SAFETY &

PHARMACOVIGILANCE OF
HERBAL & COMPLEMENTARY
MEDICINES

Phil Rasmussen
MPharm; M.P.S.; Dip Herb Med; FNZAMH; MNIMH
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Medicine Safety
• All drugs may produce adverse events (AE’s) in some
individuals.
• These can be minor (eg digestive upset after antibiotics),
or intolerable (eg thalidomide-related foetal
malformations)
• Drug development involves successive levels of safety
assessment (eg toxicological studies in rodents, tests for
mutagenicity, human clinical trials etc).
• Regulatory approval required before drugs able to be
prescribed or sold to humans
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Complementary Medicine Safety

• Hugely diverse range of products & sources.
• Some regulated as medicines, most as dietary
supplements or foods, or not at all.
• Very few if any controls on the manufacturing process for
a large %age of products being sold.
• Adulteration, substitution or use of incorrect starting
materials, can therefore occur.
• Most products available ‘over the counter’ (OTC), rather
than upon prescription, hence high potential for unwanted
interactions or errors due to no clinician involvement.
Other Safety Concerns
• User failure to inform pharmacist or doctor about products
being taken.
• Doctor or pharmacist failure to enquire about product usage
• Potential interactions with prescribed drug medications (eg
warfarin)
• Lack of practitioner intervention in chronic or serious conditions
• Practitioner mis-diagnosis
• Increasing sales through grocery & online channels
• Products or other interventions being applied for serious health
conditions, with little evidence of or chance of efficacy in some
cases
• Refs:
Edwards L et al, NZ Med J 2011 May 13; 124(1334):81-8.
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Product Quality
• Many products not manufactured under the code of Good
Manufacturing Practice (GMP)
• Raw materials often from cheapest source
• What Manufacturing procedures are in place to ensure a
consistently acceptable product?
• What Quality Assurance (QA) procedures are in place?
• Has product stability been tested & the expiry date
validated?
• Has the product quality been reviewed? (Product Quality
Review, PQR)
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Some Quality Acronyms

• GAP – Good Agricultural Practice
• GMP – Good Manufacturing Practice
• GLP – Good Laboratory Practice
• PV – Pharmacovigilance
• GPP - Good Pharmacovigilance Practice
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Herbal Manufacturing and Quality Control

Sourcing
Source herbs and raw materials from Approved suppliers – and all relevant documents & certifications

Quality Control Testing for Herbs

Sampling of herbs in designated sampling
booth according to the standard sampling
plan and samples tested or sent to approved
labs for testing.
Quality Control Testing Raw Material or Excipients
Full testing of ingredients as per test specification. For example: Manuka
honey is tested according to the specification of current edition of
Pharmacopoeia and additional testing is done for Tutin level and
Clostridium botulinum).

Botanical identification and foreign Other Analytical testing

matter quantification (Perform testing as required by the
(EP/BP/BHP or other relevant Contaminants product specification)
Pharmacopeia) (current Edition of EP)
All received herbs are inspected  Phytochemical level
macroscopically & microscopically by an • Mycotoxin/ Aflatoxin  HPLC identification
experienced Botanist for compliance to • Heavy metal: (ICM-MS)  TLC identification (Finger print)
requirements of the European or British • Pesticide: GC-MS/MS
Pharmacopoeia if stipulated, otherwise and LC-MS/M analysis. Tested by approved contract labs using
another relevant pharmacopeia or the pharmacopoeia method or other
authoritative text. validated method

Quality Assurance Approval Release of Raw Materials

If the batch meets the specification and QA requirements, authorised staff approve the analytical test report and release of the
material for further processing. Released goods are identified with PASS labels and transferred to the designated approved store
or other ingredient storage area.
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Raw material tests

• Authentication of correct species & plant part undertaken
• European Pharmacopoeia (current edition) monographs
used where available
• Methods include botanical characteristics (macroscopical
& microscopical), organoleptic characteristics, comparison
with validated reference specimens, chromatography
• Foreign material quantified (eg other plant material, soil
etc); normal limit 2%
• Heavy metal tests for non-organic herbs
• Pesticide residues
• Microbial tests
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Correct species authentication

