Herbal supplements in solid organ transplantation: friend or

foe?

Marissa L. Mako, Pharm.D.Wisconsin International Transplant Nurses

Society October 13th, 2012

• 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

Learning objectives

A common scenario

Patient case: Transplant

Patient: Thomas Transplant PMH: DDRTx (2007), a-fib, HTN, asthma

tacrolimus 2 mg po q12hmycophenolate 360 mg po q12hprednisone 5 mg po q morningmultivitamin 1 tab po dailywarfarin 5 mg po q eveningcalcium carbonate 500 mg po BIDmetoprolol tartrate 50 mg po BIDalbuterol inhaler 2 puffs po q4h as needed

Current medications:

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?

What IS herbal medicine?

PhytomedicinePhytomedicine• 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

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

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

Health claims

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

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.

Lack of standardization

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.

What’s the appeal?

ALL-NATURAL

DISTRUST OF

WESTERN MEDICINE

EASY-ACCESS

SYNERGY

SAFE

COVER ALL THE

BASES

COST

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”

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

An important reminder: product labels

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

Herbals and solid organ transplantation

Immunosuppressive therapy• Calcineurin Inhibitors/mTOR inhibitors

– Cyclosporine– Tacrolimus– Sirolimus– Everolimus

• Metabolism– Cytochrome P450 3A4 (CYP 3A4)– P glycoprotein (P-gp) transporter

Handbook of Kidney Transplantation.

Drug metabolism and elimination

CMAJ. 2004 May 11;170(10):1531-2.

Metabolism

• Induction ( enzyme activity)– Decreased drug levels

• Inhibition ( enzyme activity)– Increased drug levels

HERBALSHERBALS

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

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.

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.

St. John’s wort & cyclosporine

Reduction in bioavailability

Transplantation. 2001 Jan 27;71(2):239-41.

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

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

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.

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

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

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

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 anesthesiaNational Center for Complementary and Alternative

Medicine

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

familyNational Center for Complementary and Alternative

Medicine

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

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

Helpful resources: National Institutes of Health

Helpful resources: National Institutes of Health

NCCAM

http://nccam.nih.gov

Helpful resources: National Library of Medicine

Helpful resources: National Library of Medicine

MedlinePlus

http://www.nlm.nih.gov

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

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.

Monitoring

• Withdrawal of chronically administered herbal products must be done carefully– Monitoring of serum concentrations

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

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.

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.

Herbal supplements in solid organ transplantation: friend or

foe?

Marissa L. Mako, Pharm.D.Wisconsin International Transplant Nurses

Society October 13th, 2012