Herbal supplements in solid organ transplantation: friend or foe?

1. Herbal supplements in solid organ transplantation: friend or foe? Marissa L. Mako, Pharm.D. Wisconsin International Transplant Nurses Society October 13th, 2012

2. Learning objectives • Identify regulatory concerns with herbal supplements in the United States • Understand the indications, side effects and contraindications to common herbals • Recognize major drug interactions with herbals and discuss how this affects solid organ transplantation • Develop techniques to address barriers in discussing the risk-benefit ratio to patients in regards to herbals

3. A common scenario

4. Patient case: Transplant Patient: Thomas Transplant PMH: DDRTx (2007), a-fib, HTN, asthma Current medications: tacrolimus 2 mg po q12h mycophenolate 360 mg po q12h prednisone 5 mg po q morning multivitamin 1 tab po daily warfarin 5 mg po q evening calcium carbonate 500 mg po BID metoprolol tartrate 50 mg po BID albuterol inhaler 2 puffs po q4h as needed

5. Patient case: Transplant Thomas presents for his annual clinic visit. During your medication history, he tells you that he has been feeling down lately and has started taking two new “vitamins” that he heard will treat him naturally. You come to find out that he is taking St. John’s wort and ginkgo biloba. What is your response?

6. What IS herbal medicine? Phytomedicine Uses plant leaves, roots, bark, flowers and seeds for medicinal purposes Herbals have been used as in history since 3000 B.C. and play a role in the health practices of various cultures “Natural remedies” University of Maryland Medical Center

7. Herbal legislation 1994: Dietary Supplement Health and Education Act (DSHEA) Separated herbal supplements from food and other drugs Exempt from safety and efficacy standards Manufacturers not subject to an approval process by the Food & Drug Administration (FDA) or United State Pharmacopeia (USP) standards Am J Health Syst Pharm 1999; 56: 125. Handbook of Kidney Transplantation

8. The Food & Drug Administration Herbals fall into a separate FDA category Dietary supplements Product label Listing of ingredients Name and address of manufacturer Must have FDA approval to make certain “health claims” Legal requirement: Manufacturers may NOT make curative claims Lack of clinical evidence Food and Drug Administration

9. Health claims

10. The Food & Drug Administration Once on the market, the FDA monitors safety events “after the fact” Can intervene to remove herbals from market “Ephedra” Manufacturers must follow good manufacturing practices Does NOT certify or standardize product ingredients Food and Drug Administration

11. Lack of standardization Glisson et al: analyzed 13 St. John’s wort preparations from health food stores Analysis of supplement using high-performance liquid chromatography None of the products were within +/- 10% of their label claim for hypericin, the active chemical in St. John wort Pharmacotherapy. 2003;23:64-72.

12. Lack of standardization

13. Herbal data Estimated that up to 20% of the public (1 in 5 adults) use herbal supplements In 2005, global annual sales were around $60 billion A 2006 study found that 72.7% of liver transplant patients reported that their physician was unaware of at least 1 herbal supplement they were using Prog Transplant. 2006 Sep;16(3):226-31. Ann Epidemiol 2005; 15: 678–85.

14. What’s the appeal? ALL-NATURAL SAFE DISTRUST OF WESTERN MEDICINE COVER ALL THE BASES COST SYNERGY EASY-ACCESS

15. Common misconceptions “Herbal supplements are “natural” so they must be safe” “I’m taking immunosuppressive drugs so I need to do all I can to increase my immune system” “Herbal supplements are not really drugs, so I don’t need to tell my coordinator I’m using them”

16. Screening and detection Adequate history taking must include an assessment of herbal supplements Patients are often unwilling to disclose using herbals EXTREMELY IMPORTANT in transplant patients Numerous drug interactions Adverse effects

17. An important reminder: product labels

18. Interview techniques Always use open-ended questions, when possible “How often do you use…?” Address common indications for herbals and tailor these questions to your patient population Sleep aids Diet aids Memory/mood/headache Pain/arthritis Bladder/menopausal complaints Never be accusing Use a friendly tone

19. Herbals and solid organ transplantationImmunosuppressive therapy Calcineurin Inhibitors/mTOR inhibitors Cyclosporine Tacrolimus Sirolimus Everolimus Metabolism Cytochrome P450 3A4 (CYP 3A4) P glycoprotein (P-gp) transporter Handbook of Kidney Transplantation.

