Assessment Report On Ginkgo Biloba L., Folium D

28 January 2014
EMA/HMPC/321095/2012
Committee on Herbal Medicinal Products (HMPC)
Assessment report on Ginkgo biloba L., folium

Based on Article 10a of Directive 2001/83/EC as amended (well-established use)
Based on Article 16d(1), Article 16f and Article 16h of Directive 2001/83/EC as amended (traditional
use)
Draft
Herbal substance(s) (binomial scientific name of
Ginkgo biloba L., folium
the plant, including plant part)

Herbal preparation(s)
Dry extract (35-67:1) of Ginkgo biloba leaf is

refined and quantified to 22-27%
ginkgoflavonglycosides, represented by quercetin,
kaempherol and isorhamnetin and 5-7% terpene
lactones, represented by ginkgolides A, B, C (2.83.4%) and bilobalide (2.6-3.2%). The content of
ginkgolic acids is less than 5 ppm. Extraction
solvent: acetone 60%.
Powdered herbal substance
Pharmaceutical form(s)
Herbal preparation in solid dosage forms for oral

use.
Rapporteur
Dr Jacqueline Wiesner
Assessor(s)
Eva-Maria Eibl
Note: This draft assessment report is published to support the release for public consultation of the
draft Community herbal monograph on Ginkgo biloba L., folium. It should be noted that this document
is a working document, not yet fully edited, and which shall be further developed after the release for
consultation of the monograph. Interested parties are welcome to submit comments to the HMPC
secretariat, which the Rapporteur and the MLWP will take into consideration but no overview of
comments received during the public consultation will be prepared in relation to the comments that
will be received on this assessment report. The publication of this draft assessment report has been
agreed to facilitate the understanding by interested parties of the assessment that has been carried
out so far and led to the preparation of the draft monograph.
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European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged.
Table of contents
1. Introduction ....................................................................................................................... 4
1.2. Information about products on the market in the Member States ............................... 5
1.3. Search and assessment methodology ................................................................... 30
2. Historical data on medicinal use ...................................................................................... 30
2.1. Information on period of medicinal use in the Community ....................................... 30

2.2. Information on traditional/current indications and specified substances/preparations .. 31
2.3. Specified strength/posology/route of administration/duration of use for relevant
preparations and indications ....................................................................................... 32
3. Non-Clinical Data ............................................................................................................. 32
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 33
3.1.1. Primary pharmacodynamic................................................................................ 33
3.1.2. Secondary pharmacodynamic ............................................................................ 34
3.1.3. Safety pharmacology ....................................................................................... 35
3.1.4. Pharmacodynamic interactions .......................................................................... 37
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 37
3.2.1. Absorption ...................................................................................................... 37
3.2.2. Distribution ..................................................................................................... 37
3.2.3. Metabolism ..................................................................................................... 37
3.2.4. Elimination ..................................................................................................... 38
3.2.5. Pharmacokinetic interactions with other medicinal products .................................. 38
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal
preparation(s) and constituents thereof ....................................................................... 39
3.3.1. Single dose toxicity .......................................................................................... 39
3.3.2. Repeated dose toxicity ..................................................................................... 40
3.3.3. Genotoxicity ................................................................................................... 40
3.3.4. Carcinogenicity................................................................................................ 40
3.3.5. Reproductive and developmental toxicity ............................................................ 42
3.3.6. Local tolerance ................................................................................................ 45
3.3.7. Other special studies ........................................................................................ 45
3.4. Overall conclusions on non-clinical data ................................................................ 46
4. Clinical Data ..................................................................................................................... 48
4.1. Clinical Pharmacology ......................................................................................... 48

4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ........................................................................ 48
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ........................................................................ 50
4.2. Clinical Efficacy .................................................................................................. 58
4.2.1. Dose response studies...................................................................................... 58
4.2.2. Clinical studies (case studies and clinical trials) ................................................... 58
4.2.3. Clinical studies in special populations (e.g. elderly and children) .......................... 107
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 109

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5. Clinical Safety/Pharmacovigilance ................................................................................. 111
5.1. Overview of toxicological/safety data from clinical trials in humans ......................... 111
5.2. Patient exposure .............................................................................................. 111
5.3. Adverse events and serious adverse events and deaths ........................................ 111
5.4. Laboratory findings ........................................................................................... 118
5.5. Safety in special populations and situations ......................................................... 118
5.6. Overall conclusions on clinical safety ................................................................... 118
6. Overall conclusions ........................................................................................................ 119
Annex ................................................................................................................................ 120
List of references .................................................................................................... 120

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1. Introduction
1.1. Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
There is a monograph on Ginkgo leaf published in the European Pharmacopoeia (Ph. Eur. 7th edition
2012 (7.5), ref. 01/2011:1828).
The herbal substance consists of the whole or fragmented, dried leaf of Ginkgo biloba L.
The leaf is greyish or yellowish-green or yellowish-brown. The upper surface is slightly darker than the
lower surface. The petioles are about 4-9 cm long. The lamina is about 4-10 cm wide, fan-shaped,
usually bilobate or sometimes undivided. Both surfaces are smooth, and the venation dichotomous, the
veins appearing to radiate from the base; they are equally prominent on both surfaces. The distal
margin is incised, irregularly and to different degrees, and irregularly lobate or emarginate. The lateral
margins are entire and taper towards the base.
Synonyms: Fossil tree, Kew tree, Maidenhair Tree, Yin Xing (whole plant), Yin Xing Ye (leaves)
Constituents: (Chan 2007, van Beek 2000)
Terpenes
-
Triterpenelactones (Diterpenes: ginkgolides A, B, C, J (0.06-0.23%) and sesquiterpene:

bilobalide (up to 0.26%))
Triterpenes (steroids, phytosterols)
Carotenoids
Polyprenols (Di-trans-poly-cis-octadecaprenol) concentration ranges from 0.04% to 2.0%
Volatile terpenes
Flavonoids not less than 0.5%

-
Flavanols (catechins)
Flavones (Aglycones, monoglycosides and biflavones with a concentration of 0.4% to 1.9%)
Flavonols (the aglycones isorhamnetin, kaempferol, quercetin and myricetin have a

concentration of 0.2% to 1.4% w/w)
Organic acids
Polyacetate derived compounds
-
Alkyl phenolic acids and alkyl phenols (ginkgolic acid, cardanols (approx. 0.1%))
Long chain hydrocarbons (waxes)
Lipids
Others (Carbohydrates, miscellaneous organic compounds, inorganic compounds)
Herbal preparation(s)
1. Ginkgo biloba dry extract is a component part of the European Pharmacopoeia. Actually the
following monograph exists:

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Ginkgo dry extract, refined and quantified (Ph. Eur. 7th edition 2012 (7.5), ref.
04/2008:1827)
This extract contains several chemical constituents, among which the two main constituents
flavones glycosides (total 22.0-27.0%), represented by quercetin, kaempherol and
isorhamnetin and terpene lactones (total 5.0-7.0), represented by ginkgolides A, B, C (2.83.4%) and bilobalide (2.6-3.2%). The content of ginkgolic acids is limited with max. 5 ppm.
The limit value of 5 ppm was chosen since it complies with the detection limit recordable by
routine methods, thus allowing to assure to a maximum degree removal of these compounds
from therapeutically used extracts.
2. Powdered herbal substance
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of

vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
The monograph is established on Ginkgo folium and preparations thereof.
1.2. Information about products on the market in the Member States

Austria: Well-established use
1. Dry extract of Ginkgo biloba leaves (EGb 761); DER 35-67:1; quantified to 19.2 mg
ginkgoflavonglycosides and 4.8 mg terpene lactones (ginkgolides, bilobalide); extraction
solvent acetone
2. Dry extract of Ginkgo biloba leaves standardised to 9.6 mg ginkgoflavonglycosides and 2.4 mg
terpene lactones (ginkgolides, bilobalide)
3. Dry extract of Ginkgo biloba leaves standardised to 9.6 mg ginkgoflavonglycosides and 2.4 mg
4. Dry extract of Ginkgo biloba leaves, not further specified
5. Dry extract of Ginkgo biloba leaves; DER 35-67:1; extraction solvent: acetone 60%
6. Dry extract of Ginkgo biloba leaves (EGb 761) standardised to 9.6 mg ginkgoflavonglycosides
and 2.4 mg terpene lactones (ginkgolides, bilobalide)
8. See 6.
10. 1 coated tablet contains 20 mg dry extract of Ginkgo biloba leaves standardised to 4,8 mg
ginkgoflavonglycosides
Since when on
pharmaceutical form
Posology/daily dosage
film-coated tablets
2-3 times daily
containing 80 mg extract
The amount of tablets per day is not stated
the market?
1. 2000

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2. 1993
3. 1993
film-coated tablets
2 times daily 1 tablet; if required the dosage can be
increased to 3 times daily 1 tablet
drops
2 times daily 1 ml; if required the dosage can be
1 ml solution contains 40 mg
increased to 3 times daily 1 ml
extract
4. 1999
film-coated tablets
3 times daily 1 tablet; duration of treatment comply
containing 50 mg dry extract
with the disease pattern; should last min. 6-8

weeks
5. 1999
6. 1999
oral solution
2 times daily 1 teaspoon; duration of treatment
100 ml solution contain
comply with the disease pattern; should last 6-8
1.33 g extract
weeks
film-coated tablets
3 times daily 1 tablet during 8-12 weeks
initial treatment:
3 times daily 1 tablet for 8-12 weeks
follow-up treatment:
if required 2 times daily 1 tablet
dementia syndrome: 3 times daily 1-2 tablets
7. 1999
drops
initial treatment: 3 times daily 1 ml for 8-12 weeks
1 mg (appropriate to 18
follow-up treatment: if required 2 times daily 1 ml
drops) solution contains
dementia syndrome: 3 times daily 1-2 ml
40 mg extract
8. 1989
film-coated tablets
3 times daily 1 tablet during 8-12 weeks
follow-up treatment:
if required 2 times daily 1 tablet
dementia syndrome: 3 times daily 1-2 tablets
9. 1989
drops
3 times daily 1 ml during 8-12 weeks
1 ml contains 40 mg extract
10. 1993
coated tablets
2-3 times daily 1-2 coated tablets
Indications:
1. For the symptomatic treatment of brain-related impairment of mental performance, memory
impairment, impaired concentration, depressive mood, dizziness, and headache
2. Decrease of the brain performance with lack of concentration and weakness of memory, cold
hands and feet with numbness, prickle, and calf pain at walking
3. Frequently occurring vertigo and tinnitus (clarification by a doctor), hearing loss (clarification
by a doctor)
4. Decrease of the brain performance (such as weakness of memory, anxiety, depressive mood,
cold hands and feet
5. See 4.
6. Cerebral insufficient blood supply or rather brain disorder with symptoms of decreasing
intellectual performance and vigilance such as dizziness, tinnitus, headache, sight disorder,
weakness of memory, anxiety and depressive mood, dementia syndrome. Peripheral arterial
circulatory disorders with preservative perfusion reserve (claudication intermittent). For
supportive treatment of impaired hearing because of a cervical syndrome.
7. See 6.

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8. Cerebral insufficient blood supply and malnutrition or rather brain disorders with the symptoms
of decreasing intellectual performance and vigilance such as dizziness, headache, sight
disorder, weakness of memory, anxiety and depressive mood.
9. See 8.
10. See 8.
Belgium: Well-established use

1. Dry extract; DER 35-45:1; extraction solvent: acetone 60%; containing 24% flavones
glycosides and 6% terpene lactones (ginkgolides, bilobalide)
Since when on
pharmaceutical form
capsules, hard
Adults (> 16 years) 1 capsule 2 times daily;
max. 6 capsules per day; intake longer than
2.
film-coated tablets
a) 1 tablet 3 times daily; max. 9 tablets per day;
a) 2000
a) containing 40 mg extract
no use in children below 12 years; min. period of
b) 2006 (line
b) containing 120 mg
treatment: 8 weeks; intake longer than 3 months:
extension)
extract
under medical supervision
the market?
1. 1998
3 months: under medical supervision
b) 1-2 tablets once daily, max 2 tablets per day

3. a) 2002
a) coated tablets
a) Adults: 1-2 tablets 3 times daily
Venous insufficiency: 1 tablet 3 times daily;

max. 9 tablets per day
b) 2002
b) oral solution
b) Adults: 1-2 ml 3 times daily

Venous insufficiency: 1 ml 3 times daily;
max. 9 ml per day
Indications:
1. Symptomatic treatment of disturbance in the cerebral functions, after exclusion of all serious
pathologies; (OTC)
2. To delay the pathological symptoms typical of mild to moderate Alzheimer-type dementia with
its concomitant disturbances in memory and problems in concentrating. The primary target
group includes patients with dementia syndrome as a consequence of degenerative dementia,
vascular dementia and mixed (hybrid) forms. Before initiating the therapy, it should be
excluded that the disorder is caused by a specific underlying disease that needs other specific
treatment. (medical prescription)
3. To delay the pathological symptoms typical of mild to moderate Alzheimer-type dementia with
its concomitant disturbances in memory and problems in concentrating. The primary target
group includes patients with dementia syndrome as a consequence of degenerative dementia,
vascular dementia and mixed (hybrid) forms. Before initiating the therapy, it should be

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excluded that the disorder is caused by a specific underlying disease that needs other specific
treatment. (medical prescription).
Used in case of subjective symptoms of venous insufficiency of the lower limbs, such as heavy
legs, after exclusion of all serious pathologies (such as flebitis, thromboflebitis, thrombosis).
Czech Republic: Well-established use
1. Ginkgo biloba dry extract standardised to 35-67:1; extraction solvent acetone 60% (m/m);
(EGb 761) for specification see additional comments
2. Ginkgo biloba dry extract standardised to 35-67:1; extraction solvent acetone 60% (m/m);
(EGb 761) for specification see additional comments
3. See 1.
4. See 2.
5. Ginkgo biloba dry extract standardised to 35-67:1; extraction solvent acetone 60% (V/V); for
specification see additional comments
Since when on
pharmaceutical
the market?
form
1. 1992
oral drops, solution
in mental capacity disturbances, peripheral vascular
1 ml contains 40 mg
insufficiency, sensory disturbances: 1 ml 3 times daily;
extract
duration of use minimum 6-8 weeks

in dementia: 1-2 ml 3 times daily; duration of use minimum
8 weeks
2. 1992
film-coated tablets
in mental capacity disturbances, peripheral vascular
containing 40 mg
insufficiency, sensory disturbances: 1 tablet 3 times daily;
extract
duration of use minimum 6-8 weeks

dementia: 1-2 tablets 3 times daily; duration of use
minimum 8 weeks
3. 1995
in dementia syndromes: 1-2 ml 3 times daily; duration of
1 ml contains 40 mg
use minimum 8 weeks; after 3 months evaluation should be
extract
carried to determined, whether continuation of the

treatment is eligible
in peripheral obliterating arteriopathy, dizziness, tinnitus:
1 ml 3 times daily or 2 ml 2 times daily; duration of use
minimum 6 weeks
4. 1995
film-coated tablets
in dementia syndromes: 1-2 tablets 3 times daily; duration
containing 40 mg
of use minimum 8 weeks; after 3 months evaluation should
extract
be carried to determined, whether continuation of the

treatment is eligible
in peripheral obliterating arteriopathy, dizziness, tinnitus:

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1 tablet 3 times daily or 2 tablets 2 times daily; duration of

use minimum 6 weeks
5. 2002
in mild cerebrovascular insufficiency (dementia syndromes
1 ml contains 40 mg
such as memory and concentration disturbances, emotional
extract
lability, dizziness, tinnitus, headaches): 1-2 ml 3 times daily

in peripheral arterial occlusive disease: 1.5-2 ml 2 times
daily
in dizziness and tinnitus of vascular or involution character:
1.5-2 ml 2 times daily
duration of use minimum 8 weeks, for improvement of gait
in case of peripheral arterial occlusive disease minimum
6 weeks; after 3 month an evaluation should be carried to
determined, whether continuation of the treatment is
eligible
6. 2002
film-coated tablets
in mild cerebrovascular insufficiency (dementia syndromes
contains 40 mg
such as memory and concentration disturbances, emotional
extract
lability, dizziness, tinnitus, head aches): 1-2 tablets 3 times

daily
in peripheral arterial occlusive disease: 1.5-2 tablets
2 times daily
in dizziness and tinnitus of vascular or involution character:
1.5-2 tablets 2 times daily
eligible
7. 2006
film-coated tablets
symptomatic treatment of cerebral insufficiency:
containing 80 mg
1 tablet 2-3 times daily
extract
in peripheral arterial occlusive disease, in dizziness and

tinnitus of vascular or involution character: 1 tablet 2 times
daily
eligible
8. 2006
film-coated tablets
symptomatic treatment of cerebral insufficiency:
containing 120 mg
extract
in peripheral arterial occlusive disease, in dizziness and

tinnitus of vascular or involution character: 1 tablet 1 times
daily
eligible
For all products: In dizziness and tinnitus of vascular or involution character treatment longer than 6-8
weeks does not have any therapeutically benefit
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Indications:
1. Syndrome of dementia (primary degenerative dementia of Alzheimer type, vascular dementia,
mixed forms of dementia); for treatment of symptoms such as (loss of concentration; memory
disturbances, emotional lability) in elderly, based on chronic cerebrovascular insufficiency;
peripheral blood circulation and microcirculation disorders: peripheral arterial obstructive
disease of hind limbs at stadium 1-II according to Fontaine (claudicatio intermittens), Raynaud
syndrome, acroparesthaesia, enhanced capillary fragility, etc.; sensory disorders based on
vascular insufficiency (vertigo, tinnitus, hearing impairment and vision impairment in elderly
based on insufficient blood circulation in retina
2. See 2.
3. Syndrome of dementia (primary degenerative dementia of Alzheimer type, vascular dementia,
mixed forms of dementia); brain function disorders such as memory and concentration
disturbances, depression, dizziness, tinnitus, head aches due to organic dysfunction of CNS as
a part of complex dementia therapy; peripheral obliterating arteriopathy at stadium II
according to Fontaine scale; dizziness and tinnitus of vascular or involution character
4. See 3.
5. For symptomatic treatment of cerebral insufficiency such as memory and concentration
disturbances, emotional lability, dizziness, tinnitus and head aches; mild to moderate dementia
syndromes including primary degenerative dementia, vascular dementia and mixed forms;
peripheral arterial occlusive disease (claudicatio intermittens); dizziness and tinnitus of
vascular or involution character
6. See 5.
7. See 5.
8. See 5.
Risks:
1. Contraindications: hypersensitivity to the drug substance, bleeding dispositions. Special
warning: Not to be used in pregnancy and lactation, and in children bellow 12 years, not
intended for hypertension therapy. Interactions: caution is recommended in concomitant use
with salicylates and barbiturates. Undesirable effects: in isolated cases gastrointestinal
discomfort such as nausea, diarrhoea, very rare palpitation, hypotension, arrhythmia,
retrosternal pain
2. See 1.
3. Contraindications: hypersensitivity to the drug substance, bleeding dispositions. Special
warning: Not to be used in pregnancy and lactation, and in children bellow 12 years, not
intended for hypertension therapy. Caution is recommended in case of concomitant use of
medicinal products with similar effect (vasodilatants, medicinal products causing tachycardia
etc.). Undesirable effects: in isolated cases gastrointestinal discomfort, headaches, congestion,
allergic skin reactions, very rare haemorrhage
4. See 3.
5. Contraindications: hypersensitivity to the drug substance. Special warning: Not to be used in
children bellow 12 years, not recommended in haemorrhage, caution is recommended in case
of concomitant use of medicinal products with similar effect (vasodilatants, antiarrythmics).

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Interactions: caution is recommended in concomitant use with salicylates and barbiturates.

