What You Need to Know if Epilepsy has Touched Your Life November 2013 Enrique Feoli MD

Herbs and Epilepsy CAM

Complimentary and Alternative CAM On the rise 42% US 65% Germany 20% UK 1/6 people taking Rx also take Herbal > 50 y.o.: 2.66 herbals and 2.26 Rx 3

CAM < 40% share their use with Drs. Legislation requiring regulation/licensing of Herbs in Germany, France, Sweden, Australia. In US the Dietary Supplement Health and Education Act of 1994 removed these products from FDA jurisdiction 4

Herbs for Epilepsy Valerian root Skullcap European Mistletoe Marijuana Black cohosh Lobelia Kava Hyssop Blue vervain Yarrow Geranium Kelp Bupleurum Passion flower Carline thistle Elderberry Mugwort Lady’s slipper Aloe Betony European Peony Ginseng Flax seed oil Ginger Linden Chrysanthemum Forskolin Behen Burning bush Calotropis Gotu Kola Groundsel Lily of the Valley Tree of Heaven Yew 5

How often do people take herbs? Overall use of complementary and alternative medicines (CAM) in U.S. 1990-1997. Herbal product use increased 4x In 1997, adults - 33 million office visits regarding herbal products & high-dose vitamins; spent ~$8 billion In 1997, ~15 million adults took prescription medications with herbs and/or high-dose vitamins Eisenberg et al. JAMA 1998;280:1569-75. 6

How often do people take herbs? U.S. sales ($ millions) Gingko biloba 150 Echinacea 70 Garlic 50 Ginseng 40 Soy 35 Saw palmetto 30 St. John’s wort Valerian 16 Top 10 selling herbs and dietary supplements: 2002 7

How often do persons with epilepsy take herbs? U.S. and England studies: Up to 1 in 3 persons with epilepsy use CAM Most do not discuss their CAM use with doctors Herbs taken include ginseng, St. John’s wort, melatonin, gingko biloba, garlic and black cohosh Treat seizures (<10%), other symptoms (20%), and general health (>70%) Peebles et al. Epilepsy Behav 2000;1:74-7 Easterford et al. Epilepsy Behav 2005;6:59-62 8

Federal regulation of herbs Herbal products are classified by the government as dietary supplements. Dietary supplements are regulated by the 1994 Dietary Supplement and Health Education Act (DSHEA); prescription drugs - much more rigorous requirements of the Federal Food, Drug, and Cosmetic Act. 9

Federal standards by DSHEA Claim -- an effect on bodily structure or function, not against a specific disease. Label must include a disclaimer that FDA has not evaluated the product 10

Federal regulation of herbs Not required to be produced under Good Manufacturing Process standards, like drugs No government agency (eg, FDA) independently verifies the quality/production Could be contaminated with microbes, pesticides, toxic metals, or adulterated (eg, herbs or drugs) Potency and amount per pill/capsule may vary significantly within the same bottle or from batch to batch, or from one branded product to another 11

Federal regulation of herbs Standards set forth by the DSHEA: Manufacturers are responsible for the truthfulness of labeling claims No government agency independently reviews and verifies the claims and supporting evidence Only manufacturers control product quality and verify safety 12

Standardization How much of the active ingredient? For example, bottle says “carbamazepine 200 mg” This is a major problem for herbal products because the active ingredient (s) are usually not known the amount of the assumed active ingredient may vary from pill to pill and product to product it is usually not possible to measure levels in the blood to guide dosage 13

? The active ingredient St. John's wort standardized by its content of hypericin (typically to 0.3% hypericin) Hypericin not confirmed as the active ingredient 14

Case Problem; St john’s W, decreases the effectiveness of CBZ 40 y/o woman with epilepsy well controlled on CBZ Was feeling depressed and began to take St John’s wort. She had multiple recurrent seizures and came to the office for a follow up. She did disclose that she began a over he counter tx. Problem; St john’s W, decreases the effectiveness of CBZ You wonder whether St. John’s wort could affect your carbamazepine or birth control pill, and whether it is safe and actually helps depression 15

Herbal Anticonvulsants: Mechanisms Sedative effect/improved sleep: Valerian, Kava, Lobelia, passion flower. Increase in brain GABA/GABA receptors (Valerian, Kava) Agonist of benzodiazepine receptors (Passion flower). Antioxidants (TJ-960) 16

Herb/AED Interactions Don’t use Valerian or Kava with alcohol, barbiturates, benzos- sedation/coma. Hemorrhagic complications with Gingko and St. John’s wort. St. John’s wort can lower carbamazepine levels. Shankapulshpi (Ayurvedic formula) decreases 1/2 life of phenytoin and decreases its efficacy. Tell your physician about herb use; anticipate potential for interactions. 17

Herbs and Seizure Medications Increase Side effects Valerian Root Kava Kava Passion Flower Chamomile first 4 increase sedative and cognitive side effects. St. Johns Wart used for depression works via the liver to decrease AED levels. 18

Herbs that cause Seizures Kava Kava: GTC from toxicity and withdrawal. Marijuana: intoxication or withdrawal. Skullcap: confusion and convulsions with high doses. Ma Huang: has ephedrine, pseudoephedrine, lowers threshold. Gamolenic acid lowers seizure threshold: evening primrose oil, borage (starflower). Goldenseal: hydrastine lowers threshold. Ginseng: lowers threshold. Ginkgo biloba: GTCs reported. Neurotoxin 4’-o-methylpyridoxine. Thujone-containing herbs: wormwood, sage; lower threshold. 19

