Herbal Medication Update:Enhancing Your Herbal IQ

Andrew Burgdorf, PharmD,BCPSClinical Pharmacist

Upstate Cancer CenterJune 5th, 2015

Disclosure

• I do not have any relevant financial relationships to disclose

Learning Objectives

• Appreciate the characteristics of patients who use herbal supplements and the conditions they use them to treat

• Learn relevant legislation and regulations related to herbal supplements

• Identify benefits and risk of some popular herbal supplements

Conference Theme 2015

Nurse Practitioners: Agents of Change

How does this lecture fit in?

What can you change in your practice related to herbal medications / dietary supplements?

Herbal Case• Mr. T is a 64 yo male engineer who arrives

at your primary care office

• cc: Feeling fatigued due to insomnia, lack of interest in activities he usually likes

• Pmhx: RLE DVT (2 months ago), partial onset seizures, htn

• Allergies: nkda

• Med List: – Lacosamide (Vimpat) 200mg po BID– Rivaroxaban (Xarelto)20mg po qpm w/ dinner– Hydrochlorthiazide 12.5 mg po qday

Herbal Case

• Your patient asks about treatment options for depression including herbal supplements…

• What do you advise?

• Why?

Impact of Herbals on Society

• National Health Statistics Report– 14.8 Billion dollars were spent on non-

vitamin, non-mineral, natural products (2007)

– 17.7% of American adults had used “natural products” (other than vitamins/minerals) in the past 12 months (2012)

– Non-vitamin, non-mineral, natural products used more commonly than deep breathing, meditation, chiropractic/osteopathic intervention, massage and yoga (2012)

Note* CAM portion of NHIS survey done every 5 years

National Center for Complementary & Integrative Health (NCCIH)

nccih.nih.gov

Impact of Herbals on Society

2015 Survey of National Health Statistics

– Who is using complementary health approaches?

Women > Men

People with higher education levels

College degree or higher (42.6%)

All different age groups (18-44, 45-64, 65+)

Insured?

Private (38%), Public (24.8%), Uninsured (22.9%)

Why herbals?

• Herbal products are “natural” and therefore, “safe”

• Desire for disease prevention – health maintenance

• Easy access – no office visit, found in pharmacies, malls and the internet

• No paperwork / insurance issues

• Distrust in conventional medicine

What’s not to trust about conventional medicine?

Glaxo Agrees to Pay $3 Billion in Fraud Settlement (Published: NY Times 7/2/2012)

-Largest settlement ever involving a

pharmaceutical company-Promoting it’s best-selling antidepressants for unapproved uses (Paxil in children, Wellbutrin-sexual dysfunction

& weight loss)

-Failing to report safety data about a top diabetes drug

-“Prosecutors said the company had tried to win over doctors by paying for trips to Jamaica and Bermuda, as well as spa treatments and hunting excursions”

Top 10 US Dept of Justice / Pharma Settlements (1991-2012)

Legislation/Regulations• 1994 “Dietary Supplement Health and

Education Act” (DSHEA)

– Herbal products deemed “Dietary Supplements” not drugs

– Post marketing surveillance for safety shifted from manufacturers to FDA

• Products removed if found to be unsafe

– FDA given authority to establish Good Manufacturing Practices

– Manufacturers should provide evidence to FDA re: “a reasonable expectation of safety (Frankly, NOT enforced…)

Legislation/Regulations• 1994 “Dietary Supplement Health and

Education Act” (DSHEA)

– Formed Commission on Dietary Supplement Labels and Office of Dietary Supplements within the NIH

– Specified Labeling Requirements

• “This product is not intended to diagnose, treat, cure or prevent any disease”

• However, regulations of content and quality are NOT included

Legislation Updated

• FDA Issues Dietary Supplements Final Rule, June 2007

– Requires current good manufacturing practices (cGMP) for dietary supplements

– Ensuring products produced in quality manner, properly labeled and free from contaminants and impurities

– Industry will be required to report all serious adverse events to FDA

Legislation Update

• Final Rule 2007 (Continued)

– Manufacturers will be required to evaluate the identity, purity, strength, and composition of their dietary supplements

– New requirements being phased in from 2008 to 2010 depending on size of manufacturer

– Compliance with new regulations about GMPs = difficult to find…

New FDA proposal - July 2011• FDA safety evidence evaluation based on 3

key factors– Documented history of use, formulation

and proposed dosage, recommended duration of use

• Noted proposal weaknesses– Historical use vs. experimental data– Per IOM, historical use doesn’t guarantee

long term safety• Strong opposition from supplement lobby

Never made into law! Thanks Congress!