Pregnancy and lactation: No experience with use in humans, benefit/risk evaluation is needed.
Undesirable effects: very rare gastrointestinal discomfort, headaches, congestions, allergic skin
reactions. In isolated cases during long term use haemorrhage; one case of subdural
haematoma when 120 mg/day of ginkgo extract had been used for 2 years has been reported
6. See 5.
7. Contraindications: hypersensitivity to the drug substance. Special warning: Not to be used in
children bellow 12 years. Pregnancy and lactation: No experience with use in humans,
benefit/risk evaluation is needed. Interactions: in case of long term use concomitant
medication with medicinal products affecting clotting should be avoided. Undesirable effects:
very rare gastrointestinal discomfort, headaches, allergic skin reactions, in isolated cases
during long term use haemorrhage
8. See 7.
Combination products:
Average number of combination substances: 2-3. The main combination substances are ginkgo dry
extract and ginseng dry extract.
Additional comments:
Preparations 1. 4.
Ginkgo biloba dry extract standardised to 35-67:1; extraction solvent acetone 60% m/m; (EGb 761);
specification:
Test
Release specification
Stability specification
22.026.4 g/100 g
22.026.4 g/100 g
(DAB+Ph.Eur. 22.027.0 %)
95.0105.0% of initial value
5.46.6 g/100 g
5.46.6 g/100 g
(DAB 5.07.0 %)
90.0110.0% of initial value
Assays
-Ginkgoflavonglycosides (HPLC)
- Terpene lactones (HPLC)
Ginkgolides A,B,C
2.83.4 g/100 g (Ph.Eur+DAB)
2.83.4 g/100 g
2.63.2 g/100 g (Ph.Eur+DAB)
2.63.2 g/100 g
Proanthocyanidins (photometry)
NMT 9.5 %
Biflavones (HPLC)
NMT 0.1 %
Ginkgolic acids (HPLC)
NMT 5.0 ppm
Bilobalide
Preparations 5) 8)
Ginkgo biloba dry extract standardised to 35-67:1; extraction solvent acetone 60% (V/V); specification
Test
Limit
Ginkgolic acids as anacardic acid HPLC
NMT 5.0 ppm
Assays
- GinkgoflavonglycosidesHPLC
NLT 24.029.0 %
- TerpenesGC
Ginkgolides A,B,C,J and bilobalide
- Ginkgolides A, B and C
NLT 6.09.0 %
2.63.2 %
During second half of the year (2008) specification will be adapted in accordance with the Ph.Eur.
monograph 04/2008:1827

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Denmark: Well-established use

1. Dry extract, refined, of Ginkgo biloba L., folium (ginkgo leaf) corresponding to 9.6 mg
ginkgoflavonglycosides and 2.4 mg terpene lactones; first extraction solvent: acetone/water
60/40% (w/w)
2. Dry extract, refined, of Ginkgo biloba L., folium (ginkgo leaf) corresponding to 24 mg
ginkgoflavonglycosides and 6 mg terpene lactones; first extraction solvent: acetone 60-65%
3. Extract of Ginkgo biloba leaf (Ginkgo biloba L., folium rec.) corresponding to 14.4 mg
ginkgoflavonglycosides and 3.6 mg terpene lactones; extraction solvent: acetone 50-90%
(V/V)
4. Product with brandname
5. Product with brandname
Since when on the
pharmaceutical form
1. marketed around 1990,
film-coated tablets
1 tablet 3-4 times daily; not to be
MA in 1995
used in children below 12 years due
market?
to lack of experience
2. marketed around 1990,
film-coated tablets
MA in 1996
3. 2005
film-coated tablets
1-2 tablets daily

1 tablet daily
content is not indicated

4. 1995
film-coated tablets
not indicated

5. 1997
film-coated tablets
1 tablet three times daily
Indications:
1.
Herbal medicinal product in long-term symptoms as memory problems, concentration problems,

tiredness, dizziness (vertigo) and tinnitus in elderly people, where a doctor has excluded other
underlying disease; herbal medicinal product in trends to cold hands and feet and in walking
initiated pains in the legs, due to poor blood circulation
2. See 1.
3. Not indicated
4. Not indicated
5.
See 1.
Risks:
1. Products with ginkgo leaf should not be used in the weeks up to a planned surgery; patients that
experience spontaneous bleeding during treatment with ginkgo leaf should stop the treatment
and contact a doctor; caution in epileptics, ginkgo leaf may decrease the effect of antiepileptic
drugs or increase the vulnerability of seizures
The following text is from the SPC in DK:
Interactions with other medicinal products and other interactions:

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Antiepileptika: As stated in the chapter contraindiations in the SPC of DK: Sensitivity for ginkgo
leaves or one of the auxiliary agents
Orale antikoagulantia: Might increase the effect of oral anticoagulant
NSAID: Possible increased risk of bleedings in NSAID including acetylsalicylic acid.
Calcium antagonists: Concomitant intake of ginkgo leaf and nifedipine has caused an increased heart
frequency of 5-10% in well beings. The mechanism is not clear. Ginkgo leaf does not affect the
pharmacokinetic of nifedipine in concomitant intake in well volunteers. The combination can be used.
Proton pump inhibitors: Ginkgo leaf (multiple doses) decrease AUC for a single dose omeprazole with
25-40% and increase clearance for omeprazole from 30-45% due to an induction of omeprazoles
metabolism in CYP2C19. The interaction is not seen as clinical important. The combination can be
used.
Anti-diabetics, sulfonamides: Ginkgo leaf (multiple doses) decreases AUC for a single dose tolbutamide
with around 15%. The mechanism is not clear. The combination can be used.
The effect of concomitant intake of other medicinal products included medicine bought in other
countries and other herbal medicinal products is not known.
Side effects:
1. seldom: increased tendency to bleeding*, headache, nausea, gastrointestinal disturbances
very seldom: dizziness (vertigo), allergic skin reactions like rash and itching
*Bleeding has been noted in a single case after long-term treatment with ginkgo leaves. Clinical
sudies with standardised extracts have not shown any effect on coagulation.
2.
See 1.
We have for the time being 15 products with extract of GB with a MA. The rest are similar to the above
mentioned products, since several companies have identical versions of their products, sold with other
names. But the listed are the different extract forms as far I can see. We also have had other products
with a MA or applied for an MA, but they are either withdrawn or did not receive an MA.
Estonia: Well-established use

1. Dry extract from ginkgo leaf, corresponding to 9.6 mg of flavones glycosides and 2.4 mg
2. Dry extract from ginkgo leaf, corresponding to 14.4 mg of flavones glycosides and 3.6 mg
3. Dry extract from ginkgo leaf, corresponding to 24 mg of flavones glycosides and 6 mg terpene
lactones (ginkgolides, bilobalide)
4. Dry extract from ginkgo leaf; extraction solvent: ethanol 60% (V/V); DER 1:4,5
5. Dry extract from ginkgo leaf, corresponding to 17.6-21.6 mg of flavones glycosides and 4.05.6 mg terpene lactones (ginkgolides, bilobalide); extraction solvent: acetone 60% (m/m); 1
tablet contains less than 0.4 g ginkgolic acids; DER 35-67:1

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6. Dry extract from ginkgo leaf, corresponding to 26.4-32.4 mg of flavones glycosides and 6.08.4 mg terpene lactones (ginkgolides, bilobalide); extraction solvent: acetone 60% (V/V); 1
tablet contains less than 0.6 g ginkgolic acids; DER 35-67:1
Since when on
pharmaceutical form
tablets
oral; adults take 1 tablet 3 times daily
the market?
1. 1998
oral solution
oral; adults take 1 ml 3 times daily
1 ml contains 40 g extract
2. 1999
film-coated tablets
3. 2000
film-coated tablets
oral; adults take 1-2 tablets daily

4.2000
oral; adults take 10-20 drops 3 times daily
1 ml contains 910 mg extract

5. 2004
coated tablets
6. 2004
coated tablets

Indications:
For all products: Disorders in cerebral function (i.e. decline in memory and intellectual capacity,
indisposition and anxiety). Circulatory functional disorders of extremities.
Risks:
For all products: Gastrointestinal upset, nausea, vomiting, diarrhoea, dry mouth, headache, dizziness,
restlessness, sleep disturbance, skin rash
Average number of combination substances: 2-3. There are two combination products (capsule, gel).
The main combination substances are troxerutin and heptaminol. One capsule contains 14 mg of
extract (as dry extract) from ginkgo leaf (24% of flavones glycosides and 6% terpene lactones
(ginkgolides, bilobalide)). 1 g of gel contains 30 mg of troxerutin and 1.4 mg of extract (as dry extract)
from ginkgo leaf (24% of flavones glycosides and 6% terpene lactones (ginkgolides, bilobalide)).
France:
One product (ginkgo powder 180 mg) has been on the market as food supplement.
Since when on
pharmaceutical form
Hard capsule
From 1984-2000: 360 mg (180x2) 3 times daily
the market?
1984
From 2000: 250 mg 3 times daily

The product is marketed for vertigo, improvement of blood circulation, heavy legs, haemorrhoids,
memory deficit.

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Germany: Well-established use

All preparations MA to date are from dry extract of Ginkgo biloba leaves. They comply with the
monograph of Commission E (BAnz Nr. 133 vom 19.07.1994). Dry extract (DER 35-67:1) from Ginkgo
biloba leaf is refined and quantified to 22-27% ginkgoflavonglycosides, represented by quercetin,
kaempherol and isorhamnetin and 5-7% terpene lactones, represented by ginkgolides A, B, C (2.83.4%) and bilobalide (2.6-3.2%). The content of ginkgolic acids is less than 5 ppm.
Preparations in the following strengths are available:
30 mg/tablet: No. 1
40 mg/tablet or rather 40 mg/ml: No. 2-20, 23, 25-41, 46-50, 55-58, 63-72, 99-100, 103, 108-109
50 mg/tablet: No. 21-22, 24
60 mg/tablet: No. 92-93, 107
80 mg/tablet: No. 42-45, 59-62, 77, 80, 82-84, 88, 101-102, 110
120 mg/tablet: No. 51-54, 73-76, 78-79, 81, 85-87, 89-91, 94-98, 111-114
240 mg/tablet: No. 104-106, 115-117
Since when are the preparations on the market?
No. 2 since 1986; No. 3-4 since 1991; No. 31-34 since 1992; No. 5-7since 1994; No. 8-12, 15, 20-30,
35-45, 51-54 since 1995; No. 13-14, 16-19 since 1996; No. 57-63, 65, 67-68, 70-77, 82-89 since
1999; No. 46-50, 55-56, 64, 66, 69 since 2000; No. 78-79, 81 since 2001; No. 80, 90-93 since 2002;
No. 94-98 since 2003; No. 1 since 2004; No. 99-102 since 2005; No. 103 since 2006; No. 104-108
since 2007; No. 109 since 2008; No. 110-111 since 2009; No. 112-114 since 2010; No. 115-117 since
2011
Pharmaceutical forms:
Film-coated tablets: No. 1-4, 9, 11, 21-22, 24-28, 31-38, 42-54, 59-63, 65, 67, 69, 71-76, 78-108,
110-117
Oral drops, solution: No. 5-8, 16, 17, 30, 41, 68
Oral liquid: No. 10, 12, 14-15, 20, 23, 29, 39-40, 55-58, 64, 66, 70, 109
Capsule, hard: No. 13, 18-19
Effervescent tablet: No. 77
Posology/daily dosage:
Dementia syndrome, peripheral arterial occlusive disease, vertigo, as an adjuvant in tinnitus
2 tablets 2 times daily (=120 mg): No. 1
1-2 tablets 2-3 times daily (=80-240 mg): No. 26-28
1 tablet 2 times daily (=120-240 mg): No. 92-93
Dementia syndrome
1-2 tablets 3 times daily (=120-240 mg): No. 2-4, 9, 25, 31-38, 46-50, 63, 65, 67, 69, 71-72, 99100, 103, 108
20-40 drops (1-2 ml) 3 times daily (=120-240 mg): No. 5-8, 23, 29-30, 39-41
EMA/HMPC/321095/2012
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18-36 drops (1-2 ml) 3 times daily (=120-240 mg): No. 10, 55-58, 64, 66, 68, 70, 109
2-4 pumps (1-2 ml) 3 times daily (=120-240 mg): No. 14
20-40 drops (1-2 ml) 2-3 times daily (=80-240 mg): No. 15
1 tablet 3 times daily or 2 tablets 2 times daily (=120-200 mg): No. 21-22, 24
1 tablet 2-3 times daily (=160-240 mg): No. 42-45, 59-62, 77, 80, 82-84, 88, 101-102, 107, 110
1 tablet 2 times daily (=120-240 mg): No. 51-54, 79, 81, 112-114
1 tablet 1-2 times daily (=120-240 mg): No. 73-76, 85-87, 89
0.5-1 tablet 2 times daily (=120-240 mg): No. 78, 90-91, 94-98, 111
0.5 tablet 2 times daily (=240 mg): No. 104-106, 115-117
For the symptomatic treatment of brain-related impairment of mental performance
1-2 tablets 3 times daily (=120-240 mg): No. 11
17-34 drops (1-2 ml) 3 times daily (=120-240 mg): No. 12
1-2 capsules 3 times daily (=120-240 mg): No. 13, 18-19
25-50 drops (1-2 ml) 3 times daily (=120-240 mg): No. 16-17, 20
Peripheral arterial occlusive disease, vertigo, as an adjuvant in tinnitus
1.5-2 tablets 2 times daily (=120-160 mg): No. 9, 46-50, 63, 65, 67, 69, 103, 108
25 drops (1,25 ml) 3 times daily or rather 40 drops (2 ml) 2 times daily (=150-160 mg): No. 6
20-25 drops (1-1.25 ml) 3 times daily or rather 30-40 drops (1.5-2 ml) 2 times daily (=120-160 mg):
No. 5, 7, 40
20 drops (1 ml) 3 times daily or rather 40 drops (2 ml) 2 times daily (=120-160 mg): No. 8, 23, 2930, 39, 41
27-36 drops (1.5-2 ml) 2 times daily (=120-160 mg): No. 10, 55-58, 64, 66, 68, 70, 109
2 pumps (1 ml) 3 times daily or rather 4 pumps (2 ml) 2 times daily (=120-160 mg): No. 14
20 drops (1 ml) 3 times daily or rather 40 drops (2 ml) 2 times daily (=120-160 mg): No. 15
1 tablet 3 times daily or 2 tablets 2 times daily (=120-200 mg): No. 31-38, 71-72, 99-100
1 tablet 3 times daily (=150 mg): No. 21-22, 24
1 tablet 2 times daily (=120-240 mg): No. 42-45, 59-62, 77, 80, 82-84, 88, 101-102, 110
1 tablet 1-2 times daily (=120-240 mg): No. 51, 53-54, 79, 111-114
1 tablet 1 time daily (=120 mg): No. 73-76, 85-87, 89
For increasing the pain-free walking distance in patients with arterial occlusive disease, vertigo and
tinnitus of vascular and involutive origin
1.5-2 tablets 2 times daily (=120-160 mg): No. 11
26-34 drops (1.5-2 ml) 2 times daily (=120-160 mg): No. 12

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For increasing the pain-free walking distance in patients with arterial occlusive disease, vertigo and
tinnitus
1 capsule 3 times daily or rather 2 capsules 2 times daily (=120-160 mg): No. 13, 18, 19
25 drops (1 ml) 3 times daily or rather 50 drops (2 ml) 2 times daily (=120-160 mg): No. 16-17, 20
1 tablet 3 times daily or 2 tablets 2 times daily (=120-200 mg): No. 25
Route of administration:
For taking the medicinal product 3 times daily it should be consumed in the morning, in the afternoon
and in the evening, for a daily use of 2 times it should be taken in the morning and in the afternoon.
For film-coated tablets and hard capsules
Do not take the film-coated tablets or the hard capsules in a supine position. The tablet/capsule is
swallowed whole (not chewed) with some liquid, preferably a glass of drinking water. It can be taken
with or without a meal.
For oral drops and oral liquids
The drops are taken undiluted or in some water and afterwards washed down sufficient liquid,
preferably a glass of drinking water. The drops can be taken with or without a meal.
For effervescent tablet
The effervescent tablets are dissolved by stirring in a glass of drinking water, about 200 ml. The
tablets can be taken with or without a meal.
Duration of use:
Dementia syndrome
Treatment should last for at least 8 weeks. If there is no symptomatic improvement after 3 months, or
if pathological symptoms should intensify, the doctor should check whether continuation of treatment
is still justified.
Peripheral arterial occlusive disease
A treatment period of at least 6 weeks is required for improving performance with regard to walking
distance.
Vertigo
No therapeutic benefit is gained by extending use beyond a 6 to 8-week period.
Tinnitus
Adjuvant therapy should be administered over a period of at least 12 weeks. If treatment is
unsuccessful after 6 months, success can no longer be expected even after prolonged treatment.
Indications:
a) For the symptomatic treatment of brain-related impairment of mental performance, as part of an
overall therapeutic strategy in dementia syndromes with the following main symptoms: memory
impairment, impaired concentration, depressive mood, dizziness, tinnitus, headache.
b) For increasing the pain-free walking distance in patients with arterial occlusive disease of the legs
(Fontaine Stage II intermittent claudication), as part of physiotherapy, including gait training.

EMA/HMPC/321095/2012
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c)
Vertigo of vascular and involutive origin.
d) Adjuvant therapy in tinnitus of vascular and involutive origin.

e) Vertigo and tinnitus of vascular and involutive origin.
f)
Adjuvant therapy in tinnitus.
a-d: No. 1, 4, 8, 29-32, 35-36, 38, 45-46, 48, 51, 53-54, 65, 67, 72, 93, 103, 108-114
a, b, e: No. 2, 5, 7, 9-14, 16-21, 25, 33-34, 37, 39-44, 47, 49-50, 55-64, 66, 68-71, 77, 82-89
a: No. 3, 52, 73-76, 78-79, 81, 90-91, 94-98, 104-107, 115-117
a, b: No. 6
a-c, f: No. 15, 22-24, 26-28, 80, 92, 99-102
Risks:
Contraindications:
Hypersensitivity to Ginkgo biloba extracts or to any other component of the medicinal product.
Pregnancy.
Special warnings and precautions for use:
There are no adequate studies on the use of medicinal products containing Ginkgo biloba in children
and adolescents. It must therefore not be used in children below 12 years: No. 11-13, 15-18, 20-28,
46, 48, 78, 90-91, 94-97, 99-102, 108-110. All other products must be used in adults aged 18 or over.
In abnormal increased tendency to bleed (haemorrhagic diathesis) and concomitantly treatment with
anticoagulants the medicinal product only should be taken after consulting a doctor.
As there is evidence to suggest that preparations containing Ginkgo biloba might increase susceptibility
to bleeding, these medicinal products must be discontinued as a precaution prior to surgery.
In patients with epilepsy, onset of further seizures - promoted by intake of ginkgo preparations cannot be excluded. It has been argued that this might be associated with the 4-O-methylpyridoxine
content.
Interactions:
If a preparation containing Ginkgo biloba is taken concomitantly with anticoagulants (e.g.
phenprocoumon, warfarin, clopidogrel, acetylsalicylic acid and other non-steroidal anti-inflammatory
drugs), their effect may be potentiated.
As with any medicinal product, it cannot be ruled out that any preparation containing Ginkgo biloba
may influence the metabolism via cytochrome P450 3A4, 1A2 and 2C19 of various other medications,
which could affect the potency and/or duration of action of the medications concerned. No adequate
studies are available on this matter.
Pregnancy and lactation:
There is isolated evidence which suggest that preparations containing Ginkgo biloba can increase
susceptibility to bleeding. Therefore preparations containing Ginkgo biloba must not be used during
pregnancy (see section Contraindications).

