 2005; 113(9): 1243–1249.

•In vitro •Simple, inexpensive, useful screening tool, isolated phytochemicals and multi-ingredient extracts •But solubilizing agents can exaggerate findings as in vivo bioaccessibility issues are circumvented. •Concentrations needed to modulate enzyme systems often exceed what is achieved in vivo. •Purified compounds can’t replicate phytochemical complexity. •Secondary metabolites undergo extensive intestinal and/or hepatic metabolism – may modulate findings.

•Subjects receive single or cocktail of drugs that are markers for various enzymes. Individual drug phenotypes (e.g., pharmacokinetic profiles, drug/metabolite ratios) are then determined. •Followed by daily multiple dosing of botanical supplement (14–30 days) whereupon phenotypic profiling of the test drugs is repeated. •Comparison of pre- and post-treatment pharmacokinetic parameters gauges how drug metabolism affected. •Botanicals vary from brand to brand considerably.

•FDA released guidelines for interpreting the clinical significance of drug interactions. •For midazolam (CYP3A4) increase in AUC 2-5 fold moderate, >5 fold strong interaction. •If increases in the AUC is 2 fold or higher for these probes – could be clinically significant. •Warfarin, CYP2C9 •Omeprazole, CYP2C19 •Dextromethorphan, CYP2D6 •Digoxin, ABCB1

•A reduction in the AUC values of 30% or greater constitutes a significant interaction. •For drugs with narrow therapeutic window, values of 25% considered significant. •Rifampin acceptable probe for examining the induction of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and ABCB1.

http://www.fda.gov/Drugs/Guidance Compliance Regulatory Information/Guidances/ucm064982.htm.

• It is best to use a small handful of drugs in clinical practice and to know them REALLY well. • It is best to use a small handful of supplements in clinical practice and to know them REALLY well. • Be particularly cautious when adding a drug or supplement to any drug that has a narrow therapeutic window (ask yourself, if the dose were doubled or if it were cut in half, would it be clinically significant?) • Antiarrhythmics (e.g. amiodarone) • Anticoagulants (e.g., warfarin) • Antiepileptics (e.g., phenytoin) • Antineoplastics (e.g., sunitinib) • Aminoglycosides (e.g., gentamicin) • Immune suppressants (e.g., tacrolimus)

From: Sprouse, AA, van Breemen RB. Drug Metab Dispos 2016;44:162-171

First reports of SJW interacting with cyclosporine came out - conflicting in vitro studies indicated St. Johnʼs wort either inhibited CYP3A4 or was a potent ligand of the orphan nuclear receptor PXR. In vivo studies show it is a potent inducer of CYP subfamilies 3A and to lesser degree 2C. Hyperforin is bioavailable and exhibits an elimination half-life of 8–12 hours, so repeated dosing leads to significant accumulation. 70% of drugs are susceptible – decreased bioavailability, enhanced systemic clearance and reduced drug effectiveness. Takes roughly 7 days after discontinuation for CYP3A levels to return to Obach, et al. Pharmacol Exp Ther 2000; 29: 88–95 baseline. Moore, et al. Proc Natl Acad Sci USA 2000; 97: 7500– 7502 Kober, et al. Curr Drug Metab 2008; 9: 1027–1037 Caccia, et al. Curr Drug Metab 2005; 6: 531–543 Imai, et al. Br J Clin Pharmacol 2008; 65: 701–707

Copyright © Integrative Medicine Concept, LLC. All Rights Reserved. • The plant kingdom contains many species with phytochemicals whose structures contain methylenedioxyphenyl (MDP) moieties. • Most act as insecticides in plants but when consumed by humans they can act as mechanism- based inhibitors of CYPs.

• Berberine and hydrastine, alkaloids in goldenseal, both inhibit CYP3A4 and CYP2D6. • Cyclosporine serum concentration increased in healthy volunteers and renal transplant recipients after co-administration of 0.3g (single dose) or 0.2g (TID, 3 months), respectively, of goldenseal. • This risk would extend to other berberine rich plants: • Chinese goldthread (Coptis chinensis) • Barberry (Berberis vulgaris and other species) • Oregon grape root (Berberis aquifolium; Mahonia aquifolium)

Xin, et al. Find Exp Clin Pharmacol2006; 28: 25–29 Wu, et al. Eur J Clin Pharmacol 2005; 61: 567–572

• When Schisandra was administered either once or for up to 14 consecutive days in human clinical trials, the AUC increased: • Talinolol (ABCB1 substrate) 1.5 fold • Tacrolimus (CYP3A4/ABCB1 substrate) 2.1 fold • Midazolam (CYP3A4 substrate) 2.0 fold