20. Drug metabolism and elimination CMAJ. 2004 May 11;170(10):1531-2.

21. Metabolism Induction ( enzyme activity) Decreased drug levels Inhibition ( enzyme activity) Increased drug levels

22. HERBALS

23. St. John’s wort Most commonly purchased herbal product is the United States Used for centuries to treat depression, anxiety and sleep disorders Inducer of CYP 3A4 and P-gp Decreases plasma concentrations of: -digoxin -warfarin -cyclosporine -protease inhibitors -tacrolimus -SSRIs National Center for Complementary and Alternative Medicine

24. St. John’s wort Case report: Combined use of St. John’s wort and tacrolimus following renal transplantation Stable serum trough concentrations of tacrolimus Prior to herbal initiation: 6-10 ng/L After initiation: 1.6 ng/L Transplantation. 2002 Mar 27;73(6):1009.

25. St. John’s wort & tacrolimus On average, a 34% decrease in tacrolimus exposure was seen with combined use of tacrolimus and St. John’s wort J Clin Pharmacol. 2004;44:89-94.

26. St. John’s wort & cyclosporine Reduction in bioavailability Transplantation. 2001 Jan 27;71(2):239-41.

27. Ginkgo biloba Used to help improve memory, dementia and macular degeneration Can slow the body’s ability to metabolize medications Has blood-thinning properties Nausea and gastrointestinal upset National Center for Complementary and Alternative Medicine

29. Saw palmetto Used for urinary symptoms related to benign prostatic hyperplasia and other bladder disorders Documented interactions Anticoagulants Oral contraceptives/ hormonal replacement therapy National Center for Complementary and Alternative Medicine

30. Red yeast rice Demonstrated to possess statin-like activity Contains monacolin K, a substance identical to lovastatin Interaction with the calcineurin inhibitors which can drastically increase statin levels via CYP3A4 Case reports of rhabdomyolysis in previously stable renal transplant patients Transplantation. 2002 Oct 27;74(8):1200-1. Handbook of Kidney Transplantation.

31. Kava Commonly used for anxiety, insomnia and menopausal symptoms FDA-issued warning: Link to increased risk of severe liver damage Hepatitis and liver failure seen in studies Interaction with Parkison’s medications Can cause dystonia and altered perception Case reports of over-sedation or comas National Center for Complementary and Alternative Medicine

32. Ginseng Used for lowering blood glucose, improving stamina and enhancing the immune system Can cause changes in blood glucose levels, increase the risk of bleeding, gastrointestinal complications and lead to nervousness and agitation Documented severe menstrual irregularities Can decrease warfarin in blood Thrombosis National Center for Complementary and Alternative Medicine

33. Feverfew Commonly used for migraine headaches, tinnitus and pain associated with rheumatoid arthritis Known to cause digestive problems and bloating Chronic use can lead to loss of taste Hypersensitivity reactions are common Cross reaction with ragweed family National Center for Complementary and Alternative Medicine

34. Valerian Used to treat anxiety and sleep disorders (insomnia) Believed to increase GABA in the brain Enhances sedation Can cause headaches and dizziness Interactions Increase in the effect of other sedatives Increase in the effect of anticonvusants Increase in the effect of anesthesia National Center for Complementary and Alternative Medicine

35. Echinacea Immune-enhancing properties: commonly used to prevent and/or treat colds, flus and other infections Can decrease the effectiveness of immunosuppressants Hypersensitivity reactions are common Cross reaction with ragweed family National Center for Complementary and Alternative Medicine

36. Other herbals to be aware of… Dong quai increases lymphocyte proliferation Melatonin dizziness and confusion Black cohosh visual disturbances, low blood pressure, hepatitis Ma huang (ephedra) increases heart rate Milk thistle alterations in blood sugar