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There are no adequate studies on the use of medicinal products containing Ginkgo biloba during
lactation. Therefore preparations containing Ginkgo biloba must not be used during lactation. It is not
known whether the ingredients of the extract pass into breast milk.
Undesirable effects:
It is not possible to give any definite data on the frequency of undesirable effects reported with the
intake of preparations containing Ginkgo biloba, as such undesirable effects have emerged via
individual reports by patients, doctors or pharmacists. According to these reports, the following
undesirable effects might occur in patients taking this medicine:
Bleeding of individual organs may occur, particularly with concomitant intake of anticoagulants, e.g.
phenprocoumon, acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (see also section
Interactions).
Allergic shock may occur in hypersensitive individuals; allergic skin reactions (erythema, swelling of
the skin, itching) may also occur.
Mild gastrointestinal complaints
Headache, dizziness or aggravation of pre-existing symptoms of dizziness may occur.
The herbal substance is not on the market.
Norway: Well-established use

1. Ginkgo biloba leaf dry extract (35-67:1); first extraction solvent: Acetone 60%
2. Ginkgo biloba leaf dry extract (3-4:1); first extraction solvent: Acetone 60-65%
Since when on the market?
1. 1998
pharmaceutical form
Capsule, hard
1-2 tablets
containing 62.5 mg dry extract

2. 1996
Film-coated tablet
1-2 tablets
containing 100 mg dry extract

Indications:
Used to improve blood circulation in for example cold hands and feet
Poland: Well-established use

1. Ginkgo biloba leaf dry extract, refined (35-67:1), containing 22.0-27.0% of flavonoids
expressed as flavone glycosides, 2.8-3.4% of ginkgolides A, B and C, 2.6-3.2% of bilobalide;
first extraction solvent: Acetone 60% (m/m)
Since when on
pharmaceutical form
Capsule, hard
Oral use; adults: 120 mg in the morning and 120 mg
the market?
1993
in the evening; duration of use in patients with age

linked impairment of memory and intellectual ability
and patients with cerebral circulation disorders: First
EMA/HMPC/321095/2012
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signs of improvement are usually observed after 3

weeks of treatment; it is possible to prolong the
treatment up to 3 months; duration of use in patients
with unspecific peripheral vascular disorders: Effects
appear after many weeks of treatment (10-12 weeks
according to reults of clinical trials)
Indications:
In age linked impairment of memory and intellectual capability; adjunctively in cerebral circulation
disorders with manifestations like vertigo and tinnitus; adjunctively in patients suffering from
unspecific peripheral vascular disorders with symptoms of intermittent claudication who practice
exercises
Risks:
Adverse drug reaction:
Gastrointestinal complaints (nausea, constipation, diarrhoea), headache, bleeding, hypersensitivity
reactions (pruritus, erythema)
Interactions:
Concomitant use with anticoagulant or antiplatelet medicines increases risks of bleeding; use with
caution in patients simultaneously treated with inhibitors of proton pump, trazodone, nifedipine,
thiazides
Warnings:
Patients with coagulation disorders should not use this drug without medical supervision; the treatment
must be stopped 36 hours before surgical or dental operation
The herbal substance is on the market.
Poland: Traditional use

1. Ginkgo biloba leaf dry extract, refined (39.6-49.5:1), containing 22.0-27.0% of flavonoids
extraction solvent: Ethanol 50% (V/V)
pharmaceutical form
Before 1980
Capsule, hard
Oral use; adults: 80-160 mg 2 times

daily with meals
Indications:
In mild disorders of peripheral circulation with feeling of cold hands and legs; adjunctively in mild agelinked impairment of intellectual capability
Risks:
Adverse drug reaction:
Gastrointestinal complaints (nausea, constipation, diarrhoea), headache, sleep disorders, palpitation,
vertigo anxiety, hypersensitivity reactions (pruritus, erythema), bleeding

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Interactions:
Concomitant use with anticoagulants, antiplatelet medicines, tipranavir, herbal drugs containing Allium
sativum or Panax ginseng increases risks of bleeding; use with caution in patients simultaneously
treated with inhibitors of proton pump (decreased efficacy of IIPs), trazodone (risk of increased
adverse drug reaction of nifedipine), thiazides (risk of increased blood pressure)
Warnings:
Patients with coagulation disorders should not use this drug without medical supervision; the treatment
must be stopped 36 hours before surgical or dental operation
Other herbal medicinal products than well-established use and traditional herbal medicinal products:
1. Ginkgo biloba leaf dry extract (35-67:1) containing 24-29% of flavone glycosides, 6-9% of
trepene lactones, 2.6-3.2% of bilobalide; extraction solvent: Acetone 60% (V/V)
2. Ginkgo biloba leaf dry extract (35-67:1) containing 22-26.4% flavone glycosides, 2.8-3.4% of
ginkgolides A, B and C, 2.6-3.2% of bilobalide; extraction solvent: Acetone 60% (m/m)
3. Ginkgo biloba leaf dry extract (35-67:1) corresponding to 8.8-10.8 mg of flavone glycosides,
1.12-1.3 mg of ginkgolides, 1.04-1.28 mg of bilobalide; extraction solvent: Aceton 60% (m/m)
4. Ginkgo biloba leaf dry extract containing 21.6-26.4% of flavone glycosides, 2.8-3.4% of
ginkgolides A, B and C, 2.6-3.2% of bilobalide; extraction solvent: Acetone 60% (m/m)
5. Ginkgo biloba leaf dry extract (35-67:1) containing 22-27% of ginkgoflavonglycosides, 5-7% of
terpene lactones including 2.8-3.4% of ginkgolides A, B, C and 2.6-3.2% of bilobalide;
extraction solvent: Acetone 60% (m/m)
6. Ginkgo biloba leaf dry extract (40-50:1) containing 24-27% flavone glycosides, 2.8-3.4% of
ginkgolides A, B and C, 2.6-3.2% of bilobalide; extraction solvent: Acetone 60 % (V/V)
7. Ginkgo biloba leaf dry extract (35-67:1) corresponding to 19.2-23.2 mg of flavone glycosides
and 4.8-7.2 mg of terpene lactones (ginkgolides, bilobalide); extraction solvent: Acetone 60%
(V/V)
8. Ginkgo biloba leaf dry extract (45-55:1) containing not less than 6 mg of
ginkgoflavoneglycosides and 2-2.8 mg terpene lactones; extraction solvent: Ethanol 70% (V/V)
9. Ginkgo biloba leaf tincture (1:5); extraction solvent: Ethanol 60% (V/V)
10. Ginkgo biloba leaf tincture (1:5); extraction solvent: Ethanol 70% (V/V)
Since when on
Pharmaceutical form
Capsule, hard
Oral use; adults: 1 capsule 3 times daily; Duration
of use: First signs of improvement are usually
the market?
1. 1993
observed after 1 month of treatment. In order to fix

therapeutic effects, especially in geriatric patiens,
3-month use is recommended
2. 1993
3. 1996
Film-coated tablet
Oral use; adults: 1-2 film-coated tablets 3 times
Containing 40 mg extract
daily
Film-coated tablet
Oral use; adults: indication (a) 2 tablets 2-3 times
daily, indication (b) 2 tablets 2 times daily; duration

of use: 8-12 weeks, usually first signs of

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Since when on
Pharmaceutical form
the market?
improvement are observed after 4-week treatment,
use of 1 tablet 2 times daily as a maintenance
treatment is recommended
4. 1999
Film-coated tablet
Oral use; adults: 1 tablet 3 times daily
5. 2001
Film-coated tablet
Oral use; adults: indication (a) 1 tablet 2-3 times
daily, indication (b) 1 tablet 2 times daily; duration

of use: 8-12 weeks, first signs of improvement are
observed usually after 4-week treatment, use of 1
tablet 2 times daily as a maintenance treatment is
recommended
6. 2002
7. 2004
Film-coated tablet
Oral use; adults: 1 tablet 3 times daily; duration of
use: 8-12 weeks
Capsule, hard
Oral use; adults: indication (a) 1 capsule 2-3 times
daily, indication (b) and (c) 1 capsule in the

morning and 1 capsule in the evening
8. 2004
Film-coated tablet
Oral use; adults: 1 tablet 3 times daily; duration of
use: up to 10 weeks
9. 1997
Oral liquid
Oral use; adults and elderly: 5-10 ml 3 times daily
10. 1992
Oral liquid
Oral use; adults and elderly: 5-10 ml 3 times daily
Indications:
1. In cerebral circulation disorders with such symptoms as: impairment of memory and
intellectual capability, vertigo and tinnitus. Adjunctively in disorders of peripheral circulation
with pain during walking or feeling of cold hands and legs.
2. As symptomatic treatment in first signs of cognitive disorders caused by impaired cerebral
circulation (memory and concentration disorders); in microcirculation disorders (vertigo and
tinnitus); adjunctively for treatment of symptoms of peripheral circulation disorders
(contractions, feeling of cold legs)
3. (a) In cerebral circulation disorders with such symptoms as weakened concentration, memory
impairment, headache and vertigo, tinnitus, impaired sight and hearing
(b) In disorders of peripheral circulation with accompanying feeling of cold legs or pain
4. (a) In elderly patients manifesting impaired cognitive and neurosensorial functions (except for
Alzheimers disease and other states of profound dementia). In cerebral circulation disorders
with such symptoms as vertigo and tinnitus, impaired sight and hearing
(b) Adjunctively for treatment of symptoms of peripheral circulation disorders intermittent
claudication in chronic peripheral obliterative arterial disease (stage 2)
(c) Adjunctively for treatment of Raynauds disease symptoms
5. See 3.
6. In cerebral circulation disorders with such symptoms as: impairment of memory and
intellectual capability, headache and vertigo, tinnitus. Adjunctively in disorders of peripheral
circulation (intermittent claudication, pains in legs, acanthaesthesia)
7. (a) In age-linked impairment of memory and intellectual capability
EMA/HMPC/321095/2012
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(b) Adjunctively in cerebral circulation disorders with manifestations like vertigo and tinnitus
(c) Adjunctively in disorders of peripheral circulation with pain during walking or feeling of cold
hands and legs
8. Adjunctively in cerebral circulation disorders with such symptoms as vertigo and tinnitus;
adjunctively in disorders of peripheral circulation (feeling of cold hands and legs, dysaesthesia,
acanthaesthesia)
9. In disorders of peripheral circulation ; adjunctively in cerebral circulation disorders
10. In peripheral circulation disorders
Risks (adverse drug effects, lliteratrue):
Adverse drug reactions:
1. Very rarely gastrointestinal complaints (nausea, constipation, diarrhoea), headache,
hypersensitivity reactions (pruritus, erythema)
2. Bleeding, mild gastrointestinal complaints, headache, vertigo, allergic skin lesions
3. See 1.
4. Gastrointestinal complaints, headache, skin lesions
5. See 1.
6. Very rarely skin lesions (pruritus, erythema), gastrointestinal complaints, headache
7. See 1.
8. See 6.
9. See 4.
10. See 4.
Interactions:
1. Concomitant use with acetylsalicylic acid or antithrombotic medicines increases the risks of
haemorrhage
2. The medicinal product may enhance action of antithrombotic medicines
3. Concomitant use with acetylisalicylic acid, warfarin or thiazides is not recommended
4. Not indicated
5. See 3.
6. Concomitant use with warfarin is not recommended, in case of simultaneous use with
acetylsalicylic acid control of patient state is advised
7. See 1.
8. Possible interactions with anticoagulants, antiplatelet medicines, MAO inhibitors, thiazides,
trazodone, fluoxetine, buspirone, herbal drugs containing Hypericum perforatum, melatonin,
insulin, drugs metabolised by cytochrome P450 3A4
9. Possible interactions with antithrombotic medicines
10. Not indicated
Contraindications:
1.-8. + 9.-10.: Hypersensitivity to components of the medicinal product
Warnings:
1. Not indicated
2. The treatment should be stopped before planned surgery; patients with coagulation disorders
or using antithrombotic medicines should not use this medicinal product without medical
supervision; increase in frequency of epileptic seizures cannot be excluded
3. Not indicated
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4. Not indicated
5. Not indicated
6. The product is not recommended in case of patients showing predispositions to bleedings
7. See 6.
8. The product may cause prolongation of coagulation time
9. Linked to ethanol content
10. See 12.
Combination products with Ginkgo biloba and Allium sativum, Panax ginseng, diverse vitamins,
Aesculus hippocastanum, Crataegus monogyna and/or Crataegus laevigata, Viscum album, Arnica
Montana and Cynara scolymus exist in Poland.
Portugal: Well-established use

1. Ginkgo biloba standardised extract (EGb 761) containing 24% of ginkgo heterosides and 6% of
terpenes (ginkgolides, bilobalide)
pharmaceutical form
1989
tablets 40 mg
1 tablet 3 times daily
oral solution 40 mg/ml
1 ml 3 times daily
Indications:
Peripheral vascular disturbances arteriopathy of the legs and its trophic complications; distal
microcirculation disturbances (Raynaud). Brain vascular disturbances memory, affectivity, behaviour,
vertigo, headaches, and brain circulatory insufficiency; stroke sequels, migraine. Neurosensory and
otovestibular disturbances like hearing loss, tinnitus and vertigo.
There were pharmacovigilance actions taken on the medicinal product containing the herbal substance.
Romania: Well-established use

1. Dry extract standardised to 22-27% ginkgoflavonglycosides and 5-7% terpene lactones
(ginkgolides and bilobalide); extraction solvent: acetone/water; DER 35-67:1
Since when are the
pharmaceutical form
film-coated tablet, containing 40, 80
oral use; 120-240 mg
or 120 mg standardised extract
standardised extract per
capsule, containing 40 mg
day; min. 8-12 weeks
preparations on the market?

2001
standardised extract
oral solution, containing 40 mg/ml
standardised extract
Indications:
Symptoms associated with cerebral insufficiency, such as memory lost and depression; pathologic
cognitive deficiency in the elderly; peripheral arterial occlusive disease in Stage II (intermittent
claudication, Raynauds syndrome, acrocyanosis); neurosensory disorders of vascular origin (vertigo,
tinnitus, acuphenes)

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Risks:
Patients with known hypersensitivity to Ginkgo biloba preparations or to any of the excipients
The herbal substance is not on the market.
Ginkgo biloba dry extract comply with Ph. Eur. monograph 1827/2008
Spain: Well-established
1.
Tanakene
2.
Phar Eur monogr
3.
Phar Eur monogr
4.
Phar Eur monogr
pharmaceutical form
1. 1977
solution (4 g/100 ml)
1-1.5 ml 3 times daily
2. 1996
film-coated tablets 70 mg
3. 1994
4. 2003
Indications:
For all products: Symptomatic treatment of cerebrovascular and peripheral vascular disorders
Spain: Traditional use

pharmaceutical form
1. 1990
capsules 180 mg
2 capsules 3 times daily
2. 1992
tablets 460 mg
3. 1998
capsules 400 mg
1-2 capsules 3 times daily
Indications:
For all products: Vertigo, heavy legs, haemorrhoids
Sweden: Traditional use

1. Ginkgo biloba, dried leaf, dry extract (DER 30-40:1) acetone 60-65 %
2. Ginkgo biloba, dried leaf, dry extract (DER 35-67:1) acetone 60 %
EMA/HMPC/321095/2012
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Since when on the
pharmaceutical form
film-coated tablets
1 tablet (100 mg of extract per tablet)
market?
1. 2003, reclassified
to THMP 2012
1-2 times daily

capsules, hard
to THMP 2012
capsule) 2 times daily

film-coated tablets
to THMP 2012
1-2 tablets (50 mg of extract per

capsule) 2 times daily
oral solution
to THMP 2012
1 capsule (59.4 mg extract per
15-22.5 ml (1 ml contains 4.9 mg

extract) daily
film-coated tablets
to THMP 2012
1 tablet (38 mg of extract per tablet)

2-3 times daily
Indications:
For all products: Traditional herbal medicinal product for the treatment of long-standing symptoms in
elderly people such as difficulties of memory and concentration, vertigo, tinnitus and fatigue. Prior to
use other serious conditions should have been ruled out by a physician.
The indications are based solely on experience and use during a long period of time.
Risks:
Contraindications:
Hypersensitivity to the active substance
Special warnings and precautions for use:
The use in children and adolescents under 18 years of age is not recommended because of concerns
requiring medical advice.
If the symptoms worsen during the use of the medicinal product, a doctor or a pharmacist should be
consulted.
In patients with a pathologically increased bleeding tendency (haemorrhagic diathesis) and
concomitant anticoagulant treatment, the medicinal product should only be used after consultation
with a doctor.
Preparations containing ginkgo might increase susceptibility to bleeding, the medicinal product should
be discontinued as a precaution two weeks prior to surgery.
In patients with epilepsy, onset of further seizures promoted by intake of ginkgo preparations
cannot be excluded. It has been argued that this might be associated with the 4-O-methylpyridoxine
content.
Interactions:
The interaction potential of Ginkgo biloba has been investigated in several clinical studies. However,
[name of product] may not have been studied specifically and it is possible that [name of product] may
have a weaker or more pronounced interaction potential.
Ginkgo biloba containing products have in some studies been observed to give a modest induction of
drug metabolising enzymes, such as CYP3A4, CYP2C9 and CYP2C19. It cannot be excluded that other
co-regulated enzymes, such as UGTs (catalysing glucuronidation) may be induced as well. As induction
gives rise to increased synthesis of enzymes, the net result is mild to moderate decreases in the
plasma concentrations of the drugs metabolised by these enzymes. Induction is generally very variable
EMA/HMPC/321095/2012
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between individuals. The available study results are somewhat contradictory and it has also been
observed that CYP3A4 may be mildly inhibited, resulting in a reduced enzyme activity and increased
drug levels. As the observed inducing and inhibitory effects are quite small, this is likely not to be of
clinical relevance for most drugs, but it may, however, be relevant for drugs with a narrow therapeutic
index and in some patients.
Available studies with warfarin do not indicate that there is an interaction between warfarin and Ginkgo
biloba products, but adequate monitoring is advised when starting, when changing Ginkgo biloba dose,
when ending Ginkgo biloba intake or if changing product.
An interaction study with talinolol indicates that Ginkgo biloba may inhibit P-glycoprotein at the
intestinal level. This may give rise to increased exposure of drugs markedly affected by P-glycoprotein
in the intestine such as dabigatran etexilate. Caution is advised if combining G. biloba and dabigatran.
One interaction study has indicated that the C max of nifedipine may be increased by G. biloba. In some
individuals, increases by up to 100% were observed resulting in dizziness and increased severity of hot
flushes.
In theory, it cannot be excluded that the effectiveness of oral contraceptives may be slightly reduced in
certain individuals, why it is important to have a good compliance to the contraceptive dosing regimen.
Fertility, pregnancy and lactation:
The use should be avoided during pregnancy and lactation as there is isolated evidence to suggest that
preparations containing ginkgo can increase susceptibility to bleeding.
Undesirable effects:
Increased risk of bleeding*, palpitations, arrhythmia, restlessness, insomnia, headache, dizziness,
gastrointestinal complaints, exanthema, itching, and urticaria.
The frequencies of the adverse effects are not known.
*After longtime treatment with products containing Ginkgo biloba extracts, a few cases of bleeding
have been reported (no more details on the extracts given in the reports). However, in clinical studies
with standardised extracts, no effect on coagulation has been reported.
If other adverse reactions not mentioned above occur, a doctor or a pharmacist should be consulted.
There were pharmacovigilance actions taken on the medicinal product containing the herbal substance.
The following products have been registered according to a previous national registration scheme (so
called registered naturmedel):
Brandname 80 mg (30:1) 2x2, reg Naturmedel 1986
Brandname 40 mg (EGb 761) 1x2-3, reg Naturmedel 1988
Brandname 250 mg 1x3, reg Naturmedel 1989

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Slovenia: Well-established use

1. Ginkgo biloba leaf dry extract 35-67:1; quantified to flavonoids and terpene lactones
(ginkgolides, bilobalides); extraction solvent: acetone 60 % (m/m)
Since when on the
pharmaceutical form
hard capsule
oral use; 40 mg capsule 3 times daily;
containing 40 or 80 mg extract
80 mg capsule 2-3 times daily
market?
1998
Indications:
Treatment of symptoms of mild to moderate cerebral insufficiency and peripheral arterial occlusive
disease
Risks:
Adverse effects: gastrointestinal problems, headache and hypersensitive reactions
There were no pharmacovigilance actions taken on the medicinal product containing the herbal
substance.
Slovakia: Well-established use

1. Ginkgo biloba leaf dry extract; 40 mg standardised to 24% ginkgoflavonglycosides and 6%
ginkgolides and bilobalide
2. Ginkgo biloba leaf dry extract; 40/80/120 mg (35-67:1); 60% acetone (V/V); standardised to
22-27% ginkgoflavonglycosides, 5-7% terpene lactones of which 2.8-3.4% are ginkgolides A,
B and C and 2.6-3.2% bilobalide; content of ginkgolic acid is less than 5 ppm
3. Ginkgo biloba leaf dry extract; 40 mg standardised to 24% ginkgoflavonglycosides and 6%
ginkgolides and bilobalide
Since when on
pharmaceutical form
capsule, hard
40 mg 3 times daily
the market?
1. 1996