• Use of botanical and not just common name nomenclature
is vital
• Botanical inspection and verification critical
• Have been many instances of the wrong species being
supplied eg:
• Scutellaria lateriflora – Teucrium chamaedrys & T canadense
supplied instead.
• Berberis vulgaris – Berberis darwinii supplied instead
• Equisetum arvense – Equisetum hymele supplied instead
• Echinacea angustifolia – Echinacea pallida supplied instead
• Marrubium vulgare – Ballota spp supplied instead
 Adulteration or contamination
• Contamination with other herbs, heavy metals, soil
• Adulteration with drugs
• 24% of 2600 Traditional Chinese Med prep’ns tested in
Taiwan found to contain >1 drug compound (Huang WE, J
Clin Pharmacol 1997; 37(4):344-350).
• Chinese herbal medicines sold in New Zealand were
found to contain pharmaceutical agents, sildenafil or
tadalafil that were not disclosed on the label.
• Adulteration tests sometimes undertaken (eg
Parthenium integrifolium lacks cichoric acid, present in
Echinacea angustifolia)
• Medsafe publication. Oct 2004.
http://www.medsafe.govt.nz/hot/alerts/HerbalRemedies/HerbalRemedies.asp
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Microbial contamination
• Microbial or insect contamination (use of organic
fertilisers; improper storage etc)
• Potentially toxic microorganisms such as E coli, Staph
aureus and Pseudomonas aeroginosa, and fungal
metabolites such as aflatoxins and ochratoxins in
medicinal herbs
Tassaneeyakul W et al. Contamination of Aflatoxins in Herbal Medicinal Products in Thailand.
Mycopatholo. 2004 Sep; 158(2):239-244.
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Adverse effects reports for herbs

