Dangers in Herbs-Drug Interactions Understanding mechanisms to inform management

1. Dangers in Herbs-Drug InteractionsUnderstanding mechanisms to inform management Andrew McLachlan Centre for Education and Research on Ageing Concord RG Hospital Australia Faculty of Pharmacy University of Sydney Australia

2. This presentation • Complementary medicines use • People most at risk • Investigating herb-drug interactions • Understanding and applying the findings

3. Complimentary medicines Complementary medicines

5. Complementary medicine Complementary medicines

6. Complementary medicines Alternative medicines

7. CAM 1993* 2000* 2004* Vitamins (but not calcium or iron) 38 % 36 % 39 % Herbal medicines 10 % 13 % 21 % Mineral supplements 9 % 11% 14 % Soy products - - 4 % Chinese medicines 2 % 3 % 2 % Homeopathic medicines 4 % 4 % 2 % Total CAM user (at least one product) 49 % 52 % 52 % Australian trends in the use of supplements *data shown as percent respondents who have used these medicines within the last 12 months. MacLennan AH, Myers SP, Taylor AW.The continuing use of complementary and alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust. 2006;184:27-31.

8. US trends in the use of supplements 13% used at least 1 herbal supplements in the last 12 months n=5860 aged above 65 years Bruno JJ, Ellis JJ. Herbal use among US elderly: 2002 National Health Interview Survey. Ann Pharmacother. 2005

9. The issue • 50% of people who reported that they used complementary and alternative therapies also used conventional medicines on the same day • 57% did not report the use of complementary therapies to their doctor. MacLennan AH, Myers SP, Taylor AW.The continuing use of complementary and alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust. 2006;184:27-31.

10. Herb-drug interactions: potentially important but woefully under researchedE. ErnstEur J Clin Pharmacol 2000: 56: 523-524 • Why have only so few cases of suspected herb-drug interactions been reported in the medical literature? • Truly rare events? • Significant unreporting?

11. http://www.pharma.unibas.ch/bio/img/Humor_now_and_then/Humor_Herbal_Medicine_2.jpghttp://www.pharma.unibas.ch/bio/img/Humor_now_and_then/Humor_Herbal_Medicine_2.jpg

12. Clinical risk management of herb-drug interactions • Risk identification and assessment • Development and implementation of risk reduction strategies • Evaluation of risk reduction strategies De Smet, PAGM. Br J Clin Pharmacol 2006

13. Clinical significance of herb-drug Interactions • Patient characteristics • Nature of pharmacodynamic response • Mechanism of interaction • Safety margin of the interacting herb and drug • Quality of the product • Size of the dose • Duration of therapy • Time course of drug interaction • Order and timing of administration PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions: an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25

15. Understanding the mechanism of a herb-drug interaction allows the • prediction of other interactions • assessment of clinical significance • guide risk minimisation strategies

16. Study designs used to assess herb-drug interactions • Controlled trials in patients • Controlled trials in healthy subjects • Case reports or series • Animal studies • In vitro studies • Adverse event data • Theoretical PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions: an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25

17. Investigating drug interactions Type of study Mechanism Clinical Relevance Ethical Issues Cost Enzyme, Cells or microsomes Animals Healthy subjects Patients

18. The need to establish qualityCONSORT guidelines for reporting Gagnier JJ et al, Reporting Randomized, Controlled Trials of Herbal Interventions: An Elaborated CONSORT Statement. Ann Intern Med. 2006;144:364-367.

19. Herbal medicine product name Characteristics of herbal product (including part of plant used) Dose and qualitative description Quantitative analysis of HMP (including procedures and standardisation) The need to establish quality of herbal medicine product Gagnier JJ et al, Reporting Randomized, Controlled Trials of Herbal Interventions: An Elaborated CONSORT Statement. Ann Intern Med. 2006;144:364-367.

20. Herb-drug interactions with warfarin • To investigate the potential herbal-drug interactions with warfarin • To examine the effect of herbal medicines on clotting status • Commonly used herbal medicines • St Johns wort, Asian ginseng • ginkgo biloba, ginger • cranberry juice, garlic Jiang et al, Brit J Clin Pharmacol 2004, 2005,

21. Herb-drug interactions with warfarin • To investigate the potential herbal-drug interactions with warfarin • To examine the effect of herbal medicines on clotting status • Commonly used herbal medicines • St Johns wort • cranberry juice I will focus on these herbal medicines Jiang et al, Brit J Clin Pharmacol 2004, 2005,