Herbs and seizures Worsen seizures Ephedra Ma Huang Mate Guarana Borage oil ? Ginkgo ? Ginseng First 2 have ephedrine, last two have caffeine, last 4 not enough info-last 2 can lower seizure threshold Ginkgo has shown cognitive benefits-small cohort 4-7 patients with seizures on this but no other info provided-pervious history, etc. Ginseng effective for memory issues in animals, human data lacking 20

Bad Effects on Serum Concentration of AED’s (Herb-Drug interactions) P450 enzymes: St. John’s wort Garlic Echinacea Pine bark extract Pygenol Milk thistle American hellebore Gingko Mugwort Pipissewa 21

Side-Effects of Herbs Natural doesn’t equal safe! Herbs and herbal preparations contain many compounds. Black cohosh, Valerian, green tea have tannins - can affect absorption of Ca, Cu, Fe, Mg. Black cohosh can cause miscarriage via uterine stimulation. Lobelia - respiratory paralysis and death. 22

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Samuels et al, 2008 24

Take Home In any given person herbs may be helpful, but in most they likely are not In any given person herbs may worsen epilepsy Herbs definitely can effect AED levels No good studies Communication between doctors and patients is crucial Perspective 25

What are the Ingredients? Epi-Still is a 100% herbal formula and contains the following ingredients in therapeutic dosage: Passion flower, Skullcap, Cicuta virosa (30C), and Cuprum metallicum (30C). Hello. I was just wondering if anyone has heard of the herbal medication for seizures called Epistill? I 

Synergy 02 More than 70 minerals More than 18 amino acids Plant source silica Active ingredient? Is it just water and minerals? No trails/tests indicating that is useful

Second Part

Generics Vs Brand Name AED’s 2013

What is a generic? Generic drugs are copies of brand-name drugs that have exactly the same dosage, intended use, effects, side effects, route of administration, risks, safety, and strength as the original drug. In other words, their pharmacological effects are exactly the same as those of their brand-name counterparts Source: Medicinenet.com

So there's no truth in the myths that generic drugs are manufactured in poorer-quality facilities or are inferior in quality to brand-name drugs. The FDA applies the same standards for all drug manufacturing facilities, and many companies manufacture both brand-name and generic drugs. In fact, the FDA estimates that 50% of generic drug production is by brand-name companies

Generic Vs Brand Brand Name Generic Tylenol Acetaminophen Valium Diazepam Dilantin Phenytoin Topamax Topirmate

Basic requirements for the approval of a generic drug Bioequivalence standard 90% Confidence interval Single dose studies in healthy volunteers Typical N 20-30

? Generic drugs may have different dissolution characteristics FDA: true but this is an in vivo test that does not correlate with performance?

? Generics drugs are not tested in children and elderly? FDA: true, but if it works in adults, it should work in other populations

? Generic drugs can be associated with breakthrough sz and increased side effects? FDA: all of the support for this claims arise from patients and physician reports (anecdotes or surveys)

? Brand Med ----0---- ----0---- ----0---- 85 100 125

The Problem Professionals and patient advocacy groups do not trust generics Regulatory agencies (FDA) consider that existing rules are adequate.

The Problem Why are they both wrong? Neither has provided a scientific proof of its points Both sides are susceptible to influence through “lobbying or political pressures or financial incentives.

Why are regulatory agencies wrong Regulatory agencies established universal bioequivalence rules and never provided scientific evidence that they are safe for diff diseases or populations. Epilepsy is different, if BP goes from 125/85 to 135/95 until next check up the consequences are negligible. A sz after a long period of sz freedom may have mayor consequences

Why are regulatory agencies wrong The 80% 125% bioequivalence role has real problems Generic A 125% x3 months (optimal dose at 1500mg) Generic X 80% 1500 x 0.64= 960 mg. This sudden change by a pharmacist is consider “Safe lawful and ethical practice” This same change by a MD would never be considered safe…

Why are regulatory agencies wrong Multiple preparations expose the patient to a large number of excipients or colorants, increasing the risk of an adverse reaction.

Why are MD and patients advocacy groups wrong? The report of patients experiencing significant problems with the substitution are all anecdotal. If 1 anecdote has no scientific value 100 or 1.000.000 have no value. The reporting is heavily biased Surveys are close to meaningless

Why are MD and patients advocacy groups wrong? -Heavy emphasis on brand name -Incentives and monetary contributions to physicians and advocacy groups by companies with financial stakes are legal. The same contributions to regulatory agencies would be ilegal.

How can MD deal with the dilemma? -select ptes that should not be substituted -Sz free -Hx of status -Track what ptes get from the pharmacy, ask pte to bring the bottle, -Educate consumers, other MD’s and pharmacists. -Lobby to request mandatory notification/permission from MD and ptes

How can MD deal with the dilemma? Lobby to prohibit generic-generic substitution Who is responsible for the consequences of mandatory changes?

How could legislature deal with the current dilemma Mandatory notification to MD and ptes of substitutions Prohibit substitutions from one generic to another

Conclusions -Is there a reason for concern regarding current generic regulations? YES -Is the problem brand to generic subs NO generic to gen YES -Is the problem exaggerated and are the opinions biased due to financial interest YES