• Most comparative clinical trials show herbal medicines
have a lower frequency of adverse effects (AE’s) than
comparable drug treatments.
• Recent review found that serious AE’s have been reported
only for a few (four).
• Moderately severe AE’s have been reported for 15.
• Minor AE’s have been reported for 31 herbal medicines.
• Distinguishing between a true treatment-related AE and
an AE attributable to adulteration, contamination or other
product quality reasons, can be challenging.
• Ref: Posadzki P et al, Clin Med 2013; 13(1):7-12
 Kava (Piper methysticum)
• In early 2000’s there were increasing reports of kava
causing liver toxicity, and some countries subsequently
restricted its availability.
• Unlikely to be a single aetiological factor, as all 3 of the
main types of hepatocyte damage as a result of drug-
related adverse reactions, reported (i.e. necrosis; drug-
induced hepatitis; cholestatic hepatitis).
• Large %age of cases involve concurrent drug
administration, suggesting possible interference with their
metabolism by kava.
• Other contributing factors may have included use of less
natural manufacturing processes, use of synthetic kavalactones,
use of non-traditional parts root peelings & aerial parts
• Ref: Rasmussen, P. (2005). NZAMH SUBMISSION ON PROPOSED RECLASSIFICATION OF KAVA AS A
PRESCRIPTION MEDICINE – MEDICINES CLASSIFICATION COMMITTEE, June 2005
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Aristolochic acids
• Cases in Europe and U.S. of nephropathy, end-stage renal
failure and urothelial cancer due to chronic (6-12 months)
exposure to aristolochic acids in slimming products/dietary
supplements/TCM
• These related to Aristolochia fangchi and A. manshuriensis
which had been substituted for Clematis and Akebia species and
Stephania tetrandra
• Substitution is established practice in TCM.
• Also trade of herbal ingredients often uses Chinese Pin Yin
(common) names, rather than latin names.
• A British study found aristolochic acids in 40% of a sample of
TCM products said to contain Fang ji and Mu Tong.
• Aristolochia species and other species likely to be confused
with Aristolochia are now prohibited in unlicensed herbal
remedies
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Regulatory Requirements
• Quality expectations by consumers
• Food or Dietary Supplements – lower level or minimal
therapeutic claims possible
• Complementary Medicine – ↑’d therapeutic claims, but
GMP certification, product licensing, stability studies etc
required
• Medsafe, Therapeutic Goods Administration, MHRA, FDA
etc
• Industry or ‘in house’ protocols
• Code of GMP
• .
NZ Legal requirements for herbal
remedies:
• May only be sold by self-selection from a shop or
display if no claims of any kind are made.
• Labels must be in English.
• May be sold by a herbal remedy therapist to an
individual as a treatment if the therapist has been
requested by that individual to use his or her
judgement as to the treatment required.
Scheduled herbs:
• Only able to be sold by a doctor or pharmacist.
• Include aconite, belladonna, digitalis, ipecac,
ephedra, gelsemium, jaborandi, lobelia, nux vomica,
podophyllum, quassia, quebracho, rauwolfia,
sabadilla, senega, squill, staphisagria, stramonium,
yohimbe.
NZ Regulations
• Current Medicines Act 1981 & Medicines Regulations
1984, are very outdated
• 1996 – ANZTPA (Australia and New Zealand Therapeutic
Products Administration) joint trans-Tasman regulator
development began
• Key elements included GMP, approved ingredient list,
product approval process
• July 2007 – NZ govt postponed further legislation.
Natural Health Products Bill
• Drafted by National & Greens as an alternative to
ANZTPA
• 16 June 2011 – work started to develop a new regulator
• Like ANZTPA, has requirements for:
• Electronic product notification
• List of prohibited ingredients
• List of permitted ingredients & a process for adding new
ingredients
• Manufacturing requirements less than GMP.
 Code of Good Manufacturing
Practice (GMP)
• Organisational Structure
• Quality Assurance
• Document & Records Control
• Training & Personnel
• Audit Programmes
• Automatic Controls (computers)
• Change Control
• Master Production/Control documents
• Validation programmes
• Deviation & Error control
• Equipment calibration & maintenance
GMP (cont..)
• Air Systems/ Environmental control
• Environment monitoring
• Cleaning & Sanitation
• Label control
• Laboratory testing
• Material status & control
• Supplier assurance
• Sterilisation programmes
• Water supply
Drug Interactions
• DEFINITION: “A change in the response to
one drug or phytomedicine, due to the
introduction of another”.
• Very little data available on most
phytomedicines
• A high level of ‘misinformation’ abounds,
sometimes alleging dangerous interactions
based upon very little, if any clinical data.
• Clinical studies on humans where
pharmacokinetic parameters measured, much
more significant than in vitro studies.
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Clinical significance
• Review which evaluated various electronic
databases & other references to determine the
evidence basis of reported herb-drug interactions
• Of 162 citations of possible herb-drug interaction
‘pairs’ in the literature, only 22 were supported by
randomised clinical trials, case-control studies,
cohort studies, case series, or case studies.
• The remaining interaction pairs reflected theoretic
reasoning in the absence of clinical data.
• Warfarin the most common drug, and St Johns
Wort the most common herb, reported in these
studies.
Types of Interactions.
• Pharmacokinetic - involving influences on the
absorption, distribution, metabolism or excretion
of another medicine.
• Pharmacodynamic – agents which produce
similar or opposite effects on the sites of
action/receptors.
• Combined pharmacokinetic and
pharmacodynamic.
Influences on metabolism &
cytochrome P450.
• Cytochrome P450 (CYP450) particularly important
in oxidative drug metabolism.
• At least 57 isoforms characterised to date.
• CYP3A the most important of these, being
involved in metabolism of many drugs.
• Intestinal forms of CYP450 likely to contribute to
metabolism prior to that occurring in the liver.
• CYP450 activity increased (‘induced’) or inhibited
by repeated administration of several drugs,
foods, phytomedicines & chemical pollutants.
Egs of possible pharmacodynamic
interactions:
• Increased sedation through combination of kava
+ diazepam.
• Increased thyroid activity through combination of
bladderwrack + thyroxine.
• Reduced thyroid activity through combination of
horseradish & propylthiouracil.
• Antagonism of hypotensive drug activity with
large doses of liquorice.
Clinical Management:
• Ability to predict a possible interaction is
important.
• Not all theoretical interactions are absolute
contraindications to concurrent use.
• Increased monitoring always required after
introduction of a possible interacting agent.
• Decision-making in each case should be
clinically and scientifically-based.
• Increased practitioner knowledge of national
Adverse Drug Reactions Reporting Systems
required.
Effects by drugs on phytomedicines:

• Phytotherapy is used as the only or preferred treatment in

many cases
• Potential alterations in phytomedicinal effects following
introduction of drug therapy therefore also needs
consideration.
• This subject appears virtually uninvestigated to date
• Eg : AUC (bioavailability) of glycyrrhetic acid (from
liquorice) & paeoniflorin (from paeony) reduced by co-
administration of omeprazole and 2 antibiotics
(amoxycillin & metronidazole)
St John’s Wort safety issues
(Hypericum perforatum)
Introduction
• Numerous different product types, mostly made
from aerial flowering parts.
• Main modern usage for depression, but also as a
‘nervine’, antiviral and topical antiseptic & anti-
inflammatory.
• Level of global usage increased dramatically from
1996 following publication of a favourable meta-
analysis of clinical trials published in the BMJ.
• However, usage decreased markedly from ~2000
following reports of drug interactions and safety
concerns.
 Comparison with SSRI
 Hypericum extract WS 5570 compared with paroxetine for
tolerability in 4 controlled trials involving 1661 patients.
 Patients received Hypericum extract 600-1800mg/day or
paroxetine 20-40mg/day or placebo, for 6 weeks.
 AR’s for Hypericum comparable with placebo (risk ratio 1.1),
& significantly less than for paroxetine (risk ratio 2.4).
 AR’s for paroxetine were 10-38 times more frequent in 5 out
of 7 symptom clusters inspected.
 Sedation, anticholinergic reactions,
GI disturbance & sexual dysfunction
most common for SSRI’s & other
antidepressant drugs.
 Ref: Kasper S et al, Int Clin Psychopharmacol 2010;
25(4):204-213.
Adverse reactions:
• 4 large post-marketing surveillance studies recorded
adverse events in region of 0.1-2.4%, & a dropout rate
due to these of less than 1% (0.9%) (Schultz 2006).
• Main ones said to be skin reactions and mild digestive
upset.
• But these a similar incidence to placebo, in inert
placebo controlled clinical trials .
• Frequency of these significantly < those for all
antidepressant drugs.
• Potential drug interactions .
• Photosensitivity often said to be quite common.
CARM data
 NZ Pharmacovigilance Centre received 22 reports
featuring St Johns Wort up until Dec 2014.
 Most recent report received in 2011.

 21 of these involved female users.

 19 reports made by GP, consultant or pharmacist.

New Zealand
Pharmacovigilance Centre
Centre for Adverse
https://nzphvc.otago.ac.nz/carm/ Reactions Monitoring
NZ Pharmacovigilance data
‘Certain’ reactions ‘Probable’ reactions
Intermenstrual bleeding 1 Drug interaction 4
Drug interaction 1 Headache 2
Photosensitivity 1 INR ↑’d 2
Tinnitus 1 Serotonin syndrome 1
Pruritis 1
Rash 1
Facial oedema 1
Intermenstrual bleeding 1
Eye pain 1
Depersonalisation, depression, 1
judgement impaired, suicidal each
tendency, violent thoughts
Bronchospasm 1
Drug interactions
• Hypericum known to reduce plasma levels & thus
efficacy of several drugs.
• This 1st became apparent from a pharmacokinetic
study involving digoxin in 1999, case reports of heart
transplant rejection in patients on the
immunosuppressant drug cyclosporin, & therapeutic
failure of the antiviral indinavir, in 2000.
• These drugs mostly have narrow therapeutic indices,
& used for serious, potentially life-threatening
conditions.
• As such, these pharmacokinetic interactions can
have serious consequences.
Interactions (cont..)
• Since then, numerous publications concerning
interactions with other drugs.
• Quality of many of these reports, very poor.
• Large number based upon case reports with
inadequate data, theoretical speculation, or use of
inappropriately high concentrations of extract in in
vitro studies.
• Best information from human pharmacokinetic
studies.
• Compelling evidence now that high hyperforin-
containing prepns are more likely to reduce
bioavailability of some drugs (Godtel-Armbrust, 2007).
Mechanisms of drug interactions
 Likely mechanisms include induction of
cytochrome P450 (especially CYP3A4, CYP2C19,
CYP2C9 isoforms) &/or the cellular efflux
transporter, p-glycoprotein.
 NB Many antidepressant drugs, also interact with
other drugs through CYP450 inhibition or
induction.
 MAOI’s interact significantly with a large number of
other drugs, and tyramine-containing foods, to
produce potentially serious outcomes such as a
hypertensive crisis
 Role of Hyperforin
• Magnitude of CYP3A4 induction shown to correlate with
hyperforin content, but not hypericin or flavonoid content
(Godtel-Armbrust et al, 2007).