22. St John’s Wort • In vitro study: inhibit human CYP2D6, CYP3A4 and CYP2C9 Budzinski et al, Phytomedicine 2000 • In vivo study in healthy subjects: induce human CYP3A4, CYP2E1, CYP1A2 and P-glycoprotein • Case reports: reduce the efficacy of warfarin Fugh-Berman & Ernst, Br J Clin Pharmacol 2001

23. Comparison of German St John’s Wort Products according to hyperforin and total hypericin content Wurglics et al, J Am Pharm Assoc 2001

24. St John’s wort dose and preparation on herb-drug interaction with digoxin Mueller et al, Clin Pharmacol Ther 2004

25. TLC of Proprietary St John’s Wort Products A: Hypericin; B: Pseudohypercin; C: Hyperoside; D: Rutin; No. 5: Use in the trial -A -B -C -D TLC of different commercial St John’s wort 1 2 3 4 5 6 (British Pharmacopoeia 2001)

26. Study Design • randomised, open label, three-treatment, three-sequence, crossover design • 14-day washout period • single 25 mg dose of warfarin • with or without treatment with herbal medicines • Blood samples collectedat-48, -24, 0 and up to 168 h

27. Mechanisms of drug interactions PHARMACOKINETIC PHARMACEUTICAL PHARMACODYNAMIC

28. S-warfarin S-7-hydroxywarfarin CYP2C9 Park et al, 1998

29. Effect of St John’s wort and Asian ginseng on the Pharmacodynamics of Warfarin * *P<0.05 Jiang et al, Brit J Clin Pharmacol 2004

30. S-warfarin PK data shown Jiang et al, Br J Clin Pharmacol 2004

31. S-warfarin PK data shown Jiang et al, Br J Clin Pharmacol 2004

32. Mortality and INR Oden and Fahlen, BMJ 2002

33. Pretreatment with SJW significantly St John’s wort can reduce the effectiveness of many medicines Mills E et al. Interaction of St John's wort with conventional drugs: systematic review of clinical trials. BMJ. 2004;329:27-30.

34. Pretreatment with SJW significantly St John’s wort can reduce the effectiveness of many medicines Jiang X et al. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2004 Mills E et al. Interaction of St John's wort with conventional drugs: systematic review of clinical trials. BMJ. 2004;329:27-30.

36. Rindone and Murphy, Warfarin-Cranberry Juice Interaction Resulting in Profound Hypoprothrombinemia and Bleeding. Am J Ther 13, 283–284 (2005)

37. * 33% increase in INR response * p =0.017 Randomsied cross-over clinical trial 12 healthy male subjects 25 mg warfarin dose +/- 2 weeks treatment with cranberry juice extract MI Mohammed Abdul et al, 2006

38. MI Mohammed Abdul et al, 2006

39. MI Mohammed Abdul et al, 2006

40. Pharmacodynamic Endpoint Jiang et al, Br J Clin Pharmacol 2004, 2005 MI Mohammed Abdul et al, 2006

41. Challenges with evidence related to herb-drug interactions • Many published studies lack rigorous design • May not reflect how complementary medicines are used in practice • Not conducted in the patient group of interest • Product quality and variability is a key concern • Ginkgo biloba (based on EGb 761) • St John’s wort (hyperforin content) • Lack of surveillance on use (esp in combination)

43. Avoiding clinical significant herb-drug interactions • comprehensive history is essential • review and assess evidence • appreciate health • monitor when herbs or drugs are started and stopped • …or doses increased • understanding the likely time course of an interaction

44. In conclusion…. • Complementary medicine use is increasing • Consider the patient perspective • Clinical risk management • Focus on the people most at risk • Investigating herb-drug interactions • Understanding mechanisms • Evidence of quality • Quality of evidence • Informed application of the evidence

45. Acknowledgments St Vincent's Hospital Sydney Prof Ric Day A/Prof Kenneth Williams Dr Winston Liauw Clinical trials staff HMREC Prof Basil Roufogalis Peter Coxeter Dr Xuemin Jiang Mohammed Abdul Mohi Iqbal Dr Colin Duke Dr Alaina Ammit Dr Gray Peng Cathy Rich Claudia Kohlert-Schutt Vincent Fairfax Family Foundation The National Health and Medical Research Council (NHMRC)

46. The University of Sydneyover 150 years of tradition in education and research

47. “Show me a drug with no side effects and I’ll show you a drug with no actions” Sir Derrick Dunlop Chairman, Committee on Safety of Drugs, UK founder of the Yellow Card System 1964