2. 2008
film-coated tablet
dementia syndromes: 120-240 mg daily
peripheral occlusive disorder of arteries, vertigo,

etc.: 120-160 mg daily
3. 1992
film-coated tablet, oral solution
40 mg 3 times daily

Indications:
1. Age related disorders of blood circulation in brain (problems with concentration, vertigo and
tinnitus). Initial disorders of blood perfusion in legs.
2. Symptomatic treatment of organic brain disorders in dementia syndromes. Vertigo of vascular
or involution origin. Adjuvant treatment of tinnitus of vascular or involution origin. Extension of

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length, that patient (state II of claudicatio intermittens according to Fontaine) is able to walk
over without pain.
3. Dementia syndromes. Claudicatio intermittens, Raynaud syndrome, increased capillary
fragility. Sensory disorders based on venous insufficiency hypacusis, vertigo, tinnitus.
Risks:
1. Gastrointestinal disorders, headache, allergic reactions on skin.
2. Gastrointestinal disorders, headache, allergic reactions on skin. Haemorrhage in combination
with NSAID.
3. Gastrointestinal disorders, headache, allergic reactions on skin. Palpitations, hypotension,
arrhythmias.
There were no pharmacovigilance actions taken on the medicinal product containing the herbal
substance.
Regulatory status overview

Member State
Regulatory Status
Comments
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify:
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Croatia
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify:
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:

EMA/HMPC/321095/2012
food supplements
food supplements
no products
Page 29/120
Member State
Regulatory Status
Comments
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
no products
MA: Marketing Authorisation

TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Other: If known, it should be specified or otherwise add Not Known
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the
MSs concerned.
1.3. Search and assessment methodology

Available literature on Ginkgo biloba at the Bundesinstitut fr Arzneimittel und Medizinprodukte
(BfArM) and the incoming, on the call for scientific data for use in HMPC assessment work on Ginkgo
biloba L., folium at October 27, 2011, was used for a literature search. For most current publications a
literature search in the DIMDI-database XMEDALL was performed. Articles were filtered by using the
following terms: Ginkgo biloba included in the title, year of publication between 2004 and 2012,
Language in English or German and concerning humans. The search was performed at February 22,
2012. Further relevant literature published until time of public consultation has been taken into
account.
Only articles found to be relevant for assessment are included in the list of references.
2. Historical data on medicinal use

2.1. Information on period of medicinal use in the Community
According to the information specified above the most frequent authorised herbal preparation on
Ginkgo biloba leaves with well-established use is the refined and quantified dry extract (EGb 761)
with a DER of 35-67:1 and acetone 60% as extraction solvent. Most clinical trials were conducted with
the special extract of Ginkgo biloba leaf (EGb 761); therefore a well-established use could be proved.
Based on the data provided by the National Competent Authorities, other Ginkgo biloba leaf products
have a traditional use.
-
Powdered herbal substance
Ginkgo biloba leaf tincture (1:5); extraction solvent ethanol 60% (V/V)
Ginkgo biloba leaf dry extract, refined (39.6-49.5:1), containing 22.0-27.0% of flavonoids
extraction solvent: Ethanol 50% (V/V)
The tincture of Ginkgo biloba leaves is less then 30 years on the market and consequently the above
mentioned products can not be considered for the monograph because a tradition could not be proved.

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For a herbal preparation reported to be marketed in Poland (Ginkgo biloba leaf dry extract, refined
(39.6-49.5:1), containing 22.0-27.0% of flavonoids expressed as flavone glycosides, 2.8-3.4% of
ginkgolides A, B and C, 2.6-3.2% of bilobalide; extraction solvent: Ethanol 50% (V/V)) the tradition for
30 years was not regarded to be established initially the extract was not refined, further steps were
introduced during 80ies and 90ies in order to achieve quantification and the composition of the
relevant preparation changed.
2.2. Information on traditional/current indications and specified

substances/preparations
For the traditional powdered herbal substance the wording of the indication was discussed. The
agreement is as follows: Traditional herbal medicinal product for the relief of heaviness of legs and
the sensation of cold hands and feet associated with minor circulatory disorders, after serious
conditions have been excluded by a medical doctor. The use for vertigo and haemorrhoids does not
seem to be supported in France anymore, from the preliminary results of an ongoing re-evaluation.
Blaschek et al. (2011) describes that Ginkgo biloba leaves are used in traditional Chinese medicine
(TCM) for the treatment of asthma, hypertension, tinnitus and angina pectoris and in France for
chronic venous insufficiency.
The monograph of the commission E (1994) approved in Germany the use of undefined Ginkgo
biloba leaf preparations for disturbed arterial and cerebral blood flow, vertigo, improvement of blood
circulation and strengthening of the vessel system, particularly of the veins, as circulation stimulating
and exonerative agent and as psychotropic drug and neurotropic drug. The efficacy of the
preparations in the mentioned indications has not been proved.
The corresponding monograph on the refined and quantified extract of Ginkgo biloba leaves (DER 3567:1) described the use for the symptomatic treatment of brain-related impairment of mental
performance, as part of an overall therapeutic strategy in dementia syndromes with the following main
symptoms: memory deficit, disturbance in concentration, depressive mood, dizziness, tinnitus, and
headache. The main target group includes patients with dementia syndrome, presenting with primary
degenerative dementia, vascular dementia or mixed forms of both. Furthermore, it is used for
improving pain-free walking distance in patients with Fontaine Stage II peripheral arterial occlusive
disease (intermittent claudication), as part of physiotherapy, including gait training, for vertigo and for
tinnitus of vascular and involutive origin.
The ESCOP monograph (2003) described the use of Ginkgo biloba leaf for the symptomatic
treatment of: mild to moderate dementia syndromes including primary degenerative dementia,
vascular dementia and mixed forms; cerebral insufficiency; for neurosensory disturbances such as
dizziness/vertigo and tinnitus; for enhancement of cognitive performance; and for symptomatic
treatment of peripheral arterial occlusive disease (intermittent claudication).
The British Herbal Compendium (Bradley 2006) listed the following indications for Ginkgo biloba leaf:
Symptomatic treatment of mild to moderate dementia including primary degenerative dementia of the
Alzheimer type, multi-infarct dementia and mixed forms; treatment of symptoms, attributed to
impaired cerebral blood flow and loosely described as cerebral insufficiency, such as difficulties of
concentration and memory, confusion, lack of energy and initiative, depressive mood and anxiety;
enhancement of cognitive performance in healthy individuals; neurosensory disturbances such as
vertigo and certain types of visual dysfunction; conclusions regarding the efficacy of ginkgo in tinnitus
are conflicting; a recent meta-analysis of controlled studies revealed no significant benefit; and
symptomatic treatment of peripheral arterial occlusive disease (intermittent claudication).

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WHO monograph (1999) referred to the Commission E monograph on refined and quantified extract
of Ginkgo biloba leaves.
DeFeudis (1998) reported that the internal use of Ginkgo biloba leaves for medical purposes was first
mentioned by Liu Wen-Tai in the Ben Cao Pin Hue Jing Yaor (1505 A.D). In modern Chinese
pharmacopoeias Ginkgo biloba is used for treating dysfunctions of the heart and lungs. The leaves are
prescribed for atherosclerosis, angina pectoris, high serum cholesterol levels, dysentery and filariasis
as they improve blood circulation, benefit the brain, and are astringent to the lungs.
2.3. Specified strength/posology/route of administration/duration of use

for relevant preparations and indications
See section 1.2.
For the powdered herbal substance the recommended duration of use was discussed and agreed to be
for 2 weeks, in line with the duration agreed for Melilotus (and generally accepted for OTC drugs). The
duration of use agreed for Vitis (4 weeks) was based on clinical data, available for the preparations
concerned.
3. Non-Clinical Data
Many pharmacological studies have demonstrated that Ginkgo biloba extracts and its constituents
display many properties in vivo and in vitro. A systematic review of all these studies was not
attempted here, rather a selection of studies with emphasis on studies with relevance for the clinical
efficacy were reviewed (for a more extensive review, see Yoshikawa et al. (1999), Chan et al.
(2007), McKenna et al. (2001) and DeFeudis (1998)). Further findings from pharmacological and
pharmacokinetic studies on humans are available and are discussed in section 4.1.
Yoshikawa (1999) reported the following pharmacological effects of Ginkgo biloba:
An antioxidant action as a free radical scavenger
Relaxing effect on vascular walls
An antagonistic action on platelet-activating factor (PAF)
Improvement of blood flow or microcirculation
Stimulating effect on neurotransmitters
DeFeudis (1998):
Actions on the central nervous system
Effects on behaviour, learning and memory, and recovery from traumatic brain injury
Stress-alleviating action
Actions on neurosensory systems
Actions on the cardiovascular system
Actions on transmembrane ion channels, ionic shifts, and electrical activity of single cells
Actions on formed elements of the blood
Actions on other organs, tissues and cells

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Free radical-scavenging, antioxidant, and related mechanisms of action
3.1. Overview of available pharmacological data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof
The flavones glycosides and the terpene lactones (ginkgolide A, B, C and bilobalide) are considered as
the relevant constituents for pharmacological effects in Ginkgo biloba leaf preparations. Most
pharmacological studies have been performed using a refined and quantified dry extract of Ginkgo
biloba leaf (EGb 761). Investigations conducted with other Ginkgo biloba leaf preparations are stated
explicitly.
3.1.1. Primary pharmacodynamic

Antioxidant action
McKenna et al. (2001) reviewed an article were cultured rat primary mixed hippocampal cells
exposed to reactive oxygen species generated by nitric oxide inducers were completely protected from
an accumulation of free radicals and decreased cell survival from co-treatment with either EGb 761
(10-100 g/ml) or the flavonoids fraction of EGb 761 (25 g/ml), but not from co-treatment with the
terpene lactone constituents.
Improvement of blood flow or microcirculation
Winter (1998) investigated the effects of chronic administration of EGb 761 on brain function in the
rat. At approximately 2 months of age, treatment with either EGb 761 (n=10) or vehicle (n=20) was
begun and continued five times per week for the life of the subjects who were tested in a radial maze
throughout this period. For the first 24 months, EGb 761 rats drank 3 ml solution containing a dose of
50 mg/kg of EGb 761 (HED=8 mg/kg, which corresponds to 480 mg per single dose in a 60 kg human
being) in sweetened condensed milk diluted 2:1 in tap water. Control rats drank 3 ml of sweetened
condensed milk diluted 2:1 with tap water. Subjects were tested in an eight-arm radial maze for
continuous learning and delayed nonmatching to position. Chronic postsession administration of
EGb 761 at a dose of 50 mg/kg had no effect on continuous learning but the same dose given
presession resulted in fewer sessions to reach criterion performance as well as fewer errors. In
addition, chronically EGb 761-treated rats lived significantly longer than vehicle-treated subjects. In a
delayed nonmatching to position task using a 30-min delay in 20-month-old rats, EGb 761
administered presession produced a dose-related decrease in total, retroactive, and proactive errors in
a delayed nonmatching to position task. At the age of 26 months the group was divided in two with
half receiving 200 mg/kg EGb 761 (HED=32 mg/kg, which corresponds to 1920 mg per single dose for
a 60 kg human being) presession and the other half vehicle. A statistically significant positive effect of
treatment with EGb 761 was observed.
Lin et al. (2003) investigated the effect of EGb 761 and a native ginkgo leaf extract (made in China
from native ginkgo leaves by the Soxhlet extraction method with 95% of ethanol) on the memory
motor functions of rats with chronic cerebral insufficiency (produced by bilateral common carotid artery
ligation). The animals were divided into 4 groups. Rats in group 1, 2 and 3 received bilateral common
carotid artery ligation. The animals in group 1 were fed with the Chinese ginkgo leaf extract
(25 mg/kg, n=6) and the animals in group 2 were fed with EGb 761 (25 mg/kg, n=6). The HED of the
administered dose is 4 mg/kg, which complies with 240 mg/kg per single dose for a 60 kg human
being. Ginkgo leaf extract, solved in the drinking water, was given orally with syringes once daily after
operation. The rats in group 3 did not receive ginkgo leaf extract (n=6). Group 4 was the sham
operation group, which received neither bilateral common carotid artery ligation (operation was
performed in the same way, except that the common carotid arteries were exposed but not ligated)
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nor ginkgo leaf extract (n=4). After the operation memory and motor functions were tested for over 80
days. Spatial memory was tested with an 8-arm radial maze test and motor function was tested using
two parameters (locomotor activity and the muscle force of the hind limbs). The results indicate that
both Ginkgo biloba extracts improved spatial memory from the second week after operation, but only
EGb 761 delayed deterioration of motor functions from the fifth week after operation.
Li et al. (2003) investigated hippocampal neuron survival/growth and gene expression after prenatal
exposure of rats to EGb 761. Pregnant rats received orally administered EGb 761 (100 or
300 mg/kg/day) for 5 days (HED=16 or 48 mg/kg, which correspond to 960 or 2880 mg per single
dose in a 60 kg human being). The number of hippocampal neurons of their fetuses increased.
Moreover, it was shown that treatment of pregnant rats with EGb 761 (25, 50 or 100 mg/kg/day for 5
days) altered the expression of 187 genes in the hippocampi of male fetuses and 160 genes in those of
female fetuses. Using gene-cluster analysis, these genes were grouped into 18 distinct clusters for
males and 17 distinct clusters for females. Among these clusters, 35 genes shared a common
expression pattern in male and female hippocampal development. Of these genes, changes were
confirmed by quantitative real-time polymerase chain reaction (PCR) for genes that are mainly
involved in neuronal development, maturation and repair. These molecular and genetic results indicate
that EGb 761 increase neuronal survival and alter the expression of specific genes in the developing
hippocampus.
In the review by Chan et al. (2007) it is stated that Ginkgo biloba leave extract can protect against
the effects of neural damage. It is unclear whether the neuroprotection is from a direct action on the
neurons or from an indirect effect from modulation of blood flow and antioxidant action. When Ginkgo
biloba leave extract was injected (no route of administration or concentration is stated in the review)
into rats after global forebrain ischemia, local cerebral blood flow was significantly elevated.
Furthermore, Ginkgo biloba leaf extract can improve blood flow by increasing red blood cell
deformability and decreasing red cell aggregation, and thus, improves red blood cell fluidity and
decreases whole blood viscosity (no route of administration or concentration is stated in the review).
Inhibitory action on PAF
Koch (2005) confirmed the results of Akiba et al. (1998) principally in a more recent study. The PAFantagonistic activities of individual ginkgolides and EGb 761 were evaluated in rabbit platelets. PAFmediated aggregation of human platelets was half-maximally inhibited (IC 50 ) by ginkgolide A, B, C and
EGb 761 at concentrations of 13.7, 1.6, 33.2 M and 23.2 g/ml, respectively. Of the ginkgolides
tested, ginkgolide B exerted by far the most powerful antagonistic effect.
Akiba et al. (1998) investigated the effect of Ginkgo biloba leaf extract on rabbit platelet
aggregation. Purified ginkgolide A, B and C, which are known to be potent platelet-activating factor
(PAF) receptor-antagonists, apparently inhibited PAF-induced platelet aggregation, but not oxidantinduced aggregation. An extract of Ginkgo biloba leaves (24% flavonol glycosides and 6% terpene
lactones (2.4% bilobalide and 2, 0.8, and 1% ginkgolides A, B, and C, respectively)) also inhibited
PAF-induced platelet aggregation. The IC 50 for ginkgolide A, B, C and the extract were determined to
be 1.8, 0.5, 32 M and 31 g/ml, respectively.
3.1.2. Secondary pharmacodynamic

In the review by DeFeudis et al. (2003) it was stated that recent studies conducted with various
molecular, cellular and whole animal models have revealed that leaf extracts of Ginkgo biloba may
have anticancer properties that are related to their antioxidant, anti-angiogenic and gene-regulatory
actions. The antioxidant and associated anti-lipoperoxidative effects of ginkgo extracts appear to
involve both their flavonol glycoside and terpene lactone constituents. The anti-angiogenic activity of
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the extract may involve their antioxidant activity and their ability to inhibit both inducible and
endothelial forms of nitric oxide synthase. Flavonol glycoside and terpene lactone constituents of
ginkgo extracts may act in a complementary manner to inhibit several carcinogenesis-related
processes, and therefore the total extracts may be required for producing optimal effects.
3.1.3. Safety pharmacology

In vitro studies
Auguet et al. (1982a) EGb 761 (100 g/ml) that did not provoke contractions of rabbit aorta,
potentiated the contractile effect of norepinephrine (EC 50 from 75 to 36 nM), but had no obvious action
on the contractile effects of serotonin and dopamine. These results indicate that low concentrations of
EGb 761 might influence catecholaminergic systems by an indirect mechanism.
Auguet et al. (1982b) showed that in rabbit isolated aorta EGb 761 induced a concentrationdependent contractile response with an EC 50 of about 1.0 mg/ml. This action was antagonised by
phentolamine. Inhibitors of catecholamine re-uptake, cocaine and desipramine inhibited the contractile
effect of EGb 761. Using aortic strips prepared from reserpine-treated (resperine alleviate
catecholamine availability) rabbits decreased the response to EGb 761. This indicates that the
contractile action of EGb 761 on the rabbit aorta is mediated, at least in part, by release of
catecholamines from endogenous tissue stores.
Hellegouarch et al. (1985) showed that EGb 761 elicited in a dose-related manner contractions in
stripes of rabbit isolated vena cava with an EC 50 of about 86 g/ml. Phenoxybenzamine, which is an adrenoceptor blocker, blocked the effect of EGb 761 by about 50%.
Peter et al. (1966) Spasms of isolated guinea pig ileum were induced by histamine and barium
chloride. The spasmolytic effect induced by histamine was abolished with 12 and 40 g/15ml (=0.8
and 2.7 g/ml) Ginkgo biloba flavonoid preparation to 50 and 100%, respectively. The same effect was
observed with 120 g/15 ml (=8 g/ml) kaempferol and 200 g/15 ml (=13 g/ml) quercetin.
Induction of spasms by barium chloride showed the same results, indicating a direct action on the
muscle that is supposed to be responsible for vasodilatation.
Vilain et al. (1982) studied in more detail the effects of EGb 761 on isolated guinea pig ileum. At a
concentration of 50 g/ml, EGb 761 was either inactive, or produced a slight relaxation. At 100 g/ml
a distinct relaxation was produced, and at 200 g/ml this relaxation phase was followed by a slight
contraction. A biphasic effect, a pronounced relaxation followed by a pronounced contraction, was most
evident with 400 g/ml of EGb 761. With a concentration of 1 mg/ml of EGb 761 the duration of the
relaxation phase was decreased while the contraction phase was maintained, and at 3 mg/ml the
relaxation phase was practically non-existent while contraction was maintained. Droperidol prolonged
the relaxation produced by EGb 761 and cyproheptadine and diphenhydramine usually prolonged the
duration of the relaxation and decreased the amplitude of the contraction. Phentolamine,
hexamethonium, picrotoxin, methysergide and cimetidine did not affect the response of the ileum to
EGb 761.
In vivo studies
Peter et al. (1966) examined further the influence of Ginkgo biloba flavonoid preparation (diluted in
Cremophor EL and intra-arterial injected) on blood pressure in cats, rabbits, rats and guinea pigs.
Cats received consecutively in approx. 15-20 min interval 330 g/kg, 1 mg/kg, and 3.3 mg/kg
flavonoid preparation per 0.5 ml solution/kg with 1 ml/min. There were no changes in blood pressure