• Most reports involving drug interactions involve

preparations with relatively high (>2.5%) hyperforin levels.
• Hyperforin also induces P-glycoprotein.
• Low hyperforin-containing Hypericum extract didn’t alter
ethinylestradiol or ketodesogestrel p’cokinetics from a low
dose oral contraceptive (Lovelle), (Will-Shahab et al, 2009), or
midazolam AUC, in healthy volunteers (Mueller, et al 2009).
• Clinical studies with Hypericum preps with <1% hyperforin
show antidepressant efficacy but without the
predisposition to such drug interactions
Combining with oral contraceptives
 A small number of case reports of unwanted
pregnancies have been published or reported to
pharmacovigilance agencies.
 5 case reports to German authorities as at end
2002.
 No case reports to CARM as at Dec 2014.
 Most of these reports made between 1995-2005.
 ‘Typical use’ combination oc failure rate 9% ;
‘Perfect use’ combined oc failure rate 1%
(Centers for Disease Control and Prevention;
www.youngwomenshealth.org).
Safety with other antidepressants:
 High hyperforin preparations may reduce plasma levels of
amitryptiline, nortryptiline or bupropion.
 Combining Hypericum with other antidepressant drugs
widely reported as unsafe, due to the risk of excessive
serotonergic enhancement resulting in the serious & life-
threatening serotonin syndrome.
 This said to be particularly the case for SSRI’s
 However, this largely based upon speculative
or theoretical rather than sound
clinical data.
 Relatively few case reports of serotonin syndrome
involving SJW and SSRI’s.
Case reports
 Only 1 case of suspected SS reported to CARM, involving
clomipramine + hypericum; not serious
 Only 3-5 published case reports of suspected SS reported
in patients on combined antidepressant & Hypericum
(Bryant 2004; Dannawi 2002; Bonetto, 2007).

 One case where patient took 200-250mg tryptophan for 2

days, & ‘several’ Hypericum tabs, for ecstacy detox’n
(Bryant, 2004).

 Other a 27yr old woman with generalised anxiety

disorder, also on buspirone; sympts of nervousness,
hyperactivity, blurred vision after 3/52 Hyp (Dannawi 2002) .
 3rd case involved addition of the 5-HT agonist eletriptan
to a regimen of fluoxetine (60mg/day) & Hypericum
(Bonetto, 2007).
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Pharmacovigilance (PV)
• Assessing the risks and benefits of medicines in order to
determine what action, if any, is necessary to improve
their safe use
• Providing information to users to optimise safe and
effective use
• Monitoring the impact of any action taken
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Pharmacovigilance – post market

surveillance
• While reports of Adverse Events (AE’s) relatively
infrequent, under-reporting is a concern
• Clinicians and product manufacturers should make every
effort to encourage such reports & that the quality of the
data obtained is robust
• Important to monitor the safety of the company’s products
once they are on the market and for the duration of the
product’s lifetime
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Receiving Adverse Event Reports

• Duration of usage of the product(s)
• Dose(s) taken and how
• Time line (time of day, onset of reaction)
• Detailed description of the manifestation & duration of
reaction
• Whether any pre-existing medical conditions/allergies
• Concurrent medication – drugs, dietary supplements,
other herbal products; their dosage & duration of
usage.
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Pharmacovigilance System Master File

(PSMF)
• PSMF content should be in line with that required by the EMA
Guideline on Good Pharmacovigilance Practices (GVP) Module
II – Pharmacovigilance system master file and will be updated
as the guidance is revised.
• Main sections of the PSMF are:
• Qualified Person (QPPV) details
• Organisational structure (including service providers and
partners)
• All potential sources & routes by safety data which may be
received by the company (including literature, partners, service
providers, business partners, marketing activities etc.)
• Computerised systems & databases which contain data or
interact with the PV process
• Description of key processes for management of PV activities
• PV system performance monitoring and how this is done
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Signals
• Signal Detection - Assessment of individual cases which may be new
safety signals.
• A new or unexpected serious adverse reaction report can raise a signal &
the need to take further action).
• There is an increase in the frequency or severity of expected AHR’s
received as spontaneous reports from any source.
• A cluster of reports is received from one source or location, or is related to
one product batch
• Safety related changes made to the labelling of a similar product.
• Routine safety reviews to review interval and cumulative data on the
products.
• Signal Validation – if we detect a signal, how we assess it and confirm if its
real including the criteria we use & what the outcome might be (valid, not
valid, continue monitoring).
• Signal Assessment and prioritisation – if the signal is valid, how does
this affect the benefit-risk assessment and how serious is the change, what
action is required.
• Signal tracking – how we document the above, including the time all of the
above has taken and the implementation of any actions.
•
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Some resources
• The Essential Guide to Herbal Safety, by Simon Mills &
Kerry Bone, Churchill Livingstone, 2005.
• www.herbblurb.com
• Rasmussen, P. (2015), Phytomed Medicinal Herbs. St
John’s wort Safety concerns in clinical practice. Webinar,
2015.