37. Herbals to avoid in transplant recipients St. John’s wort Alters immunosuppressant levels Ginseng Immune-enhancing, bleed risk Kava Warning for hepatitis/liver failure risk Red yeast rice Increased risk of rhabdomyolysis Ginkgo biloba Alters drug metabolism, bleed risk

38. Helpful resources: National Institutes of Health

39. Helpful resources: National Institutes of Health NCCAM http://nccam.nih.gov

40. Helpful resources: National Library of Medicine

41. Helpful resources: National Library of Medicine MedlinePlus http://www.nlm.nih.gov

42. How do we accurately inform our transplant patients? A non-judgmental approach is best Be OPEN and HONEST about the potential consequences Provide resources Ask patients where they stand… Discourage use or make sure the entire healthcare team is aware that patient must be more closely monitored

43. Patient case: Transplant Patient: Thomas Transplant PMH: DDRTx (2007), a-fib, HTN, asthma What is your response? Thank you for informing me of this Mr. Transplant. It’s great to see that you are taking initiative on your health, however, St. John’s wort has a serious interaction with your anti-rejection drug, tacrolimus. In addition, the combination of ginkgo biloba and warfarin puts you at an increased risk for bleeding. In order to keep both your kidney and you healthy, it is very important to stop taking these supplements.

44. Monitoring Withdrawal of chronically administered herbal products must be done carefully Monitoring of serum concentrations

45. Key points Healthcare professionals must be prepared to discuss the implications of herbal medications with their patients when their use is being requested PATIENT EDUCATION IS ESSENTIAL

46. References 1) Ehrlich SD. Botanical Medicine. University of Maryland Medical Center. 2011. www.umm.edu. 2) Klepser TB, Klepser ME. Unsafe and potentially safe herbal therapies. Am J Health Syst Pharm 1999; 56: 125. 3) Danovitch, Gabriel M. Handbook of Kidney Transplantation. Fifth Ed. Philidelphia: Lippincott Williams & Wilkins, 2010. 4) Herbal supplements. Food and Drug Administration. 2012. www.fda.gov. 5) Glisson JK, Rogers HE, Abourashed EA, et al. Clinic at the health food store? Employee recommendations and product analysis. Pharmacotherapy. 2003;23:64-72. 6) Peng CC, Glassman PA, Trilli LE, Hayes-Hunter J, Good CB. Incidence and severity of potential drug–dietary supplement interactions in primary care patients: an exploratory study of 2 outpatient practices. Arch Intern Med 2004; 164: 630–6. 7) Wheaton AG, Blanck HM, Gizlice Z, et al. Medicinal herb use in a population-based survey of adults: prevalence and frequency of use, reasons for use, and use among their children. Ann Epidemiol 2005; 15: 678–85.

47. References 8) Christians U, Jacobsen W, Benet L, et al. Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet. 2002;41(11):813-51. 9) National Center for Complementary and Alternative Medicine. National Institutes of Health. A quick guide to herbal supplements. www.nih.gov. 2012. 10) Bolley R, Zulke C, Kammerl M, et al. Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4 system with St John’s wort. Transplantation. 2002 Mar 27;73(6):1009. 11) Hebert MF, Park JM, Chen Y, et al. Effects of St. John’s Wort (Hypericum perforatum) on Tacrolimus Pharmacokinetics in Healthy Volunteers. J Clin Pharmacol. 2004;44:89-94. 12) Barone GW, Gurley BJ, Ketel BL, et al. Herbal supplements: a potential for drug interactions in transplant recipients. Transplantation. 2001 Jan 27;71(2):239-41. 13) Prasad GV, Wong T, Meliton G, et al. Rhabdomyolysis due to red yeast rice in a renal transplant recipient. Transplantation. 2002 Oct 27;74(8):1200-1. 14) Tirona RG, Bailey DG. Herbal product-drug interactions mediated by induction. Br J Clin Pharmacol. 2006 Jun;61(6):677-81.

48. Herbal supplements in solid organ transplantation: friend or foe? Marissa L. Mako, Pharm.D. Wisconsin International Transplant Nurses Society October 13th, 2012