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or breathing rate. Heart rate was increased by 9% at the high dose. Analogue to these results, no
effects on blood pressure, heart and breathing frequency were gained in rabbits.
Oppositional results were observed in rats and guinea pigs. In rats, at the low (330 g/kg) and high
dose (3.3 mg/kg) blood pressure increased by 6 and 28%, respectively for about 13 min with a low
rise of heart rate (7%) and a more pronounced rise in breathing rate (13 and 10%, respectively). In
guinea pigs, an initial short increase on blood pressure (7%) at the low dose was observed followed by
a decrease of 23% for 11 min. Heart rate dropped by 11% and breathing rate increased by 56%. A 10fold higher dose caused at first increase in blood pressure (48%) for 3 min and a subsequent decrease
of 21% for about 13 min. This was accompanied by reduction in heart rate of 16% for 15 min and a
rise in breathing rate of 48%. The increase in breathing rate was affected by intravenous injection
itself and not by the specific effect of the ginkgo preparation. This was shown in control experiments
with the same amount of physiological sodium chloride solution.
Experiments with only Cremophor EL resulted in a rise of blood pressure (between 20 and 50%), heart
frequency (8%) and breathing rate (100%).
Brunello et al. (1985) Oral treatment of rats with EGb 761 (100 mg/kg/day, p.o., HED for a 60 kg
human=968 mg/day) elicited a biphasic effect on the norepinephrine metabolite normetanephrine
(NMN) content in the cerebral cortex: An initial decrease was evident after 45 min. followed by a
marked increase that was evident after 14 days. Chronic treatment with EGb 761 reduced the density
of -adrenoceptor (no subtype specified) binding to cerebral cortex and -adrenergic-stimulated
adenylate cyclase activity after 2 months. Thus, an increase in norepinephrine levels is inducing adrenergic receptor regulation and functional activity.
Kehr et al. (2012) The effect of repeated oral administration of EGb 761 and some of its
characteristic constituents on extracellular levels of dopamine (DA), noradrenaline (NA), serotonin (5HT), acetylcholine (ACh) and the metabolites 3,4- dihydroxyphenylacetic acid (DOPAC), homovanillic
acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the medial prefrontal cortex (mPFC) of awake
rats was investigated by use of in vivo microdialysis technique. Subacute (14 days, once daily), but not
acute, oral treatment with EGb 761 (100 and 300 mg/kg) or the flavonoid fraction, which represents
about 24% of the whole extract caused a significant and dose-dependent increase in extracellular DA
levels in the mPFC. Repeated administration of EGb 761 also caused a modest but significant increase
in the NA levels, whereas the concentrations of 5-HT and those of the metabolites DOPAC, HVA and 5HIAA were not affected. The same treatment regimen was used in a subsequent study with the aim of
investigating the effects of two Ginkgo-specific acylated flavonols, 3-O- (2-O-(6-O-(p-hydroxytrans-cinnamoyl)--D-glucosyl)--L-rhamnosyl)quercetin (Q-ag) and 3-O-(2- O-(6-O-(p-hydroxytrans-cinnamoyl)--D-glucosyl)--L-rhamnosyl)kaempferol (K-ag). Both compounds together represent
about 4.5% of the whole extract. Repeated oral treatment with Q-ag (10 mg/kg) for 14 days caused a
significant increase in extracellular DA levels of 159% and extracellular acetylcholine (ACh) levels of
151% compared to controls. Similarly, administration of K-ag (10 mg/kg) induced a significant rise of
DA levels to 142% and ACh levels to 165% of controls, whereas treatment with isorhamnetin, an Omethylated aglycon component of EGb 761 flavonol glycosides had no effect. None of the tested
flavonoids had a significant effect on extracellular DOPAC and HVA levels. The effect on
neurotransmitter levels seems not to be a general effect of flavonols but rather to be a specific action
of acylated flavonol glycosides which are present in EGb 761. The direct involvement of these two
flavonol derivatives in the increase of dopaminergic and cholinergic neurotransmission in the prefrontal
cortex may be one of the underlying mechanisms behind the reported effects of EGb 761 on the
improvement of cognitive function.

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3.1.4. Pharmacodynamic interactions

No specific data on pharmacodynamic interactions in animals are reported, as there are various clinical
data on this topic.
3.2. Overview of available pharmacokinetic data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof
The whole Ginkgo biloba leaf extract represents the active substance. Because the extract consists of a
lot of constituents (known only in part), pharmacokinetic studies can only apply to certain constituents.
The quantified constituents of the Ginkgo extract are the following: flavonoid glycosides, ginkgolides A,
B and C, and bilobalide. The extract contains less than 5 ppm ginkgolic acids.
3.2.1. Absorption
Moreau et al. (1986) studied the absorption of radiolabelled
plants grow under supply of
14
14
C EGb 761 in rats. They let Ginkgo
C-acetate. The absorption of the radiolabelled EGb 761 was estimated to
be at least 60%. A site of absorption in the upper gastrointestinal tract is suspected since specific
radioactivity in blood peaked after 1.5 hours.
3.2.2. Distribution
Moreau et al. (1986) further analysed the distribution of radiolabelled EGb 761. The
pharmacokinetics of the extract, based on blood specific activity data versus time course, were
characteristic of a two-compartment model with an apparent first order phase and a biological half-life
of approximately 4.5 hours. During the first 3 hours, radioactivity was preliminary associated with the
plasma, but through a gradual uptake after 48 hours. The specific activity in erythrocytes matched that
of plasma. Glandular and neuronal tissues and eyes showed a high affinity for the labelled substance.
3.2.3. Metabolism
Chatterjee et al. (2005) investigated the effects of EGb 761 on hepatic CYP450 in rats (no subtypes
mentioned). Oral administration of EGb 761 (100 mg/kg/day, HED for a 60 kg human=968 mg/day)
for 4 days strongly increased liver CYP450 content and altered the ex-vivo biotransformation of
androstendione, as well as metabolism of endogenous steroids. However, no effect on the urinary
steroid profile was observed in man after intake of 240 mg/day EGb 761 for 28 days. In view of these
results, the authors concluded that the effects of EGb 761 on drug metabolism enzymes are specific for
rats and may not be extrapolated to man.
Gaudineau et al. (2004): The following study was conducted to examine the inhibition of CYP1A2,
CYP2C9, CYP2D6, CYP2E1, and CYP3A4 by EGb 761 and its constituents. As a general observation,
EGb 761 inhibited all the P450s studied except CYP2D6 (K i >900 g/ml). The activity of CYP2C9 was
the most affected by EGb 761 (K i =144 g/ml). CYP1A2 (10624 g/ml), CYP2E1 (12742 g/ml),
and CYP3A4 (15543 g/ml) were also inhibited but to a lesser extent. The terpenoidic fraction
inhibited only CYP2C9 (K i =156 g/ml) whereas the flavonoidic fraction of EGb 761 showed high
inhibition of CYP2C9, CYP1A2, CYP2E1, and CYP3A4 (K i s between 4.9 and 55 g/ml).
Von Moltke et al. (2004): The in vitro study was used to determine whether any of 29 constituents
of Ginkgo biloba can be considered as potentially important inhibitors of any of the five major CYP
isoforms in human liver microsomes. Significant inhibitory activity was observed for the flavonol
aglycones (kaempferol, quercetin, apigenin, 4-OH-methyl apigenin, myricetin, tamarixetin), which

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yielded IC 50 values for CYP1A2 or CYP3A of less than 10 g/ml. Quercetin was also a strong inhibitor of
CYP2C9 (IC 50 =7.8 g/ml, 25.8 M), as was myricetin for CYP2D6 (IC 50 =9.6 g/ml, 30.2 M). An
inhibitory effect on CYP2C9 and CYP3A was also observed for amentoflavone, sesamin, (Z,Z)-4,4(1,4-pentadiene-1,5-diyl)diphenol and 3-nonadec-8-enyl-benzene-1,2-diol. The principal components
of Ginkgo biloba (terpene lactones and flavonol glycosides) showed no significant inhibition of these
human CYPs in vitro. It was concluded that a number of flavonol aglycones, as well as the biflavonol
amentoflavone, are inhibitors of several human CYP isoforms in vitro. Inhibition of CYP2C9 is of
potential concern, since this enzyme is responsible for clearance of some drugs (such as S-warfarin)
that have narrow therapeutic ranges in clinical practice. The importance of the in vitro findings requires
evaluation in clinical studies.
3.2.4. Elimination
Moreau et al. (1986) examined beside the absorption and distribution also the elimination of
radiolabelled EGb 761. Three hours after oral administration of the extract to rats expired
14
C-CO 2
represented 16% of the administered dose and 38% after 72 hours. Further 21% were eliminated in
the urine and 29% in faeces.
3.2.5. Pharmacokinetic interactions with other medicinal products

Ohnishi et al. (2003) examined the effects of a Ginkgo biloba leaf extract on the pharmacokinetics of
diltiazem, a substrate for CYP3A in rats. Ginkgo biloba leaf extract was manufactured in Japan and
contained over 24% flavonol glycosides and 6% terpene lactones and less than 1 ppm ginkgolic acids.
It contained 1.8% ginkgolide A, 0.85% ginkgolide B, 1.09% ginkgolide C and 2.32% bilobalide. The
addition of ginkgo extract to small intestine and liver microsomes inhibited the formation of Ndemethyl-diltiazem, a metabolite of diltiazem produced by CYP3A4, in a concentration-dependent
manner in vitro, with an IC 50 of about 50 and 182 g/ml, respectively. A single oral administration of
20 mg/kg (HED=194 mg per single dose) ginkgo extract decreased transiently both, the rate of
formation of this metabolite and total amount of CYP in intestinal or hepatic microsomes. Pretreatment
with ginkgo extract significantly decreased the terminal elimination rate constant and increased the
mean residence time after 3 mg/kg intravenous applied diltiazem. The authors concluded that these
results indicated that the concomitant use of Ginkgo biloba leaf extract in rats increased the
bioavailability of diltiazem by inhibiting both intestinal and hepatic metabolism, at least in part, via a
mechanism-based inhibition of CYP3A.
Yoshioka et al. (2004a) studied the ability of Ginkgo biloba leaf extract to influence the
pharmacokinetics of nifedipine, a substrate of CYP3A, in rats. Oral treatment with 20 mg/kg
(HED=194 mg per single dose) Ginkgo biloba leaf extract with simultaneous intravenous administration
of 2.5 mg/kg nifedipine did not affect pharmacokinetic parameters. However, maximum plasma
nifedipine concentration, the area under the concentration-time curve and absolute bioavailability after
oral administration of 5 mg/kg nifedipine were significantly reduced by simultaneous oral treatment
with Ginkgo biloba leaf extract. The conclusion of the authors is that these results suggest that the
concomitant oral use of Ginkgo biloba leaf extract appeared to reduce the first-pass metabolism of
orally administered nifedipine by inhibiting CYP3A in rats.
Hellum et al. (2008) investigated Ginkgo biloba (solubilised in ethanol) for its in vitro inhibitory
potential of CYP3A4 mediated metabolism and P-glycoptrotein (P-gp) efflux transport activity. C-DNA
baculovirus expressed CYP3A4 and Caco-2 cells were used. Ketoconazole and verapamil were applied
as positive control inhibitors, respectively. A validated HPLC methodology was used to quantify the
formation of 6-OH-testosterone and scintillation counting was used to quantify the transport of 3Hdigoxin (digoxin is a recommended and established substrate for P-gp transport experiments in Caco-2
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cells). Ginkgo biloba inhibited CYP3A4 activity (IC 50 value of 66866 g/ml) and P-gp activity (IC 50
value of 23.6 g/ml). The low IC 50 value for Ginkgo biloba may indicate an inhibition of P-gp in the
small intestine in vivo.
3.3. Overview of available toxicological data regarding the herbal

substance(s)/herbal preparation(s) and constituents thereof
In crude Ginkgo extracts a group of alkylphenols (e.g. ginkgolic acids, ginkgol, bilobol) has been
described to exhibit potential contact allergenic and toxic properties. A maximum concentration of
5 ppm has to be maintained to comply with the Ph. Eur. and to ensure safety of use for Ginkgo biloba
leaf extracts.
3.3.1. Single dose toxicity

Ginkgo biloba extract
DeFeudis (1998) reports of acute toxicity data. Therefore, the LD 50 values in mice are 7.73, 1.1 and
1.9 g/kg by oral, i.v. and i.p. administration of EGb 761, respectively. LD 50 values for rats are
comparable with 1.1 and 2.1 g/kg by i.v. and i.p. EGb 761 administration. Acute toxicity of orally
administered EGb 761 in the rat was not determinable because the extract showed until a dose of
10 g/kg no lethal effects. Higher doses could not be administered.
Isolated compounds
Leistner and Drewke (2010) reviewed recent experiences with Ginkgo biloba and its derived
products with a view to ginkgotoxin. Known from reported cases of intoxication, at sublethal doses,
symptoms of poisoning are eleptiformic seizures, unconsciousness, and paralysis of the legs. A dosage
of 11 mg/kg of the isolated ginkgotoxin triggered seizures in guinea pigs. Administration of 30 to
50 mg/kg ip was followed by atrioventricular block or ventricular fibrillation and death of the animals.
An LD 50 of ca. 30 mg/kg ip was determined for a rabbit. A higher dose of 400 to 600 mg/kg ip was
needed to elicit convulsions in rats. Ginkgotoxin is a constituent of Ginkgo biloba seeds and leaves.
Accordingly, extracts derived from dried Ginkgo biloba leaves contain ginkgotoxin. A HPLC analysis
revealed that different allopathic medications offered by various companies contain between 11.4 and
58.62 g of ginkgotoxin in a recommended maximum daily dose (120-240 mg). The presence of
ginkgotoxin in Ginkgo biloba products raises the question if this could cause any undesirable health
effects such as seizures. Assuming in a worst case scenario that all ginkgotoxin (58.6 g) taken up by
one daily dose ends up in the blood serum, a concentration of ginkgotoxin in human plasma of 53 to
80 nM calculated for 6 or 4 L of blood, respectively, would result. This is on the same order of
magnitude as vitamin B 6 levels in blood plasma, which are reported to be 114 nM. At present it cannot
be ruled out that Ginkgo biloba medicinal products may lower the threshold for seizures in epileptic
patients.
Liu and Zeng (2009) investigated the cytotoxicity of ginkgolic acid (15:1, prepared in own laboratory
and determined by the LC-MS method, purity >99%) using in vitro bioassay systems. First,
cytochrome P450 enzymes involved in ginkgolic acid metabolism were investigated in rat liver
microsomes. Then, two in vitro cell-based assay systems, primary rat hepatocytes and human
hepatoma cells HepG2, were used to study and the measurement of MTT reduction was used to assess
cell viability. Results indicated that the cytotoxicity of ginkgolic acid in primary rat hepatocytes was
lower than in HepG2 cells. Ginkgolic acid was demonstrated less cytotoxicity in four-day-cultured
primary rat hepatocytes than in 20-hour cultured ones. Co-incubation with selective CYP inhibitors, naphthoflavone and ketoconazole, could decrease the cytotoxicity of ginkgolic acid in primary rat
hepatocytes. Consequentially, pretreament with selective CYP inducers, -naphthoflavone and
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rifampin, could increase the cytotoxicity of ginkgolic acid in HepG2 cells. These results suggest that
HepG2 cells were more sensitive to the cytotoxicity of ginkgolic acid than primary rat hepatocytes, and
CYP1A and CYP3A could metabolise ginkgolic acid to more toxic compounds.
3.3.2. Repeated dose toxicity

Ginkgo biloba extract
Salvador (1995) reported of no chronic toxicity. There was no evidence of organ damage or
impairment of hepatic and renal functions when EGb 761 was administered orally to rats and mice over
a period of 27 weeks in doses ranging from 100 to 1,600 mg/kg.
DeFeudis (1998) stated that chronic toxicity studies in the rat (27 weeks) and dog (26 weeks),
conducted with EGb 761 doses of 20 and 100 mg/kg/day initially and then gradually increased to 300,
then 400 and 500 mg/kg/day in rats and to 300, then 400 mg/kg/day in dogs, showed no evidence of
organ damage and no impairment of hepatic or renal function.
Isolated compounds
Hecker et al. (2002): The cytotoxic potential of ginkgolic acids was assessed in this in vitro study.
Test subjects were the human keratinocyte cell line HaCaT and the rhesus monkey kidney tubular
epithelial cell line LLC-MK 2 . The influence of a defined mixture of ginkgolic acids on cell growth,
viability, integrity and morphology was investigated in more detail. EGb 761, which contains less than
5 ppm ginkgolic acids, was used as reference substance. The results confirm, that ginkgolic acids,
which are basically removed during production of the standardised extract EGb 761, carry a
considerable cytotoxic potential. As shown by the neutral red uptake assay, ginkgolic acids strongly
reduce the number of viable cells, whereas EGb 761 displayed a much lower activity in this test
system. The IC 50 values in HaCaT and LLC-MK 2 cells after incubation with EGb 761 were 889 mg/l and
1481 mg/l, respectively. For the test mixture the IC 50 concentrations in HaCaT and LLC-MK 2 cells were
22 mg/l and 4.6 mg/l, respectively. A concentration dependent release of LDH was observed when cells
were incubated in the presence of ginkgolic acids (1-100 mg/l). In contrast, even at a concentration of
1800 mg/l EGb 761 did not cause release of LDH above controls. Since ginkgolic acids interacted with
the assay for acid phosphatise (ACP), no index of lysosomal damage could be established by this
method. Incubation of HaCaT cells with ginkgolic acids for 18 h increased the proportion of apoptotic
cells from about 6% (control) to nearly 80% at concentrations of 30 mg/l. Electron microscopic
analysis of HaCaT cells revealed a drug induced formation of myelinosomes possibly due to the
inhibition of lysosomal enzymes, while morphological evaluation of LLC-MK2 cells indicated that the
cytotoxic activity of ginkgolic acids in these cells is primarily mediated by transformation of
mitochondria, which is probably induced by uncoupling of oxidative phosphorylation.
3.3.3. Genotoxicity
A Ginkgo biloba leaf extract was tested positive for gene mutations in bacteria and equivocal and
negative for chromosome mutations in two separate in vivo tests in peripheral erythrocytes and bone
marrow cells in mouse. ( NTP Technical report 578, 2013)
3.3.4. Carcinogenicity
Major findings from NTP report:
NTP Technical report 578 (2013) has tested a Gingko biloba leaf extract for carcinogenesis in two year
studies in rats and mice.