Product Quality Issues• Product labeling and content do not

match!

– Ginseng study showed differences from 11% to 328% of labeled active ingredient

• Contamination/Adulteration

– Accidental

• Misidentified plants collected

– Purposeful

• Natural sleep remedy contains estazolam

• Swiss “All Natural” Skin Cream has Triamcinolone

– DNA testing found 4 of 5 products didn’t contain products on the labels

– Unlabeled ingredients found: radish, house plants, wheat, garlic, legumes, soy / peanut derivatives

– Cease & desist letters sent to GNC, Walgreens, Walmart & Target

– AG Demanded to know what quality procedures being used

Independent Quality Programs• In the US, out of thousands of

manufacturers of herbal products, only a handful are involved in such programs

• However, look for products from manufacturers that are forthcoming with information

– Website discusses quality measures

– Information on testing available upon request

– Restriction of sales outlets

One example - Dietary Supplement Verification Program (DSVP)

• Not for profit program of the U.S. Pharmacopeia

– Thorough manufacturing and quality control document review

– On-site manufacturing facility audit

• USP standards and FDA GMP standards

– Random off-the-shelf testing

Dietary Supplement Verification Program (DSVP) - continued

– ~10 manufacturers participate

– The symbol ensures verification of

• What is on the label is in the bottle

• No harmful level of contaminants

• Supplement will break down & release in the body

• Made according to FDA current GMPs for sanity & well controlled procedures

Review of some popular herbal medications / dietary supplements

• Echinacea

• Probiotics

• Melatonin

• Co-enzyme Q10

• Glucosamine

• Fish Oil / Omega 3-FAs

• St. John’s Wort

Echinacea(purple cone flower)

• Uses

– Traditionally used to fight or prevent colds, flu, or other infections

– Belief is that it stimulates the immune system

– Less commonly, for wounds and skin issues (i.e. acne or boils)

• Studies

– Does NOT appear to prevent colds or other infections

– Course of cold or flu NOT shortened (2 NCCAM studies)• National Library of Medicine, Medline Plus

– Rating “C”, unclear scientific evidence for use

Echinacea(purple cone flower)

Warnings

– Limit use to 8 weeks or less

Avoid

Using for allergies or asthma

If taking immunosuppressants (Prednisone, Cyclosporine)

If patient has transplanted organ

If patient has autoimmune disorder (Rheumatoid Arthritis, Lupus)

Melatonin• Uses

– Insomnia, jet lag

– Usually derived from synthetic or animal sources

• Mechanism

– Produced endogenously by the pineal gland

– Thought to control circadian rhythm & promote sleep

• Studies

– Some show decreased sleep latency & improved sleep duration

– Other randomized studies show mixed results

Melatonin• Side effects

– Altered mental status, disorientation, tachycardia, flushing, pruritus, abdominal cramps, headache, hypothermia

• Warnings

– Caution related to driving and heavy equipment

– May alter estrogen levels affecting hormone sensitive cancers

• Drug interactions

– Blood thinners – Melatonin may decrease coagulation factors

– Nifedipine + Melatonin may increase BP / HR

– CYP1A2 Inhibitor – May increase fluvoxamine levels

Probiotics• What are they?

