The Year s Top 50 Drug Interactions Continuing Pharmacy Education UW Herbal / Drug Interactions to Watch For

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1 The Year s Top 50 Drug Interactions Continuing Pharmacy Education UW Herbal / Drug Interactions to Watch For Gary W. Elmer, Ph.D. Department of Medicnial Chemistry, elmer@u.washington.edu 11/18/01 Dietary Supplement Education Alliance Survey (Harris Interactive) July 2001 N= % take dietary supplements on a regular basis 46% take multivitamins 23% take herbal and specialty products (15% botanicals, 8% non botanical supplements) 95% indicate satisfaction; 75% very satisfied or extremely satisfied 25% wrong about expecting immediate results from herbals Only 49% consult with health care providers about taking supplements Most believe they have sufficient information on using supplements Top 20 Selling Herbals - Mass Market, 52 weeks ending Jan7,2001 from Food, Drug, and Mass Market Retail, HerbalGram vol 51 Product M $ rank in ginkgo ginseng garlic echinacea St. John s wort saw palmetto soy 41.0 NA 8. valerian kava evening primrose milk thistle grapeseed bilberry black cohosh 6.2 NA Herbal Sales in 2000 Sales off 15% in Mass market (retail store sales including pharmacies) in 2000 compared to 1999 Sales increased 1% in all channels of trade in 2000 Steps for Detecting Herbal/Drug Interactions Is the patient taking any herbal supplements? What are they REALLY taking? Note: Consumerlab.com is systematically evaluating dietary supplements for label claim and quality! ( $16/yr Hypericin Content of St. John s Wort adapted from LA Times, Aug 31,1998 Product- % label claim $/tab Nature s Resource Nature s Herbs Safeway Select Trader Joe s Kira Enzymatic Therapy Jarrow Formulas Futurebiotics Pure Source Sundown Herbals

Phenolics Content of Echinacea adapted from Consumer s Reports, March, 1999 Product- Phenolics (%) $/tab American Fare 4.5.

6.05 Nature s Way 1.5.11 Nature s Fingerprint 1.2.26 Nature s Made 1.1.17 Nature s Resource 1.1.07 Sundown Herbals 0.8.

2 Phenolics Content of Echinacea adapted from Consumer s Reports, March, 1999 Product- Phenolics (%) $/tab American Fare One-A-Day Sunsource Echinex Your Life Nature s Herbs Celestial Seasonings Rite Aid Nature s Way Nature s Fingerprint Nature s Made Nature s Resource Sundown Herbals Ginseng Tests 6 major ginsenosides adapted from Consumer reports, Nov 1995 Product- -%- Walgreen s Gin-Zing 7.6 Herbal Choice 6.8 American Ginseng 5.5 Natual Brand Korean 3.9 Ginsana (extract) 2.8 KRG Korean Red 2.2 Solgar Korean 2.0 Naturally Korean 0.2 Rite Aid Imperial 0.2 Time Magazine Apr 30, 2001 Why don't you ever see the headline "Psychic Wins Lottery!"? 2

New USP Herbal Monographs - 9th supplement to the USP 24 - NF 19 Chamomile feverfew powdered feverfew ginkgo oriental ginseng powdered oriental ginseng St. John s wort powdered St.

3 New USP Herbal Monographs - 9th supplement to the USP 24 - NF 19 Chamomile feverfew powdered feverfew ginkgo oriental ginseng powdered oriental ginseng St. John s wort powdered St. John s wort saw palmetto Others being developed: cranberry, echinacea, ephedra, American ginseng, Siberian ginseng, hawthorn, kava, licorice, milk thistle, nettle root, ginger, valerian, comfrey Product Selection Issues Select name brands recognized for quality select standardized products that give potency per unit of the product select products used in the positive clinical trials select standardized extracts where appropriate select products that have batch numbers, expiry dates, and have the new label elements avoid complex herbal mixtures Some Name Brand Botanicals Warner Lambert Quanterra Mental (ginkgo) Quanterra Prostate (saw palmetto) Whitehall-Robins Healthcare Centrum botanicals line Pharmaton (Boehringer Ingelheim) Ginsana (ginseng) Ginkoba (ginkgo) Venastat (horse chestnut) Movana (St. John s wort) SK-Beecham Alluna (valerian and hops) Phyto-Phamica - multiple products Nature s Way - Ginkgold and others Product Selection Issues Select name brands recognized for quality select standardized products that give potency per unit of the product select products used in the positive clinical trials select standardized extracts where appropriate select products that have batch numbers, expiry dates, and have the new label elements avoid complex herbal mixtures 3

Product Selection Issues Select name brands recognized for quality select standardized products that give potency per unit of the product select products used in the positive clinical trials select

Interactions Use the best references to look up potential herbal/drug interactions References with Good Herbal/Drug Interactions Discussion Hansten and Horn s Drug Interactions Analysis and

