Herbal supplements in solid organ
transplantation: friend or foe?
Marissa L. Mako, Pharm.D.
Wisconsin International Transplant Nurses Society
October 13th, 2012
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
A common scenario
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
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?
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
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 highperformance 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?
ALLNATURAL
SAFE
DISTRUST OF
WESTERN
MEDICINE
COST
SYNERGY
EASYACCESS
COVER
ALL
THE
BASES
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
HERBALS
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
-cyclosporine
-tacrolimus
-warfarin
-protease inhibitors
-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 statinlike 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 anesthesia
National 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 family
National 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 populationbased survey of adults: prevalence and frequency of use, reasons for use,
and use among their children. Ann Epidemiol 2005; 15: 678–85.
References
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•
•
•
•
•
•
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):12001.
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