– Microorganisms that have beneficial properties for the host

– Most come from food-derived products such as cultured milk products

• Common products– VSL#3 (Bifidobacterium breve, B. longum, B. infantis, Lactobacillus

acidophilus, L. plantarum, L. paracasei, L. bulgaricus, Streptococcus thermophilus)

– Align (B. infantis)

– Culturelle (L. rhamnosus GG)

– DanActive (L. casei)

– Mutaflor (E. coli Nissle 1917)

– Florastor (S. boulardii)

Probiotics• Uses

– Constipation, IBS, GI inflammation, allergy/atopic dermatitis

– Infectious diarrhea (C.Diff – separate story) (Evidence supports modest reduction in duration of illness)

• Mechanism(s) of action– Suppression of growth or epithelial binding/invasion by

pathogenic bacteria

– Improvement of intestinal barrier function

– Modulate the immune system

• Suppress inflammatory cytokines

• Increase protective cytokines

– Modulation of pain perception

Probiotics• Side effects

– Constipation, flatulence, thirst

– Reports of fungemia

• Warning(s)

– Lactose intolerance, yeast allergy, immunocompromised

– Not all probiotics are alike

• Considerable differences exist in composition, doses, and biologic activity between various commercial preparations

– Benefits observed clinically with one species (or combination of species) are not necessarily generalizable to another

Glucosamine Sulfate

• Mechanism

– Lessens inflammation and cartilage degradation

– Believed to beneficially affect the imbalance between rates of synthesis and degradation of cartilage

Glucosamine Sulfate• Uses

– Osteoarthritis of the knee

• Can be used with or without chondroitin

• Studies have shown that Glucosamine is as effective as NSAIDs

• Subgroup analysis of 2006 NEJM study by Clegg et al. Showed glucosamine/chondroitin may be effective for moderate to severe knee pain (p=0.02)

• Osteoarthritis Research Society International (2008) Guideline for Management of Hip/Knee OA

– Glucosamine +/- chondroitin may provide symptomatic benefit in Knee OA (Discontinue if no response in 6 months)

– Glucosamine (1500mg/day)& chondroitin in Symptomatic Knee OA

» May have structure modifying effects

Glucosamine Sulfate• Uses (Continued)

– Temporomandibular joint disorder (TMJ)

• Studies support Glucosamine/Chondroitin used in combination

– Efficacy lacking in treatment of back pain

• In general, considered safe and well tolerated

– Multiple 3 year studies exhibit fairly clean safety profile

• Warnings

– Contraindicated in folks who are allergic to shellfish

– Caution in diabetics

• Glucose metabolism may be altered

Glucosamine

2005 Cochrane Review

Summarizes Glucosamine for OA

– May reduce their pain

– May improve their physical function

– Low likelihood of side effects

– Best effects usually seen within 6 months

Omega 3 Fatty Acids (Fish Oil)

• Uses

– Cardiovascular protection

• Lots of epidemiologic data / clinical trial data showing reduction in cardiovascular disease – ideal consumption is unclear

• GISSI-Prevention Study, largest RCT, showing 15% reduction in composite endpoint of death, non-fatal MI, non-fatal stroke (secondary prevention trial)

• ORIGIN Trial did NOT demonstrate cardioprotective effects (NEJM July 2012)

– Hyperlipidemia – HIGH triglycerides

Omega 3 Fatty Acids (Fish Oil)

– DepressionFinnish study shows lack of fish oil linked with

depression

– Cancer PreventionThe role of Omega 3s in cancer prevention is

inconclusive

– Others as well

Omega 3 Fatty Acids(Fish Oil)

Side Effects– Fishy taste, loose stools and nausea– Generally, well tolerated

Warnings– May increase bleeding time– May decrease TG, while causing bump in LDL

EPA = eicosapentainoic acid, DHA = docosahexainoic acid

Omega 3 Fatty Acids (Fish Oil)• 2011 AHA Statement –

Triglycerides and Cardiovascular Disease– Triglyceride lowering is

better with marine-derived Omega-3 PUFA

– Non-Marine Omega-3 is derived from alpha-linolenic acid (plant based)

• Triglyceride reductions have been less consistent

Omega 3 Fatty Acids(Fish Oil)

• The ORIGIN Trial Investigators (Outcome Reduction with Initial Glargine

Intervention) (NEJM 2012)• Double blind, 2x2 design, 6.2 yrs follow up• 12,536 patients (High risk for CV events and