4 Product Selection Issues Select name brands recognized for quality select standardized products that give potency per unit of the product select products used in the positive clinical trials select standardized extracts where appropriate select products that have batch numbers, expiry dates, and have the new label elements avoid complex herbal mixtures Steps for Detecting Herbal/Drug Interactions Use the best references to look up potential herbal/drug interactions References with Good Herbal/Drug Interactions Discussion Hansten and Horn s Drug Interactions Analysis and Management Hansten PD and Horn JD. Applied Therapeutics Top 100 Drug Interactions Hansten PD and Horn JD. H&H Publications 2001 The Review of Natural Products. Facts and Comparisons Publishing Group, St. Louis MO efacts through UW Healthlinks Natural Medicines Comprehensive Database. Online version updated daily. UW Healthlinks The Natural Pharmacist base free Original Literature 4

5 Evaluation of Herbal/Drug Interactions Speculative e.g. St. John s Wort and tyramine containing foods due to MAOI effects In vitro effects e.g. St. John s Wort and microsomal studies showing inhibition of CYP3A4 In vivo - animal studies e.g. Kava and alcohol In vivo - human case reports e.g. Kava and SSRI In vivo - healthy human volunteer studies e.g. indinivir and St. John s Wort In vivo - clinical studies in patients Interactions with St. John s Wort (SJW) -indinavir- Study: 8 healthy volunteers; crossover study indinavir q8h x 3 then blood samples taken repeat after 2 weeks of SJW (0.3% hypericin) Results: AUC before SJW = 30.8 AUC after SJW = ref: Piscitelli et al. Lancet 355: , (p=0.0008) Interactions with St. John s Wort -cyclosporin- Study: 2 case reports case 1: 61yr had transplant 11mos earlier; cyclosporin, azathioprine, steroids for 11 mos. Unexplained heart failure noted after SJW started. case 2: 63yr had transplant 20mos earlier: same senario as case 1. Ref: Ruschitzka et al. Lancet 355: ,2000 Seven cases of decreased warfarin effect with St. John s Wort. Yue etal., Lancet 355: ,2000 Patient INR prior INR during Length of treatment yr yr d 61 NA 1.1 years mos ? years 5

6 Interactions with St. John s Wort -digoxin- Study: placebo controlled study in volunteers, n=25 5d of digoxin then SJW 900mg/d or placebo for 10d Results AUC placebo = 17.2 AUC SJW = 12.9 p=0.004 Ref: Ruschitzka et al. Lancet 355: ,2000 Probable Interaction Between Warfarin and Ginseng Janetzky and Morreale, Am J. Health-Syst Pharmacy 54: , yr old male on warfarin for 10 years with an INR of 3-4 started ginseng (INR= 3.1, 4 weeks prev) INR declined to 1.5 after 3 weeks on ginseng INR increased to 3.3 after stopping ginseng causing CYP induction? SSRIs and St. John s Wort Lantz et al. J Geriatr Psychiatry and Neurol 12:7-10, yr old female on sertraline took SJW on advise of natural food store clerk became disoriented with vomiting, dizziness, headache apparent additive effect 4 additional similar cases reported Coma from the health food store: interaction between kava and alprazolam Ann Int Med 125: , yr old male hospitalized in a lethargic and disoriented state on alprazolam, cimetidine, terazosin took kava prev. 3 days alpha pyrones in kava known to bind to GABA receptors (benzodiazepines) apparent additive effect oversedation Bleeds associated with ginkgo use Patient age Ginkgo use Other therapy Bleed 70 1 week Aspirin Iris mos Warfarin Intracerebral years None Subdural mos None Subarachnoid 4 1. NEJM 336:1108, Neurology 50: , Lancet 352:36-37, Neurology 46: ,1996 ref 6

Probe Ki (ug/ml) Inhibition type 1A2 Phenacetin 19.6 Competative 2C9 S-warfarin 9.7 Competative 3A4 Testosterone 59.5 Competative 2E1 Chlorzoxazone 46.

7 Popular Herbals Containing Flavonoids Ginkgo 24% flavone glycosides St. John s Wort 0.3% hypericin/3% hyperforin Ginseng 7% ginsenosides Echinacea 3% phenolics Saw plametto 85% fatty acids Pycnoginol 60%-95% proanthocyanidins Bilberry 25% anthocyanidins Ginkgo inhibition of CYP CYP Probe Ki (ug/ml) Inhibition type 1A2 Phenacetin 19.6 Competative 2C9 S-warfarin 9.7 Competative 3A4 Testosterone 59.5 Competative 2E1 Chlorzoxazone 46.8 Uncompetative Putting Druggists to the Test: Prescription for Disaster? Consumers Reports October 1999 Consumer s Reports shopped 25 pharmacies Coumadin Rx OTC ginkgo 16/25 gave wrong advice only 5/25 warned patient 2A6 Coumarin None Potentiation of Warfarin by Dong Quai Page and Lawrence, Pharmacotherapy 19: , yr old women with atrial fibrillation stabilized on warfarin for 2yr started Dong Quai for perimenopausal Sx INR increased INR back to normal after stopping Dong Quai Page and Lawrence, Pharmacotherap y 19: ,1999 7