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Summarising the major findings of the NTP Technical report, rodents dosed with Ginkgo biloba extract
showed increased rates of a variety of lesions in the liver, thyroid gland, and nose. These lesions
included hypertrophy in the liver and thyroid gland in rats and mice, liver hyperplasia in male and
female rats, hyperplasia and atrophy of the epithelium in the nose of male and female rats.
Increased incidences of cancers of the thyroid gland were seen in female rats and liver cancers in male
and female mice.
Mononuclear cell leukemia was observed in male rats at 300 and 1000 mg/kg. The increased incidence
of mononuclear cell leukemia in rats is probably a background finding, as this strain of rats has a
highly variable background rate for this tumor.
View of the HMPC based on a detailed assessment of the NTP technical report with respect to the
development of a monograph:
No carcinogenicity was observed in the nose, but benign respiratory epithelium tumours (adenoma)
were observed in 2 female rats at the intermediate dose level (300 mg/kg). The occurrence of
adenoma did not show a dose response and occurred in one sex only. However, there were dosedependent morphological changes in the nose. It should be noted that these lesions may have been
secondary effects from oesophageal reflux due to gavage application and/or a secondary effect to
repeated irritant and inflammatory stimulation. To be able to draw a definitive conclusion of the nose
findings additional information from the pathology report would be needed. Induction of CYP 450
enzymes in the nose may also have contributed to these lesions. The mechanism of the non-neoplastic
lesions in the nose in rodents has not been fully established, and therefore the risk to humans cannot
be finally assessed. However, the proposed explanations are plausible and there was no increase of
neoplastic changes. Thus, these findings are considered of limited relevance for human safety.
Carcinogenic effects associated with Ginkgo biloba extract administration are mostly characteristic of
lesions related to hepatic enzyme induction. Carcinogenic activity of Ginkgo biloba extract in liver was
more pronounced in mice than rats. The relation of thyroid lesions to increased metabolic activity in
liver is well known in rodents, and rats are especially sensitive to that mechanism which is in
correlation to study results where hepatic effects were more severe in mice that in rats, but thyroid
effects were more pronounced in rats (Hernandez et al. 2009, Li et al. 2009, Silva Lima & van der Laan
2000).
In principle the lesion in thyroid and liver are considered due to promotion by thyroid and liver enzyme
induction and not due a genotoxic mode action.
Effects seen in nose olfactory and respiratory epithelium in rat and mouse might be considered related
to secondary effects from oesophageal reflux due to gavage application or to induction of metabolising
enzymes and be a secondary effect to repeated irritant and inflammatory stimulation or enzyme
induction via systemic exposure. Furthermore only adenomas occurred and only in the 300 mg/kg dose
female group. However as exposure data of the nasal epithelium are missing there are not enough
data for a final conclusion.
Mononuclear cell leukemia observed in the 2-year carcinogenicity study in rats given Ginkgo biloba
might be considered a background finding and is considered of limited relevance to humans.
The NTP studies do not provide evidence for an increased cancer risk following the use of Ginkgo biloba
extracts at the approved posology. There is plausible evidence for the main effects in liver and thyroid
gland to be caused by rodent specific mechanisms not relevant for humans. For the morphological
changes in the olfactory epithelium in female rats, amechanistic explanation has not been
demonstrated, although there are plausible explanations proposed. The MCLs in male rats are
considered of limited relevance to humans. These effects however were not seen in the low dose
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groups providing margins of exposure of at least 5 to 6 compared to the NOEL for these effects based
on a mg/m2 calculation of the human equivalent dose.
Conclusion:
At present there is no proof for an increased cancer risk identified for patients taking Ginkgo medicinal
products at their approved posology.
3.3.5. Reproductive and developmental toxicity

Monograph relevant extract
Eimazoudy and Attia (2012) evaluated potential anti-implantation and abortifacient effect of
EGb 761 in albino female mice. EGb 761 was orally administered in 0 (control), 3.7, 7.4 and
14.8 mg/kg bw/day (HED=19.8, 39.6, 79.3 mg per daily dose) for 28 days (thereafter mated with
normal fertile male), from day 1 to day 7 of pregnancy or from the 10th to 18th day of pregnancy,
respectively. Vaginal smears were performed daily. On the 20th day of pregnancy, the females were
killed by cervical dislocation and their kidneys, liver, brain, placenta, spleen and ovaries were removed
and weighed. The ovaries were prepared for histological examinations, and then ovarian follicles were
counted. Maternal toxicity, estrous cycle, reproduction hormones, ovarian follicle counts, resorption
index, implantation index, fetal viability and foetuses, and placenta mean weights were evaluated.
There was a dose-dependent ovarian toxic effect of EGb 761. Ovarian follicle counts, resorption index,
implantation index, fetal viability were significantly reduced in 14.8 mg/kg bw/day dose. Treatment
with this dose induced disruption of estrous cycle and caused maternal toxicity, in addition to fetal
toxicity.
DeFeudis (1998) reported of studies were oral administration of 100, 400 or 1600 mg/kg/day of
EGb 761 to rats and 100, 300 or 900 mg/kg/day to rabbits did not elicit teratogenic effects or affect
reproduction.
Rudge et al. (2007) evaluated the effect of EGb 761 treatment given orally once a day in a dose of
200 mg/kg (HED=32 mg/kg which corresponds to 1935 mg per daily dose for a 60 kg human being)
from day 0 to 20 of pregnancy of streptozotocin-induced diabetic rats. The maternal reproductive
performance (not histopathological determined) and the maternal and fetal liver antioxidant systems
were examined. Four experimental groups were studied: G1 = non-diabetic untreated rats (control),
G2=non-diabetic rats treated with EGb 761, G3=diabetic untreated rats and G4=diabetic rats treated
with EGb 761. Maternal and fetal liver samples were obtained for superoxide dismutase (SOD),
catalase (CAT), glutathione peroxidise (GSH-Px), and total glutathione (GSH-t) determinations. The
diabetic (G3) and treated diabetic (G4) groups of rats presented significant maternal hyperglycemia,
reduced term pregnancy rate, impaired maternal reproductive outcome and fetal-placental
development, decreased GSH-Px (G3 and G4=0.60.2) and SOD (G3=223.084.7; G4=146.140.8),
and decreased fetal CAT activity (G3=22.410.6; G4=34.414.1) and GSH-t (G3 and G4=0.30.2),
compared to the non-diabetic groups (G1 and G2). For G1, maternal GSH-Px=0.90.2 and
SOD=274.180.3; fetal CAT=92.682.7 and GSH-t=0.60.5. For G2, EGb 761 treatment caused no
toxicity and did not modify maternal or fetal-placental data. EGb 761 at the nontoxic dose used, failed
to modify the diabetes-associated increase in maternal glycemia, decrease in pregnancy rate, decrease
in antioxidant enzymes, and impaired fetal development when the rats were treated throughout
pregnancy.
Components and other extracts
Shiao and Chan (2009) investigated the effects of ginkgolide B on mouse oocytes maturation,
fertilisation, and sequential embryonic development in vitro and in vivo. Ginkgolide B induced a
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significant reduction in the rate of oocyte maturation, fertilisation, and in vitro embryonic development.
Treatment of oocytes with 1-6 M ginkgolide B during in vitro maturation led to increased resorption of
postimplantation embryos and decreased placental and fetal weights. Data obtained using an in vivo
mouse model further disclosed that consumption of drinking water containing 3-6 M (estimated daily
intake is 325-625 g/kg with a HED of 29-55 g/kg, versus human daily intake of 130 g/kg)
ginkgolide B led to decreased oocyte maturation and in vitro fertilisation, as well as early embryo
development injury, specifically, inhibition of development to the blastocyst stage in vivo.
Chan (2005) showed that ginkgolide A and ginkgolide B treatment (both 5 and 10 M) of mouse
blastocysts induces apoptosis, decreases cell numbers, retards early postimplantation blastocyst
development, and increases early-stage blastocyst death in vitro.
Baron-Ruppert and Luepke (2001) assessed the adverse properties of alkylphenols in different
fractions, gained as water insoluble compounds (decanter sludge) during production of EGb 761, for
their embryotoxic effects in the hens egg test (HET). A fraction enriched for ginkgolic acids (16%) and
biflavones (6.7%) was found to induce death of 50% of the chick embryos (LD 50 ) at a dose of
1.8 mg/egg (approx. 33 ppm). A similar strong lethal effect was observed for a fraction which
contained 58% ginkgolic acids but less than 0.02% biflavones with LD 50 at a dose of 3.5 mg/egg
(64 ppm). In contrast, an extreme low toxic potential was shown in a fraction containing 1% ginkgolic
acids and 16% biflavones with LD 50 at 250 mg/egg or 4540 ppm. Thus, the present investigation
confirms the high toxic potential of ginkgolic acids, although it cannot be excluded that biflavones or
some other constituents in the different fractions may amplify the adverse effect of these substances.
Since no contribution of alkylphenols to the therapeutic efficacy of Ginkgo biloba extracts has been
confirmed and their elimination during the manufacturing process does not cause technical problems,
the authors concluded that these results further support the requirement for the completest possible
removal of these compounds under toxicological considerations.
Floissac and Chopin (1999): The effect of Ginkgo biloba on embryological development in chick
embryos was the subject of this article. Fertile chick eggs (n=387) were injected with one of five
dosages of Ginkgo biloba (not further specified) diluted in physiological saline. The Ginkgo biloba doses
were equivalent to single human doses of 20, 40, 80, 120, and 240 mg. Control eggs (n=74) received
physiological saline only. On developmental day 7, the embryos were examined for viability and
malformations. A trend to decreasing viability with increasing Ginkgo biloba dosage was observed, but
the trend was not statistically significant. Increasing dosages of Ginkgo biloba were accompanied by
increasing frequencies of malformations particularly subcutaneous bleeding. Embryos exposed to the
three highest dosages of Ginkgo biloba had statistically significant increases in total malformations
(p<0.05) and subcutaneous bleeding (p<0.05). These dosages represented the suggested daily dose
range for adults. In conclusion it was stated, that Ginkgo biloba should be used with caution during
pregnancy.
Fernandes et al. (2010) verified whether an aqueous Ginkgo biloba extract (manufactured in Brazil
with the following composition: 28.2% flavonoid glycosides; 8.3% terpene lactones; 15% quercetin;
10.9% kaempferol; 2.3% isorhamnetin; 1.4% ginkgolide A; 1.1% ginkgolide B; 3.0% ginkgolide C;
0.9% ginkgolide J; 0.7% bilobalide and less than 5 ppm (0.81%) of ginkgolic acids) affects embryonic
development when administered to pregnant rats during the one-cell-to-blastocyst period, which
includes the phase of tubal transit and implantation. Pregnant rats received 0, 3.5, 7.0 and
14.0 mg/kg/day of aqueous Ginkgo biloba extract by gavage, from the 1st to the 8th day of pregnancy.
No significant toxic effect was found on the maternal organism and for embryonic parameters.
Zehra et al. (2010) determined gross structural malformations to the mice fetuses of the mothers
given a standardised Ginkgo biloba extract (not further specified) during pregnancy. Pregnant females
were divided into three groups (A, B and C), of 6 mice each. The two experimental groups A and B
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received 78 and 100 mg/kg/day, respectively, whereas group C served as control. Both experimental
groups were given the drug orally throughout the gestational period. The animals were sacrified on the
18th day of gestation. Forty-nine fetuses from groups B and C and 50 fetuses from group A were
recovered. There was a significant (p<0.05) decrease in weight and crown-rump length of fetuses in
group B as compared to those from group A and C. Further, fetuses from groups A and C did not show
any gross abnormalities, whereas those from group B exhibited a high frequency of malformations
including round shaped eye and orbits (48%), syndactyly (40.8%), malformed pinnae (44.1%),
nostrils, lips and jaws (all three together 42.8%). These results indicate that Ginkgo biloba extract is
harmful to the developing fetuses in vivo.
Pinto et al. (2007) evaluated the effects of a Ginkgo biloba extract (composed of 28.2% of
ginkgoflavonglycosides; 8.3% of terpene lactones; 15% of quercetin glycosides; 10.9% of kaempferol
glycosides; 2.3% of isorhamnetin glycosides and less than 5 ppm of ginkgolic acids) during the periods
of organogenesis and fetogenesis. 0, 3.5, 7 and 14 mg/kg body weight/day Ginkgo biloba extract was
administered orally in 1 ml of aqueous solution to pregnant rats from the 8th to 20th day of pregnancy.
After killing the rats on the 21st day the following parameters were evaluated: maternal body weight;
food and water intake; maternals liver, kidney and ovary weights; resorption index; post-implantation
loss; mean of live fetuses; fetuses and placenta mean weight; fetusesliver, kidney, lung and brain
weights; fetusesexternal malformations. The maternal parameters of toxicity did not changed
significantly, whereas the treatment Ginkgo biloba extract resulted in a significant decrease in the
fetuses mean weights. The results suggest that Gingko biloba extract administration with 7 and
14 mg/kg/day to rats in the organogenic and fetogenic periods can lead to fetal intra-uterine growth
retardation, although it did not cause maternal toxicity.
Amin et al. (2012) assessed the protective effects of Ginkgo biloba extract (GBE, purchased from
General Nutrition Corporation, Pittsburgh, USA) against chemotherapeutic-induced reproductive
toxicity using a data mining tool, namely Neural Network Clustering (NNC) on two types of data:
biochemical & fertility indicators and Texture Analysis (TA) parameters. GBE (1 g/kg/day,
HED=9677 mg per daily dose) was given orally to male albino rats for 26 days. This period began 21
days before a single cisplatin (CIS) intraperitoneal injection (10 mg/kg body weight). GBE given orally
significantly restored reproductive function. Tested extract also notably reduced the CIS-induced
reproductive toxicity, as evidenced by restoring normal morphology of testes. In GBE treated mice the
attenuation of CIS-induced damage was associated with less apoptotic cell death both in the testicular
tissue and in the sperms. CIS-induced alterations of testicular lipid peroxidation were markedly
improved by the examined plant extract. NNC has been used for classifying animal groups based on
the quantified biochemical & fertility indicators and microscopic image texture parameters extracted by
TA. NNC showed the separation of two clusters and the distribution of groups among them in a way
that signifies the dose-dependent protective effect of GBE.
Al-Yahya et al. (2006): The effects of Ginkgo biloba (50 mg tablet contains 50 mg of Ginkgo biloba
extract and 12 mg of ginkgo flavone glycosides, which correlates to 24%) on reproductive, cytological
and biochemical toxicity was evaluated in Swiss albino mice. The mice received 25, 50 or
100 mg/kg/day oral doses of an aqueous suspension of Ginkgo biloba for 90 days. The following
parameters were evaluated: reproductive organ weight; motility and content of sperms; spermatozoa
morphology; cytology of the testes chromosomes; study on reproduction; biochemical study on
proteins, nucleic acids, malondialdehyde (MDA) and nonprotein sulfhydryl (NP-SH). Significant changes
were observed in the weight of caudae epididymis, prostate, chromosomal aberrations, rate of
pregnancy and pre-implantation loss. The evaluation of biochemical parameters showed depletion of
nucleic acids, NP-SH and increase of MDA, which elucidated the role of free radical species in the
induced changes in testis chromosomes and the reproductive function.

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Ondrizek et al. (1999a) analysed the effect of Ginkgo biloba (not further specified) at 0.1 and
1 mg/ml on sperm DNA and on the fertilisation process. Zona-free hamster oocytes were incubated for
1 hour in Ginkgo biloba or control medium before sperm-oocyte interaction. The DNA of Ginkgo bilobatreated sperm was analysed with denaturing gradient gel electrophoresis. Oocyte penetration and
integrity of the sperm BRCA1 exon 11 gene were measured as main outcomes. The results show that
high concentrations of Ginkgo biloba could inhibit the penetration of oocytes by sperm. The oocytes
treated with Ginkgo biloba were visibly degenerated. There was abnormally high sperm binding on the
oocyte surface. The lower concentration of Ginkgo biloba produced a numerically lower percentage of
penetration, although this was not significant. Antioxidants have been used to prevent oxidative
damage to cellular membranes. In this case, however, the antioxidant property of this herb did not
help improve sperm penetration. Exposure of sperm to Ginkgo biloba had no effect on DNA
denaturation.
Ondrizek et al. (1999b) analysed sperm motility parameters in the presence of Ginkgo biloba (not
further specified) at 0.12 and 1.2 mg/ml. Sperm were incubated in Ginkgo biloba or control medium
and parameters were measured on a Hamilton-Thorn analyser after 1, 4, 24 and 48 hour at 37C.
There were no significant differences in the motility and the kinematic parameters on Ginkgo biloba
versus the control at the low concentration tested. However, when the concentration of Ginkgo biloba
was increased sperm motility was inhibited at 24 and 48 hours. Sperm curvilinear velocities were lower
after 24 and 48 hours in the high concentration of Ginkgo biloba compared with the control. There
were no differences in the other remaining kinematic parameters (Hyperactivation and beat cross
frequency) for the high concentrations of Ginkgo biloba.
3.3.6. Local tolerance

Peter et al. (1966) administered rabbits and guinea pigs by intramuscular injections 50 and
200 g/kg in 0.5 ml solution concentrated Ginkgo biloba extract. Injections were well tolerated.
Histologically, a moderate to strong oedematous loosening of intact muscle fibres without necroses was
noted. At the injection site inflammatory reactions as signs of resorption as well as mild interstitial
mesenchymal activation were noted after administration of both Ginkgo biloba extract and placebo. No
necroses were observed.
After intraarterial administration of 15 mg/kg in 3.0 ml solution concentrated Ginkgo biloba extract to
rabbits the intima and the media of the arteries were undamaged and unsuspicious. The same results
were observed in guinea pigs and cats.
3.3.7. Other special studies

Ahlemeyer et al. (2001) questioned whether ginkgolic acids also have, besides allergenic and
genotoxic effects, neurotoxic effects. In the presence and in the absence of serum ginkgolic acids
caused death of cultured chick embryonic neurons in a concentration-dependent manner. Ginkgolic
acids-induced death showed features of apoptosis as chromatin condensation, shrinkage of the nucleus
and reduction of the damage by the protein synthesis inhibitor cycloheximide was observed,
demonstrating an active type of cell death. However, further indicators of apoptosis (DNA
fragmentation detected by the terminal-transferase-mediated ddUTP-digoxigenin nick-end labelling
(TUNEL) assay and caspase-3 activation) were not seen after treatment with 150 M ginkgolic acids in
serum-free medium, a dose which increased the percentage of neurons with chromatin condensation
and shrunken nuclei to 88% compared with 25% in serum-deprived, vehicle-treated controls. These
findings suggest that ginkgolic acid-induced death showed signs of apoptosis as well as of necrosis.
Ginkgolic acids specifically increased the activity of protein phosphatase type-2C, suggesting it to play
a role in the neurotoxic effect mediated by ginkgolic acids.
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3.4. Overall conclusions on non-clinical data

Pharmacodynamic
The pathomechanism of AD and other forms of dementia is still under discussion. According to this,
diverse models exist about the development of the most common forms of dementia (degenerative
dementia (AD) and vascular dementia). So it is difficult to estimate which model represents the
pathomachanism of the disease. But a final conclusion is not possible.
In animal experiments, Ginkgo biloba extract was shown to improve spatial memory deficits in a
transgenic mouse model of AD, as well as to improve acquisition of working memory in young and
aged rats. However, the precise neurochemical correlates of these behavioral effects of Ginkgo biloba
extract are not completely understood.
The pharmacological effect on blood flow or microcirculation, the inhibitory action on PAF as well as an
antioxidant action as a free radical scavenger could be supportive of a possible neuroprotective effect.
The pharmacological actions could already be observed at doses which are of clinical relevance as well
at doses which were 2-8 folds higher as the human equivalent dose.
The Ginkgo biloba extract EGb 761 contains standardised amounts of flavonoids and ginkgolides. In
animal models of Alzheimers disease (AD), these antioxidants and neuroprotectants inhibit amyloid
42-induced hippocampal neuron dysfunction and death, amyloid -induced pathological behaviours
and amyloid aggregation, and enhance neurogenesis.
Moreover, EGb 761 and Ginkgo biloba extracts may modulate catecholamine (DA) release in the
prefrontal cortex.
These characteristics might generally support a clinical relevance of the above mentioned supposed
mechanisms in the pathophysiological process underlying common forms of dementia including AD and
VaD.
The results of the safety pharmacology studies indicate that Ginkgo biloba extracts are active on
venous and arterial preparations in vitro (at least in part via release of catecholamines). The effect on
isolated guinea pig ileum indicates a direct action on the muscle. Effects on blood pressure, heart rate
and breathing rataes are difficult to interpret because of the deviant route of administration and
because of the interference with the diluent.
Pharmacokinetic
A set of pharmacokinetic studies are presented mostly for the extract EGb 761. The rate of absorption
after oral administration of radiolabelled EGb 761 to rats was estimated to be 60%. The maximum
concentration was reached after 1.5 hours.
Especially studies concerning pharmacokinetic drug interactions are mentioned, which were performed
using different Ginkgo biloba extracts, so the content percentages of active principles are different and
in consequence the potential interaction effects described not necessary should be reproducible for the
monograph relevant Ginkgo biloba preparation.
Oral administration of EGb 761 strongly increased liver CYP P450 content. With regard to the
unchanged steroid profile in man, it is assumed that the effects of EGb 761 on drug metabolising
enzymes are specific for rats and may not be extrapolated to man. But on the other hand experiments
with human liver microsomes have shown that Ginkgo biloba leaf dry extract can affect CYP enzymes
in vitro.