IFG, IGT, or Diabetes) to get… 1-g capsule n-3 fatty acids or placebo daily and

insulin glargine or standard care• This intervention did NOT reduce the

incidence of CV events in high risk patients

Omega 3 Fatty Acids(Fish Oil)

• Environmental contaminants

– Some of fish oil excitement balanced by concerns here

– Found in low levels in fresh water and in oceans

• PCBs

• Methylmercury

• Dioxin

Lovaza(Omega -3-acid ethyl ester)

Prescription Medication

– FDA approved in conjunction with diet to reduce very high triglyceride levels in adult patients (TG >500 mg/dL)

– Dosing

4g once daily or 2g po bid

Fish/Fish Oil & Chemo Interaction?

• Daenen, et al. JAMA Oncology, April 2, 2015 “Increased plasma levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After consumption of Fish and Fish Oil”– Amsterdam, Netherlands– Background: Mice model shows protective fatty

acid (16:4) neutralized chemotherapy activity– Plasma levels of FA (16:4) examined in healthy

volunteers (after fish oil / fish)– Conclusion

• Avoid fish oil, mackeral & herring fishes the day before, the day of and the day after chemotherapy

Co-Enzyme Q10 (Co-Q10)

• Most common purported uses

– Angina, cardiovascular disease, congestive heart failure (Also, Infertility, Migraine prophylaxis, Parkinson's disease, Periodontal disease, strength and stamina)

• Mechanism of action

– Anti-oxidant & membrane stabilizing capabilities

– Necessary for ATP production

– Scavenges free radicals, reduces mitochondrial damage, & maintains myocardial calcium channels (All during times of cardiac ischemia)

Co-Enzyme Q10 (Co-Q10)• Drug Intxns / Drug-Disease Intxns

– Warfarin

• Co-Q10 antagonizes warfarin• Co-Q10 structurally similar to vitamin K

– Theophylline

• Co-Q10 reduces clearance of theophylline, risk for causing persistent vomiting, cardiac arrhythmias and intractable seizures

– Statins (Lovastatin, Simvastatin, Atorvastatin)

• May reduce Co-Q10 levels

– Cancer patients

• Due to it’s anti-oxidant properties, it may interfere with radiation and/or chemotherapy

St. John’s Wort(Hypericum perforatum)

• Uses

– Mild to moderate depression

– Nerve pain, anxiety, sleep disorders

• Evidence

– Some studies share comparable efficacy with Imipramine (TCA) and SSRIs in mild to moderate depression

– 2 Other NCCAM studies – no better than placebo in major depression of moderate severity

St. John’s Wort (Hypericum perforatum)

• Side Effects– Common: headache, fatigue, GI– Infrequent: photosensitivity, elevated

LFTs

• Drug Interactions !!!– Induces CYP 3A4, 1A2,

2C9 & P-glycoprotein– Additive effects w/ SSRIs– Wide range of drugs effected

• Warfarin, Digoxin, Cyclosporine,Tacrolimus, HIV protease inhibitors, oral contraceptives, anti-convulsants, some chemotherapy

Generalized practice advice

Drug Interaction Concerns

• Practitioners must seriously consider risk vs. benefit when combining herbals with

– Blood thinners

• Aspirin, Clopidogrel, Heparin, LMWH, Warfarin

• Dabigatran? Rivaroxaban? Apixaban?

– Narrow therapeutic index drugs

• Levothyroxine, HIV Drugs, Anti-convulsants, Digoxin, Cyclosporine/Tacrolimus

– Oral contraceptives

– Chemotherapy

https://nccih.nih.gov/health/herbs/understanding-interactions

Special Populations

Elderly

– Increased sensitivity to medications in general

– Likely to be on other prescription medications (drug interaction potential)

– Bleeding risk with some herbals

• Pediatrics, pregnant/lactating, & end organ dysfunction

Food for Thought

• What patients are good candidates for herbal supplements?

• Who should you discourage from using herbals?

• How will you manage patients who take herbal supplements? What questions will you ask?

• Did you document your advice to use caution with herbal supplements?