Curcumin and Piperine

• Low aqueous solubility of curcumin and its rapid metabolism and elimination from the body have constituted major obstacles to clinical use. • Nanoencapsulation, curcumin complexed with phosphatidylcholine, and inclusion of the black pepper alkaloid, piperine, enhance tissue distribution and bioavailability. • Note: The spiciness of black pepper is due to the MDP-containing phytochemical, piperine, and related pungent alkaloids known as piperamides. • Piperine causes inhibition of CYP3A4 and at doses of 20 mg can cause clinically relevant drug interactions especially for drugs with narrow therapeutic indices. • Acute induction followed by rapid inhibition of CYP3A4 and ABCB1.

Gurley BJ, et al. Planta Med 2012; 78(13):1490-514 Bedada SK, et al. Drug Res 2016; Oct 24

• Risk of clinically significant drug interaction using standardized extracts at typical doses: • Black cohosh (Actaea racemosa): LOW • Echinacea (E. purpurea): LOW • Ginkgo (G. biloba): LOW, doses 240 mg SE or less • Milk thistle (Silybum marianum): LOW • Panax ginseng: LOW • Kava (Piper methysticum): LOW

Gurley BJ, et al. Planta Med 2012; 78(13):1490-514

• Resveratrol (1 gram per day for 4 weeks in healthy volunteers) resulted in significantly increased post-intervention dextromethorphan/dextrorphan molar ratio (p = 0.01), suggesting inhibition of CYP2D6 activity – change was 70%. • Even more significant increase in CYP2C9 phenotypic index of 171%.

Chow, et al. Cancer Prev Res; 3(9) September 2010

•No clinically significant drug interactions observed using approved CYP probe drugs and P-gp probe substrates when P. ginseng administered for 2 weeks in healthy volunteers. •P. quinquefolius did not interact with indinavir (CYP3A4) in human volunteers.

•P. ginseng 1 gram/d for 6 weeks, no Kim DS, et al. J Ginseng Res 2016; 40(4):375-81 Andrade AS, et al. BMC Complement Altern Med 2008; 8:50 significant change in INR in patients on Lee YH, et al. Int J Cardiol 2010; 145(2):275-6. warfarin.

• Ginseng is commonly contraindicated in those with hypertension, particularly “red” or steamed ginseng. • Systematic review and meta-analysis assessed whether ginseng has an effect on BP. • 17 studies satisfied eligibility criteria (n=1381). • No significant effect of ginseng on SBP, DBP and MAP was found. • “Ginseng appears to have neutral vascular affects; therefore, should not be discouraged for concern of increased blood pressure.”

Komishon AM, Shishtar E, Ha V, Sievenpiper JL, et al. The effect of ginseng (genus Panax) on blood pressure: a systematic review and meta-analysis of randomized controlled clinical trials. J Hum Hypertens. 2016 Oct;30(10):619-26.

•Herbs with potent diuretic activity – be thoughtful on those meds that can be toxic to kidneys (e.g., lithium), in combination with other meds that are diuretics, etc. •Mucilage rich plants are less of an issue than often thought when it comes to “blocking” absorption. •Pregnancy, breastfeeding, neonates, elders, those with impaired renal, hepatic function and those on drugs with narrow therapeutic window – dose low and go slow.

•A growing number of clinicians are adding acupuncture, nutrition counseling, imaging services, and skin care or dietary supplements to their practice’s offerings. •Medscape’s 2014 physician compensation survey found that 21% of physicians offered ancillary services to their patients.

www.medscape.com/features/slideshow/compensation/2014/public/overview

•Brief summary of the relevant opinion from the Code of Medical Ethics of the American Medical Association states: •Physicians may sell health-related goods at cost, provided that they take adequate precautions to assure that patients are not pressured into making purchases. •Products sold should be evaluated for their scientific validity. •Physicians may ethically advise the use of and provide free health- related non-prescription goods from their offices. •Physicians should not participate in exclusive distributorships.

www.ama-assn.org/ama/pub/physician-resources/medical-ethics/

•Dispensing of nonprescription products by trained/knowledgeable health care professionals can be done ethically. •If what you’re adding (time, products, etc.) has a genuine benefit to your patient and you are not violating the four principle ethics (beneficence, non-maleficence, autonomy, justice) – there is nothing ethically wrong with making money while you’re doing it. •Legally? Check with your state medical board.

“Our office sells dietary supplements to you at a___ markup from cost. You are under no obligation to purchase these products from my office; you may purchase the same products elsewhere or not at all; and your quality of care in my office will not be affected by your decision to purchase or not purchase products from my office.”