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An in vitro study indicates that EGb 761 inhibits activity of CYP1A2, CYP2C9, CYP2E1 and CYP 3A4, in
which the activity of CYP2C9 was the most affected. Another in vitro study with an ethanolic Ginkgo
biloba extract supports the inhibitory effect on CYP3A4 activity and proposes also an inhibitory effect
on P-gp activity. In vivo studies in animals confirmed inhibition activity of Ginkgo biloba leaf extract on
CYP3A4. Nervertheless, some interaction that occurred in the animal assays could not be extrapolated
to humans.
Toxicology
A study report on a carcinogenesis study with a Ginkgo biloba extract (different from the Pharm. Eur.
Specification but nevertheless similar) in rats and mice for two years raised questions about possible
carcinogenic effects.
The NTP studies do not provide conclusive evidence for an increased cancer risk for the use of Ginkgo
biloba extracts at the recommended doses. There is plausible evidence for the main effects in liver and
thyroid gland to be caused by rodent specific mechanisms not relevant for humans. For adenomas in
olfactory epithelium in rats and MCLs in male rats a conclusive mechanistic explanation is currently not
provided. These effects however were not seen in the low dose groups providing margins of exposure
of at least 5 to 6 compared to the NOEL for these effects based on a mg/m2 calculation of the human
equivalent dose.
It can be concluded that at present there is no proof for an increased cancer risk identified for patients
taking Ginkgo medicinal products at their approved posology.
However as any potential of Ginkgo biloba extracts for inducing gene mutations in vivo cannot be
excluded due to missing of such data and as there are significant differences in the extract tested in
the NTP study and the extract EGb 761, mostly marketed in pharmaceuticals in Europe, with respect to
exposure to ginkgolides (LPT Report No. 29879, 2013) in mice, data of in vivo gene mutation assays in
target organs of carcinogenesis in mice for Ginkgo biloba extracts are considered necessary to fully
exclude any in vivo mutagenic potential of Ginkgo biloba extracts to be involved in the induction of
tumors in rodents and further exclude any relevance for human use.
Limited studies concerning single dose and repeated dose toxicity, as well as local tolerance are
mentioned above as there is sufficient and well-documented experience available in humans (see
section clinical data).
The results show LD 50 values for mice and rats for single dose toxicity. With 7.73, 1.1 and 1.9 g/kg for
mice and >10, 1.1 and 2.1 g/kg for rats by oral, i.v. and i.p. EGb 761 administration, respectively.
Furthermore, no evidence of organ damage or impairment of hepatic and renal functions by chronic
EGb 761 administration in rats, mice and dogs was observed. The data of single dose and repeated
dose toxicity of isolated compounds are administered in much higher doses than clinically relevant.
Most of the available reproductive and developmental toxicity studies are conducted with Ginkgo biloba
extracts different from the monograph relevant extract or with single components present in Ginkgo
biloba extracts. The studies are conducted in vitro as well as in vivo in mice, rats, rabbits and chicken.
The results of a current investigation showed a dose-dependent ovarian toxic effect of EGb 761 in rats
at HED: 20-80 mg per daily dose. The effect on fertility was represented by significantly reduced
ovarian follicle counts, resorption index, implantation index and fetal viability. In contrast to these
results, older studies indicate no teratogenic effects or reproductive toxicity of EGb 761 orally
administered to rats (100, 400 or 1600 mg/kg/day) and to rabbits (100, 300 or 900 mg/kg/day).
In vitro and in vivo studies conducted with single components of Ginkgo biloba (ginkgolide A and B
with a HED of 29-55 g/kg versus a human daily intake of 130 g/kg) indicated significant reduction
on oocyte maturation, fertilisation and embryonic blastocysts development. The high toxic potential of
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ginkgolic acids and the following completest possible elimination during manufacturing ginkgo extracts
was confirmed in an in vivo study.
There is evidence that ginkgo containing preparations can increase the disposition for bleeding.
Therefore, Ginkgo biloba leaf dry extract must not be used during pregnancy.
Contrary results are reported in two studies regarding the effect of Ginkgo biloba extracts on
embryonic development (day 0-18 and 0-20, respectively). High dose administration of EGb 761 (HED:
1935 mg/kg per daily dose) caused no toxicity on maternal or fetal-placental data compared to low
dose administration of a not specified Ginkgo biloba extract (HED: 417 and 535 mg/kg per daily dose)
which caused high frequency (40-48%) of structural malformations. Another study supports harmful
effects of ginkgo containing extracts on embryonic development. A low dose (HED: 68 and 135 mg/kg
per daily dose) given from day 8-20 of pregnancy showed also toxic effects on embryonic
development. Whereas no developmental toxic effects were found in a study from day 1-8 of
pregnancy at low doses (HED: 33, 68, 135 mg/kg per daily dose).
Further, a protective effect of ginkgo containing extracts against chemotherapeutic-induced
reproductive toxicity was observed.
In summary, a lot of pharmacological, pharmacokinetic and toxicological studies conducted with
preparations of Ginkgo biloba leaf extract and its constituents exist. In considering the abovementioned pharmacological data, clinical findings and derived indications for a well-established use can
be supported by these studies. Pharmacokinetic studies of Ginkgo biloba leaf preparations and its
constituents are available and give an evidence for numerical quantity values and bioavailability.
Adequate toxicological data are mentioned, but for one, with no clinical relevance. As for these studies,
which were performed, either no specific characterised extract was used or the applied doses were
higher than the highest corresponding human dose of 120-240 mg or ginkgolic acids values were
higher than those applied in clinical use, since the declaration of the Ginkgo biloba leaf extract in the
Ph. Eur. states a maximum value of 5 ppm of ginkgolic acids.
4. Clinical Data
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
4.1.1.1. Primary pharmacodynamics
Effect on cognition
Gener et al. (1985): In a double-blind trail 60 volunteers (57-77 years) with age-related mental
deterioration participated to estimate the action of EGb 761 on the central nervous system.
Quantitative pharmaco-electroencephalography (EEG) was used to assess the vigilance-promoting
effects of the drug. Subjects were divided into three groups (n=20 in each group) and received
randomly 3x40 mg/day EGb 761, 5 mg nicergoline or placebo. Analysis of the whole group for vigilance
revealed no significant advantage of EGb 761 over the two reference substances. However, a
subclassification of the subjects showed that the vigilance of those persons with a more unfavourable
initial situation measured in the resting EEG could be clearly improved by chronic EGb 761 medication.
This increase in vigilance was reflected at the behavioural level by an improvement of reaction times
compared with the reference substances. These results show that chronic EGb 761 medication has a
positive effect in geriatric subjects with deterioration of mental performance and vigilance, and this

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effect is reflected at the behavioural level. In contrast, healthy subjects with a good initial state
achieve hardly any improvement.
Elsabagh et al. (2005) conducted a placebo-controlled and double-blind study to compare the effects
of LI 1370 after acute and chronic treatment on tests of attention, memory and executive function in
92 healthy subjects (18-26 years). Participants were randomly allocated to receive a single dose of
LI 1370 (120 mg, n=26) or placebo (n=26). Another 40 were randomly allocated to receive LI 1370
(120 mg/day, n=20) or placebo (n=20) for a 6-week period. The acute dose of LI 1370 significantly
improved performance on the sustained-attention task and patter-recognition memory task; however,
there were no effects on working memory, planning, mental flexibility or mood. After 6 weeks of
treatment, there were no significant effects of LI 1370 on mood or any of the cognitive tests. In
conclusion, performance in tests of attention and memory was improved after acute administration of
LI 1370. However, there were no effects after 6 weeks, indicating that tolerance develops to the
effects in young, healthy subjects.
Santos et al. (2003) performed a double-blind, placebo-controlled study with 48 healthy men (60-70
years). Participants randomly received oral 80 mg/day dried Ginkgo biloba extract (produced by Maze
Produtos Qumicos e Farmaceuticos Ltda., 100 mg contained 24% flavonoide, 6.1% terpenoide, 2.7%
bilobalide, 1.7% ginkgolide A, 0.9% ginkgolide B, and 0.8% ginkgolide C) or placebo for a period of 8
months. Evaluation of cognitive alterations was based on a number of neuropsychological tests
including single photon emission computer tomography (SPECT) and measures of blood viscosity. The
experimental group showed a reduction in blood viscosity, improved cerebral perfusion in specific areas
and improved global cognitive functioning. In contrast, these parameters were opposite in the control
group. These results suggest that Ginkgo biloba dry extract appears to be effective in the treatment of
cognitive deficits in elderly.
Effect on blood flow
Guinot et al. (1989): An open study was conducted to examine the antagonistic activity of EGb 761
on PAF-induced platelet aggregation. 6 healthy volunteers received a single oral administration of
15 ml liquid extract (dose not indicated). Ex vivo platelet aggregation was determined by
aggregometry on platelet-rich plasma. There was a reduction in platelet aggregation at all doses of
PAF, as well as with 1 M ADP and adrenaline. The most significant decreases occurred with 75 nM PAF
4 hours after intake (p<0.05) and 300 nM 4 (p<0.01) and 8 hours after intake (p<0.05). There were
no concomitant changes in coagulation, skin bleeding time, haematological and biochemical laboratory
tests, blood pressure or pulse. The results provide a possible explanation for the clinical efficacy of
EGb 761 in the treatment of peripheral vascular disease.
Mehlsen et al. (2002) examined possible vasodilating effects of a Ginkgo biloba extract (Gibidyl
Forte, produced in Denmark, containing 9.6 mg ginkgoflavonglycosides and 2.4 mg terpenlactones per
tablet) on forearm haemodynamics. 16 healthy subjects with a median age of 32 years (range: 21-47)
received three tablets daily of Ginkgo biloba or placebo. The study was performed in a randomised,
double-blind, cross-over design for 6 weeks. Forearm blood flow was significantly higher during active
treatment after 3 and 6 weeks as compared with placebo treatment for 3 and 6 weeks (p<0.05). Mean
arterial blood pressure was unchanged, making the calculated FVR significantly lower during active
treatment (p<0.02). It was concluded that oral treatment with a Ginkgo biloba extract (Gibidyl Forte)
is able to dilate forearm blood vessels causing increments in regional blood flow without changing
blood pressure levels in healthy subjects.
4.1.1.2. Secondary pharmacodynamics
No data available.

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4.1.1.3. Safety pharmacology

No data available.
4.1.1.4. Pharmacodynamic interactions
Aruna and Naidu (2007): Coadministration of Ginkgo biloba (not further specified) at an oral dose of
120 or 240 mg, either with cilostazol or clopidogrel to 10 healthy male volunteers in a randomised,
open-label, crossover study did not enhance antiplatelet activity. Ginkgo biloba potentiated the
bleeding time prolongation effect of cilostazol. No significant correlation exists between prolongation of
bleeding time and inhibition of platelet aggregation.
Wolf (2006) suggests that coadministration of aspirin and EGb 761 to 50 healthy male volunteers
(20-44 years) in a double-blind, double-dummy study did not prolong coagulation parameters,
including bleeding time and agonist-induced platelet aggregation, compared to aspirin alone. These
results indicate that coadministration of the two drugs does not constitute a safety risk.
Jiang et al. (2005) analysed the effect of EGb 761 (80 mg three times daily) on clotting status and
pharmacodynamics of warfarin in an open-label, three-way, crossover and randomised study. 12
healthy male subjects received a single 25 mg dose of warfarin alone or after 7 days pre-treatment
with EGb 761. Dosing with Ginkgo biloba extract was continued for 7 days after warfarin
administration. International normalised ratio of prothrombine time and platelet aggregation were not
affected by Ginkgo biloba coadministration. Therefore, EGb 761 at recommended doses does not
significantly affect clotting status or pharmacodynamics of warfarin in healthy subjects.
Jiang et al. (2006) investigated herb-drug interactions of Ginkgo biloba and warfarin. 24 healthy
subjects received a single warfarin dose (25 mg) with or without pretreatment with Commission E
recommended daily doses of EGb 761.The data were analysed using a population pharmacokineticpharmacodynamic modelling approach. Ginkgo biloba did not affect the pharmacokinetics or
pharmacodynamics of S-warfarin in healthy subjects.
Duche et al. (1989) found that EGb 761 showed no effect on the hepatic microsomal drug oxidation
system. 24 healthy male volunteers (19-35 years) in a randomised, double-blind study design received
a single dose of 10 mg/kg antipyrine following a division in three groups and a treatment with
400 mg/day of EGb 761 (group 1), 300 mg/day phenytoin (group 2) or placebo (group 3). The
elimination half-life of antipyrine was measured before and on the last day of the administration of the
treatments. The results indicate that the half-life of antipyrine was not affected by EGb 761 and
placebo treatment, whereas it was significantly decreased (p<0.05) from 12.2 to 6.8 hours after
phenytoin control treatment.
4.1.2. Overview of pharmacokinetic data regarding the herbal

substance(s)/preparation(s) including data on relevant constituents
4.1.2.1. Absorption
The main pharmacokinetic parameters of the bioavailable terpene lactones after a single oral dose of
120 mg EGb 761 given either as tablets (Kressman et al. 2002) or as a solution (cited in Biber
2003 from Fourtillan et al. 1995) to 12 healthy volunteers are presented in table 1 and 2. The
mean absolute bioavailability was 80% for ginkgolide A, 88% for ginkgolide B and 79% for biloalide
given as a solution.

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Table 1. Pharmacokinetic parameters of terpene lactones in 12 healthy volunteers after single

oral administration of 120 mg EGb 761 (Kressmann et al. 2002)
Ginkgolide A
Ginkgolide B
Bilobalide
C max (ng/ml)
22.22 4.57
8.27 1.82
54.42 13.62
t max (h)
1.17 0.39
1.54 0.50
1.21 0.45
AUC 0- (ng h/ml)
121.35 22.92
59.88 11.39
217.24 44.07
T (h)
3.93 0.40
6.04 1.48
3.19 0.40
Data are mean values SD
Table 2. Pharmacokinetic parameters of terpene lactones in 12 healthy volunteers after single

oral administration of 120 mg EGb 761 (cited in Biber 2003 from Fourtillan et al. 1995)
Ginkgolide A
Ginkgolide B
Bilobalide
C max (ng/ml)
33.29 9.12
16.46 5.02
18.81 8.84
t max (h)
1.06 0.72
1.17 0.69
1.17 0.80
AUC 0- (ng h/ml)
146 21.50
109.90 20.60
78.97 38.98
T (h)
4.50 1.55
10.57 3.56
3.21 0.64
Data are mean values SD
According to Fourtillan et al. (1995) food intake did not modify bioavailability of ginkgolides A, B and
bilobalide, although their rate of absorption was slowed, as revealed by a delayed T max .
Biber (2003): In a dose-response study, 12 healthy volunteers received 80, 120 and 240 mg
EGb 761 as a solution. The results are shown in table 3.
Table 3. Pharmacokinetic parameters after oral administration of EGb 761 in healthy volunteers
(Biber 2003)
Extract dose
Constituent dose
C max
(mg)
(mg)
(ng/ml)
80
1.056
120
240
T max (h)
AUC (ng h/ml)
T (h)
15.2 2.8
0.61 0.21
69.9 18.4
4.5 2.5
1.584
25.3 9.9
0.60 0.20
103.2 16.3
4.5 1.6
3.168
42.9 9.1
0.75 0.20
211.1 37.6
5.1 1.4
80
0.560
6.53 1.23
1.29 0.62
43.75 8.77
6.5 2.6
120
0.840
9.12 1.48
0.92 0.25
70.03 19.55
8.5 3.0
240
1.680
18.11 4.16
1.21 0.32
140.69 33.62
9.9 2.0
80
2.280
30.2 12.6
0.86 0.40
114.7 56.7
5.5 3.6
120
3.420
35.2 8.3
0.67 0.18
128.1 58.4
4.0 1.7
240
6.840
58.6 19.1
0.72 0.20
247.1 107.1
4.9 2.5
Ginkgolide A
Ginkgolide B
Bilobalide
As reported in the German monograph of the Commission E, the absolute oral bioavailability was 98100% for ginkgolide A, 79-93% for ginkgolide B and > 70% for bilobalide after oral administration of
EGb 761 (Commission E monograph on Ginkgo biloba leaf dry extract, 1994).

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Chan et al. (2007): After an oral dose of EGb 761 (80 mg) maximum plasma levels of ginkgolide A
(C max =15 ng/ml) and ginkgolide B (C max =4 ng/ml) were attained at 1.4-2.0 hours. The half-lives of
ginkgolide A and ginkgolide B were 3.9 and 7 hours.
Woelkart et al. (2010) investigated bioavailability and pharmacokinetics of ginkgo terpene lactones
of three different Ginkgo biloba L. preparations; ginkgo fresh plant tincture, where 1 ml contains the
equivalent of 920 mg Ginkgo biloba leaves as active ingredient (ethanol for extraction, DER=1:9), one
new ginkgo fresh plant extract tablet (250 mg) comprises 90 mg of ginkgo fresh plant extract (ethanol
for extraction, DER=3-5:1) and EGb 761 tablets (40 mg). The study was conducted in a randomised,
open, parallel group design with 24 healthy volunteers. Subjects received a single oral dose of the
different formulations with diverse amounts of terpene trilactones. The applied oral doses were the
corresponding maximum registered daily dose, which is 2512 mg of the tincture, 1000 mg of the fresh
plant extract tabvlets and 120 mg for EGb 761. The results demonstrate relative bioavailability of
different Ginkgo biloba L. preparations.
Table 4. Maximum concentrations (median) of terpene lactones in plasma after administration of
the maximum daily dose of different ginkgo preparations (Woelkart et al. 2010)
Ginkgo plant fresh tincture
Ginkgo fresh plant extract tablet
EGb 761
Bilobalide
3.53
11.68
26.85
Ginkgolide A
3.62
7.36
16.44
Ginkgolide B
1.38
4.18
9.99
C max (ng/ml)
Wjcicki et al. (1995): The following table shows pharmacokinetic parameters of the flavonol
glycosides quercetin, kaempferol and isorhamnetin after a single administration of EGb 761 (no dose
mentioned) in three different formulations in an equal amount given to 18 volunteers.
Table 5. Pharmacokinetic parameters of flavonol glycosides after a single oral dose of EGb 761 to
healthy subjects (Wjcicki et al. 1995)
Capsules
Drops
Tablets
C max (ng/ml)
12.16 0.60
13.79 0.77
13.45 0.74
t max (h)
2.47 0.05
2.00 0.07
2.00 0.08
AUC 0-24 h (ng h/ml)
63.71 2.99
64.66 3.62
60.15 3.46
C max (ng/ml)
26.73 1.19
30.02 1.28
28.94 1.24
t max (h)
2.44 0.06
2.03 0.08
2.03 0.08
138.43 6.69
138.08 7.08
130.37 6.92
C max (ng/ml)
7.26 0.37
9.62 1.61
7.81 0.31
t max (h)
2.44 0.07
2.03 0.08
2.03 0.08
34.63 1.99
39.99 6.13
31.55 1.89
Quercetin
Kaempferol
Isorhamnetin
Data are mean values SE

4.1.2.2. Distribution
No data available.

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4.1.2.3. Metabolism
Chang et al. (2006): In the following in vitro study the effect of Ginkgo biloba extract constituents on
procarcinogen-bioactivating human CYP1 enzymes was investigated. It was shown that the aglycones
of quercetin, kaempferol, and isorhamnetin inhibited CYP1B1, CYP1A1, and CYP1A2. The most potent
inhibitor of CYP1B1 was isorhamnetin with a K i -value of 30.1 nM, whereas quercetin was with
K i =41850 nM the least potent inhibitor of CYP1A2. Ginkgo biloba extract also reduced
benzo[a]pyrene hydroxylation, and the effect was greater with CYP1B1 than with CYP1A1 as the
catalyst. In summary, these novel findings from the present study indicate that Ginkgo biloba extract
and the flavonol aglycones, isorhamnetin, kaempferol, and quercetin, preferentially inhibit the in vitro
catalytic activity of human CYP1B1.
4.1.2.4. Elimination
No data available.
4.1.2.5. Pharmacokinetic interactions with other medicinal products
Studies with defined Ginkgo biloba extract (EGb 761)
Robertson et al. (2008): Evaluation of an open-label study in 14 healthy volunteers showed that
lopinavir, ritonavir and fexofenadine (probe drug for P-gp) exposures were not significantly affected by
Ginkgo biloba (according to an internet research the used extract is probably EGb 761) administration
of 120 mg twice daily for 2 weeks. However, Ginkgo biloba decreased midazolam (probe drug for
CYP3A4) AUC 0- and C max by 34% (p=0.03) and 31% (p=0.03), respectively, relative to baseline.
Uchida et al. (2006): This study was performed to demonstrate the influence of repeated oral
administration of EGb 761 (120 mg three times daily for 28 days) on CYP2C9 and CYP3A4. CYP2C9
probe (tolbutamide, 125 mg) and CYP3A4 probe (midazolam, 8 mg) were orally administered to 10
male healthy volunteers (mean age SD: 24.9 2.6 years) before and after EGb 761 intake, and
they received 75 g glucose after tolbutamide administration. AUC 0- for tolbutamide after EGb 761
intake was slightly but significantly (16%) lower than that before EGb 761 intake. Concomitantly,
EGb 761 tended to attenuate AUC 0-2 of blood glucose-lowering effect of tolbutamide. AUC 0- for
midazolam was significantly (25%) increased by EGb 761 intake and oral clearance was significantly
(26%) decreased.
Markowitz et al. (2003) assessed in normal volunteers (n=12) aged 22-40 years the influence of
EGb 761 on the activity of CYP2D6 and 3A4 normal volunteers phenotyped as CYP2D6 extensive
metabolisers. Probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity)
were coadministered orally at baseline, and following treatment with EGb 761(120 mg twice daily) for
14 days. Urinary concentrations of dextromethorphan and dextrorphan were quantified and
dextromethorphan metabolic ratios (DMRs) were determined at baseline and after EGb 761 treatment.
Likewise, plasma samples were collected (0-60 hours) for alprazolam pharmacokinetics at baseline and
after EGb 761 treatment to assess effects on CYP3A4 activity. Validated HPLC methods were used to
quantify all compounds and relevant metabolites. No statistically significant differences were found
between baseline and post-EGb 761 treatment DMRs indicating a lack of effect on CYP2D6. For
alprazolam there was a 17% decrease in the area under the plasma concentration versus time curve
(AUC); (p<0.05). However, the half-life of elimination was not significantly different after EGb 761
administration indicating a lack of hepatic CYP3A4 induction. The usual interpretation of altered C max
and no variation in the half-life of elimination is that absorption rather than hepatic enzyme activity
has been affected.