Advice for Patients• Communication is the key

– NCCAM/AARP Survey - Respondents >50yoa, 69% of those who use CAM do not discuss it with their doctors

• Peri-Operatively

– Discontinue herbal supplements 2 weeks prior to surgery

• Bleeding risk

• May effect anesthesia

Advice for Patients• Before taking herbal supplements it is best

to consult with your healthcare provider

• Some herbals can be helpful, some herbals can be harmful…

– Discontinue if you notice adverse effects and contact your healthcare provider

– Consider contraindications and potential drug interactions

– Beware of biased information on safety and efficacy of herbal supplements

– Avoid multi-supplement combination products

Advice for PatientsFDA’s “6 Tip-offs to Rip-offs”

• Disease-related claims that are… “not worth the risk”

– Weight loss

– Memory loss

– Sexual performance

– Serious diseases (Cancer, DM, Heart Disease, Alzheimers)

• Tip Offs

– One product does it all!

– Personal testimonials

– Quick fixes

– Miracle cure

– Conspiracy theorieswww.fda.gov/ForConsumers/ConsumerUpdates/ucm341344.htm

Herbal Case• Mr. T is a 64 yo male engineer who arrives

at your primary care office

• cc: Feeling fatigued due to insomnia, lack of interest in activities he usually likes

• Pmhx: RLE DVT (2 months ago), partial onset seizures, htn

• Allergies: nkda

• Med List: – Lacosamide (Vimpat) 200mg po BID– Rivaroxaban (Xarelto)20mg po qpm w/ dinner– Hydrochlorthiazide 12.5 mg po qday

Herbal Case

• Your patient asks about treatment options for depression including herbal supplements…

• What do you advise?

• Why?

Resources

• nccih.nih.gov– National Center for Complementary and

Integrative Health

• mskcc.org/aboutherbs– Memorial Sloan Kettering Cancer Center,

About Herbs

Questions?

Thank you…

References• Centers for Medicare & Medicaid Services. 1997 National Health Expenditures

Survey. www.cms.hhs.gov/statistics/nhe• Clarke, T, et al. "National Health Statistics Reports: Trends in the Use of Complementary Health

Approaches Among Adults: United States, 2002-2012." US Department of Health and Human Services, 10 Feb. 2015. Web.

• Clegg, et al. Glucosamine, Chondroitin Sulfate and the Two in combination for Painful Knee Arthritis, NEJM, 2006: 354(8): 795-808

• Daenen, L, et al. "Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid (16:4) After Consumption of Fish and Fish Oil." JAMA Oncol (2015): E1-E9. 2 Apr. 2015. Web.

• Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey JAMA. 1998;280(18):1569-1575.

• Kris-Etherton, Penny, William S. Harris, and William J. Appel. "Fish Consumption, Fish Oil, Omega 3 Fatty Acids and Cardiovascular Disease." Circulation 106: 2747-757.

• McQueen, Cydney E., ed. Pharmaceutical Care with Dietary Supplements, Concepts and Common Sense. Bethesda: American Society of Health System Pharmacists, 2007

• Memorial Sloan-Kettering Cancer Center. 12 May 2015 <www.mskcc.org/aboutherbs>

• National Center for Complementary and Integrative Health NIH. 30 May 2015 <nccih.nih.gov>

References• Schneiderman, Eric T., Attorney General, and Martin J. Mack, Executive Assistant

Attorney General. "Cease and Desist Notification." Letter to Alexander Gourlay, President. 2 Feb. 2015.

• Schneiderman, Eric T., Attorney General, and Martin J. Mack, Executive Assistant Attorney General. "Cease and Desist Notification." Letter to Brian C. Cornell, CEO. 2 Feb. 2015.

• Schneiderman, Eric T., Attorney General, and Martin J. Mack, Executive Assistant Attorney General. "Cease and Desist Notification." Letter to Doug McMillan, President/CEO. 2 Feb. 2015.

• Schneiderman, Eric T., Attorney General, and Martin J. Mack, Executive Assistant Attorney General. "Cease and Desist Notification." Letter to Michael G Archbold, CEO. 2 Feb. 2015.