8 Fig. 1 Patient INR Values Tea Taken 5 4 7/27 INR value 3 12/15/ /10 1 1/12/00 2/16 4/5 5/26 6/30 8/29 9/7 8/2 10/8 8/7 8/18 11/7 0 10/17 12/6 1/25 3/15 5/4 6/23 8/12 10/1 11/20 Date!"HAM AND EGGS - A day's work for a chicken; A lifetime commitment for a pig." From Lam AY, Mohutsky MA and Elmer GW. Ann Pharmacother in press Lycium barbarum Herbal/Drug Interactions Additive Effects Avoid combinations with additive activities hawthorn and cardiac drugs ginkgo and aspirin; ginkgo and warfarin St. John s Wort and SSRI, kava and benzodiazepines CYP Inhibition several examples but largely unexplored ginkgo, danshen, dong quai, CYP Induction St. John s Wort with 3A4 possibly ginseng Effects on Absorption (p-glycoprotein) Digoxin, cyclosporin and St. John s Wort From: Scott GN and Elmer GW. Update on drug and natural product interactions Am J Health Systems Pharmacy in press 2001 Table 1 Documented Herbal/Drug Interactions Mechanisms Observation Herbal Evidence Use caution with St. John s Case reports Induction of Indinavir ( ) 9 Oral contraceptives, Wort 71 and human CYP3A4 cyclosporin benzodiazepines and studies 65, 67, 71, 72 ( ) other CYP3A4 substrates Induce 6, 76, Digoxin ( ) Case report p=glycoprotein 77 2C19 and 2D6 Induce 2C19 and Amitriptyline substrates Case report 2D6? ( ) 70 Other antidepressants SSRI additive effect Ginkgo In vitro and case reports Case report Inhibition of platelet adhesion and CYP2C9 GABA agonist additive effect Dong Quai Case report Inhibition of and in vitro platelet adhesion? Ephedra Case reports Additive adrenergic effects Toxicity with sertraline 74, 75 Warfarin ( INR) 42, 43 Aspirin (bleed) Toxicity with 5, 39 trazodone Warfarin ( INR) Toxicity with caffeine and other stimulants. 15, 16 Ginseng Case report CYP2C9 induction? Warfarin ( INR) 54 Glucosamine Human study Increased insulin Decreased resistance glucose tolerance Ipriflavone Case report CYP 1A2 inhibition Theophylline 14, 58 and in vitro ( ) Kava Case report Benzodiazepine Toxicity with additive effect Alprazolam 81 Tolbutamide, phenytoin, and other 2C9 substrates and other anti-platelet adhesion drugs Other anti-platelet adhesion drugs Antihypertensives Tolbutamide, phenytoin, and other 2C9 substrates. Avoid use with hypoglycemic drugs and insulin Caffeine, clozapine and other 1A2 substrates Other benzodiazopines and dti From: Scott GN and Elmer GW. Update on drug and natural product interactions Am J Health Systems Pharmacy in press 2001 Table 2 Less Well Documented Herbal/Drug Interactions Evidence Mechanisms Use caution Herbal with Cat s claw In vitro Inhibition of CYP3A4 17 Protease inhibitors, cyclosporin and many other 3A4 substrates Chamomile In vitro Inhibition of CYP3A4 17 Protease inhibitors, cyclosporin and many other 3A4 substrates Echinacea In vitro Inhibition of CYP3A4 17 Protease inhibitors, cyclosporin and many other 3A4 substrates Garlic Case Inhibition of platelet Anticoagulants and anti-platelet reports of aggregation aggregation drugs bleeds Goldenseal In vitro Inhibition of CYP3A4 17 Protease inhibitors, cyclosporin and many other 3A4 substrates Eleutherococcu Case report Possibly an adulterated Digoxin s senticosus (Siberian ginseng) product; increased the digoxin assay value without signs or symptoms of digoxin toxicity leading to the conclusion that the interaction involved the assay but not the actual 79, 80 serum digoxin level What can we do? dialog with NDs and other prescribers recommend the best products (not the cheapest!) ask patients about herbals they may be taking herbals should not usually be recommended for acute or serious illnesses avoid herbal use with drugs with narrow therapeutic window, esp. warfarin, cyclosporin, digoxin, HIV protease inhibitors, theophylline, carbamazepine stay informed Melatonin Case report Additive cardiovascular effects 62 Decreased nifedipine effect 8

Herbal/Drug Interactions. Gary W. Elmer 11/12/09

Herbal/Drug Interactions. Gary W. Elmer 11/12/09 Herbal/Drug Interactions Gary W. Elmer 11/12/09 Elmer et al. Ann Pharmacother. 2007;40:1617-24. Table 4a Significant Risk of CAM-drug Adverse Interaction n=5052 (16,173 interviews) Potential Event Mechanism