EMA/HMPC/321095/2012
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Greenblatt et al. (2006): The study shows that short-term exposure to EGb 761 in a dosage of
360 mg per day does not influence the kinetics of CYP2C9 activity. 11 healthy volunteers received
single 100 mg doses of flurbiprofen, a probe substrate for CYP2C9, and EGb 761 or placebo in a
randomised, double-blind, 2-way crossover study. None of the mean kinetic variables differences for
flurbiprofen with either placebo or EGb 761 were significant. Based on HPLC analysis, each 60 mg
ginkgo tablet contained 6.6 g of amentoflavone and 61.2 g of quercetin, both previously identified as
CYP2C9 inhibitors. These amounts were apparently too low to inhibit CYP2C9 function in vivo. These
results confirm previous controlled clinical studies showing no effect of ginkgo on the kinetics of
warfarin, which is known as a substrate of CYP2C.
Zadoyan et al. (2011): The objective of this open-label, single-center, randomised, threefold crossover study was to assess the in vivo herbal drug-drug interaction potential of EGb 761 with respect to
the activities of the five major human drug-metabolising cytochrome P450 (CYP) enzymes. 18 healthy
volunteers received in random order placebo twice daily, EGb 761 120 mg twice daily, and EGb 761
240 mg in the morning and placebo in the evening for 8 days. After the mentioned pretreatment, on
day 8, administration was performed together with the orally administered phenotyping cocktail:
150 mg caffeine, 125 mg of tolbutamide, 20 mg omeprazole, 30 mg dextromethorphan, and 2 mg of
midazolam. No relevant pharmacokinetic interaction was assumed if the 90% CIs for EGb 761/placebo
ratios of pharmacokinetic parameters were within the 0.70-1.43 range. The results show respective CIs
were within the specified margins for all ratios except CYP2C19 for EGb 761 120 mg twice daily (90%
CI 0.681-1.122) and for CYP2D6 for EGb 761 240 mg once daily (90% CI 0.667-1.281). These findings
were attributed to the intraindividual variability of the metrics used. In conclusion, EGb 761 has no
relevant effect on the in vivo activity of the major CYP enzymes in humans and therefore has no
relevant potential to cause respective metabolic drug-drug interactions.
Blonk et al. (2012) studied the effect of EGb 761 on the pharmacokinetics of raltegravir in an openlable, randomised, two-period, crossover phase I trial in 18 healthy volunteers between the ages of 18
and 55 years. Subjects received 120 mg EGb 761 twice daily for 15 days plus a single dose of
raltegravir (400 mg) on day 15, a washout period, and 400 mg of raltegravir on day 36 or the test and
reference treatments in reverse order. Pharmacokinetic sampling of raltegravir was performed up to
12 hours after intake on an empty stomach. All subjects completed the trial, and no serious adverse
events were reported. Steady-state EGb 761 increased the mean exposure to raltegravir (AUC 0- ) by
21% and the C max by 44%. The apparent elimination half-life of raltegravir did not appear to be
influenced by EGb 761. Geometric mean ratios (90% CI) of the area under the plasma concentrationtime curve from dosing to infinity (AUC 0- ) and the maximum plasma concentration (C max ) of
raltegravir with EGb 761 versus raltegravir alone were 1.21 (0.93 to 1.58) and 1.44 (1.03 to 2.02).
Besides EGb 761 did not reduce raltegravir exposure, the observed increase in C max may be caused by
a change in absorption than by inhibition of the metabolim of raltegravir, because the elimination halflife of raltegravir remained unaffected. At which the increase in C max is not considered to be of clinical
importance. A possible explanation for the increase in the C max and bioavailability of raltegravir when
combined with EGb 761 could be the inhibition of P-gp by EGb 761. Although in vitro characterisation
of raltegravir transport by drug transporters indicates that raltegravir is a weak P-gp substrate, one
must be cautious because it is not yet confirmed in human studies.
In the article by Zagermann-Muncke (2006) the role of transport proteins in view of
pharmacokinetic interactions is discussed. The ABC transporter P-gp can be both inhibited and induced,
whereas P-gp substrates are usual substrates of CYP3A4 as well. Expression and activity of both
proteins are apparently regulated in part through the same menchanisms. Thereby differentiation of
effects is hindered. A list of P-gp substrates, inducers and inhibitors is given. The concomitant intake of
a P-gp substrate and a P-gp inhibitor is possibly leading to a higher bioavailability of the P-gp
substrate. This could be clinically relevant for drugs with narrow therapeutic index. Genetically based
EMA/HMPC/321095/2012
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MDR-1 (gene that encodes for P-gp) polymorphism can change transport function and expression of Pgp, therefore efficacy and tolerance of drugs, which are P-gp substrates, can vary between humans.
Jiang et al. (2005) analysed the effect of EGb 761 (80 mg three times daily) on pharmacokinetics of
warfarin in an open-label, three-way, crossover and randomised study. 12 healthy male subjects
received a single 25 mg dose of warfarin alone or after 7 days pre-treatment with EGb 761. Dosing
with Ginkgo biloba extract was continued for 7 days after warfarin administration. There was no
relevant influence on the apparent clearance of S- and R-warfarin. EGb 761 did not affect the apparent
volumes of distribution or protein binding of either S-warfarin or R-warfarin. Therefore, EGb 761 at
recommended doses does not significantly affect the pharmacokinetics of warfarin in healthy subjects.
Lu et al. (2006): To examine whether ticlopidine coadministration with EGb 761 would affect
pharmacokinetics of ticlopidine 8 healthy volunteers were included in a sequential 3-phase study.
Subjects were treated with a single oral dose of 250 mg ticlopidine alone or after pretreatment with
EGb 761 (40 mg 3 times daily) for 4 days. Ticlopidine and EGb 761 significantly inhibited the organic
anion transporting polypeptide (OATP-B)-mediated uptake of [H]-estrone-3-sulfate in a
concentration-dependent manner. When EGb 761 is coadministered with ticlopidine there were no
changes in the pharmacokinetic parameters of ticlopidine.
Kudolo et al. (2006): A study is described which was designed as a double-blind, placebo-controlled,
crossover trial to determine if the coingestion of EGb 761 and metformin would alter the
pharmacokinetic properties of metformin in type 2 diabetic patients and in non-diabetic persons. The
participants ingested either EGb 761 (120 mg/day as a single dose) or placebo for 3 months. At the
end of the period the non-diabetic persons took a single 500 mg dose of metformin and the diabetic
subjects took his/her prescribed metformin dose (250-850 mg) with 120 mg EGb 761.The
pharmacokinetic parameters of metformin (500 mg) were all significantly different (p<0.05) between
the normal glucose tolerance and 8 out of 10 diabetic subjects who received metformin during the
placebo cycles. During the EGb 761 cycles, only the elimination half-life in the type 2 diabetic patients
was significantly increased. In conclusion, coingestion of 120 mg EGb 761 and 500 mg metformin did
not significantly affect the pharmacokinetic properties of metformin.
Gardner et al. (2007): The purpose of this randomised, double-blind, placebo-controlled, parallel
clinical trial was to determine potential adverse effects of concomitant intake of aspirin and EGb 761 on
platelet function. EGb 761 (300 mg/day) was compared with placebo for effects on measures of
platelet aggregation among adults (6910 years) consuming 325 mg/day aspirin. Participants were
afflicted with peripheral artery disease (PAD) or had risk factors for cardiovascular disease. Outcome
measures included platelet function analysis (PAF-100 analyser) using ADP as agonist, and platelet
aggregation using ADP, epinephrine, collagen and ristocetin as agonists. There were no clinically or
statistically significant differences between treatment groups for any agonists, for either PAF-100
analysis or platelet aggregation. In conclusion, in older adults with PAD or cardiovascular disease risk,
a relatively high dose of EGb 761 combined with 325 mg/day daily aspirin did not have a clinically or
statistically detectable impact on indices of coagulation examined over 4 weeks, compared with the
effect of aspirin alone. No adverse bleeding events were observed.
Studies with other Ginkgo biloba extracts
Bressler (2005) presented in a review article known drug interactions with Ginkgo biloba (not
further specified). In a table interactions with the following prescription drugs are listed: alprazolam,
haloperidol, trazodone, omeprazole, aspirin, ibuprofen, nifedipine and warfarin. To specify these
interactions, systemic exposure to alprazolam may be slightly decreased by Ginkgo biloba. Ginkgo
biloba can increase the effectiveness and decrease the extrapyramidal side effects of haloperidol and
can increase the risk of sedation when taken together with trazodone. Plasma concentrations of

EMA/HMPC/321095/2012
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omeprazole may be reduced when the medicinal product is taken together with Ginkgo biloba which
can result in decreased efficacy of the drug. Administration of Nifedipine and Ginkgo biloba at once
may elevate plasma concentrations of the cardiovascular agent. Based on the suspected mechanism of
action that Ginkgo biloba can also inhibit CYP3A4, it may causes increased levels of drug, prolonged
drug effects, and increased drug toxicity. The risk of bleeding may be increased when Ginkgo biloba is
administered concomitantly with aspirin, ibuprofen or warfarin.
Mahadevan and Park (2008) mentioned with references to the primary literature interactions of
Ginkgo biloba extract with the following substances: antidepressants (i.e. trazodone), antiepileptics,
antidiabetics, diuretics, and nonsteroidal anti-inflammatory drugs, as well as other herbal drugs. These
interactions are believed to be affected mainly by flavonol glycosides and the terpene lactones by
selectively inhibiting particular enzymes, including cytochrome P450. However, others reported no
effect on clearance of cytochrome P450 substrates by ginkgo leaf extract.
Yoshioka et al. (2004b): The effects of Ginkgo biloba leaf extract (manufactured in Chiba, Japan) on
the pharmacokinetics of nifedipine (NFP), a calcium-channel blocker, were studied using 8 healthy
volunteers. Concomitant oral administration of Ginkgo biloba (240 mg) did not significantly affect any
of the mean pharmacokinetic parameters of either NFP or dehydronifedipine, a major metabolite of NFP
after oral intake of 10 mg NFP. Still, the C max of NFP in 2 subjects was approximately doubled by GBE,
and they had severer and longer-lasting headaches with Ginkgo biloba than without Ginkgo biloba,
with dizziness or hot flushes in combination with Ginkgo biloba extract. In addition the mean heart rate
after oral administration of NFP with ginkgo extract tended to be faster than that without Ginkgo biloba
extract at every time point. In conclusion, Ginkgo biloba extract and NFP should not be simultaneously
ingested as much as possible and careful monitoring is needed when administering NFP concomitantly
with Ginkgo biloba to humans.
Fan et al. (2009a): The aim of the present study was to assess the effects of Ginkgo biloba extract
(not further specified) on the pharmacokinetics of talinolol, a P-glycoprotein substrate. 12 healthy male
volunteers took a single 100 mg oral dose of talinolol either alone (control group) or after pretreatment with 120 mg Ginkgo biloba extract three times daily for 14 days. Ginkgo biloba extract
treatment considerably increased talinolol AUC 0-24 and C max by 21% (p=0.002) and 33% (p=0.002),
respectively, whereas t and t max indicated no alteration. The results suggest that Ginkgo biloba
extract significantly inhibited P-glycoprotein in humans.
Fan et al. (2009b) investigated the effects of single and repeated Ginkgo biloba extract ingestion on
the oral pharmacokinetics of talinolol. Ten healthy male volunteers participated in a 3-stage sequential
study. Plasma concentrations of talinolol were measured by HPLC after talinolol 100 mg was
administered alone, with a single oral dose of Ginkgo biloba extract (120 mg), and after 14 days of
repeated Ginkgo biloba extract ingestion (360 mg/day). A single oral dose of GBE did not affect the
pharmacokinetics of talinolol. Repeated ingestion of Ginkgo biloba extract significantly increased C max
(36%), AUC 0-24 (26%) and AUC 0- (22%) of talinolol without significant changes in elimination half-life
and the time to C max . These results indicate that long-term use of Ginkgo biloba extract significantly
influence talinolol disposition in humans, likely by affecting the activity of P-glycoprotein inhibition
and/or other drug transporters.
Yin et al. (2004) designed this study to investigate the potential herb-drug interaction between
Ginkgo biloba leaf extract (containing 22.9% flavonol glycosides and 6.8% terpene lactones) and
omeprazole, a widely used CYP2C19 substrate. 18 healthy Chinese subjects with different CYP2C19
genotypes received a single omeprazole 40 mg at baseline and then at the end of a 12-day treatment
period with Ginkgo biloba leaf extract (140 mg, 2 times daily). The resulting pharmacokinetic
parameters of omeprazole, and its metabolites, 5-hydroxyomeprazole and omrprazole sulfone, show
that Ginkgo biloba leaf extract can induce omeprazole hydroxylation in a CYP2C19 genotype-dependent
EMA/HMPC/321095/2012
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manner and concurrently reduce the renal clearance of 5-hydroxyomeprazole. In conclusion,

coadministration of Ginkgo biloba with omeprazole or other CYP2C19 substrates may significantly
reduce their effect.
Kim et al. (2010) evaluated the potential pharmacokinetic interactions between ticlopidine and
Ginkgo biloba extract (not further specified). 24 healthy Korean male volunteers (244.3 years)
participated in this open-label, randomised, 2-period, 2-treatment, 2-sequence, singledose, crossover
study. All volunteers were randomly assigned to a sequence group for the 2 treatment, separated by a
1-week washout period between the treatments. Group 1 received ticlopidine 250 mg alone and group
2 ticlopidine 250 mg with Ginkgo biloba extract 80 mg. Concentrations of ticlopidine were determined
by using HPLC and ultraviolet detection. The geometric mean ratios of the ticlopidine/ginkgo group to
the ticlopidine test group were 1.03 for C max , 1.08 for AUC 0-last , and 1.10 for AUC 0- . In conclusion,
coadministration of Ginkgo biloba extract and ticlopidine was not associatetd with any significant
changes in the pharmacokinetic profile of ticlopidine compared with ticlopidine administered alone.
Mauro et al. (2003): An open label, randomised, crossover investigation was conducted in 8 healthy
volunteers aged 20-28 years to determine the effect of Ginkgo biloba leaf extract (containing 24%
flavone glycosides and 6% terpene lactones, ethanolic extracting solvent, 80 mg three times daily) on
digoxin (0.5 mg) pharmacokinetics. No significant difference between treatments was observed with
respect to AUC 0- , C max , T max , Cl, t and k e of digoxin. In conclusion, the concomitant use of Ginkgo
biloba leaf extract and digoxin did not appear to have any significant influence on the pharmacokinetics
of orally administered digoxin in healthy volunteers.
Lei et al. (2009a): To assess the effect of Ginkgo biloba extract (manufactured by Now Foods,
Bloomingdale, IL, USA) on the pharmacokinetics of bupropion 14 healthy male volunteers ingested a
single oral dose of 150 mg bupropion alone and during treatment with Ginkgo biloba extract
240 mg/day (two 60 mg capsules taken twice daily) for 14 days. Ginkgo biloba extract administration
resulted in no statistically significant effect on the pharmacokinetic parameters of bupropion.
Lei et al. (2009b): The following study was performed to examine the effect of concurrent
administration of Ginkgo biloba (manufactured by Now Foods, Bloomingdale, IL, USA) on the singledose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CYP2C19 extensive
or poor metabolisers. In a randomised, 2-phase crossover design 14 healthy volunteers received a
single 200 mg oral dose of voriconazole without pretreatment (control) and after pretreatment with
120 mg of Ginkgo biloba capsules twice daily for 12 days. In between of the study phases there was a
4-week washout period. The results show that administration of Ginkgo biloba 120 mg twice daily for
12 days to CYP2C19 extensive metabolisers and poor metabolisers had no statistically significant effect
on the pharmacokinetics of single-dose voriconazole. Therefore, the pharmacokinetic interactions
between voriconazole and Ginkgo biloba may have limited clinical significance.
Zuo et al. (2010): The objective of the following study was to assess the possible pharmacokinetic
interaction between Ginkgo biloba extract (composed of 24% flavone glycosides and 6% terpene
lactones, manufactured in China) and diazepam, when administered simultaneously to 12 Chinese
healthy male subjects. The pharmacokinetic parameters of diazepam and one of its metabolites, Ndemethyldiazepam, were compared after oral administration of diazepam (10 mg) in the absence or
presence of oral Ginkgo biloba extract (120 mg 2 times daily) for 28 days. The 90 % CIs of the ratios
of mean pharmacokinetic parameters of diazepam presence and absence of Ginkgo biloba extract were
well within the 80-125% bioequivalence range. These results suggest that Ginkgo biloba extract, when
taken in normally recommended doses over a 4-week time period, may not affect the
pharmacokinetics of diazepam via CYP2C19 and the excretion of N-desmethyldiazepam in healthy
volunteers. There was also no drug-drug interaction observed between Ginkgo biloba and diazepam.

EMA/HMPC/321095/2012
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Mohutsky et al. (2006) conducted two open-label, crossover pharmacokinetic studies in healthy
volunteers to determine the effect of Ginkgo biloba extract (Ginkgold, Natures Way, Springville, UT)
on 2 probe substrates of CYP2C9, diclofenac and tolbutamide. Diclofenac study: Diclofenac potassium
50 mg (immediate release) was administered to 12 subjects twice daily for 14 days. Gingko biloba
extract tablets, 120 mg twice daily, were given concurrently on days 8-15. Tolbutamide study:
Tolbutamide was administered as single 500 mg oral dose to 6 subjects. After a minimum of a 2-week
washout period, the subjects started Ginkgo biloba treatment phase consisting of 120 mg Ginkgo
biloba extract twice daily for 3 days. On day 4, the patients received a second 500 mg dose of
tolbutamide. No interactions between Ginkgo biloba extract and CYP2C9 probe substrates were
observed in vivo as evidenced by the lack of effect on the steady-state pharmacokinetics of diclofenac
or on the urinary metabolic ratio of tolbutamide.
Gurley et al. (2005) noted no effect of Ginkgo biloba on cytochrome P450 activity in this open-label
study. The aim of this study was to determine whether long-term supplementation, beside others, of
Ginkgo biloba (60 mg four times daily standardised to 24% flavone glycosides and 6% terpene
lactones) affected cytochrome P450 activity. 12 healthy volunteers (60-76 years) were randomly
assigned to receive each botanical supplement for 28 days followed by a 30-day washout period. Probe
drug cocktails of 8 mg midazolam, 100 mg caffeine, 500 mg chlorzoxazone and 5 mg debrisoquine
were administered before and at the end of supplementation. Pre- and post-supplementation
phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1 and CYP2D6. Comparisons of preand post-Ginkgo biloba phenotypic ratios revealed no significant changes in the CYP activity tested in
this study.
Yasui-Furukori et al. (2004) designed the study to examine the effect of Ginkgo biloba extract
(manufactured in Ichoha Sainoshin, Aihoupu Co., Kagoshima, Japan) on the pharmacokinetics of
donepezil in 14 elderly patients with Alzheimers disease. Subjects received donepezil 5 mg/day,
supplemented with Ginkgo biloba extract 90 mg/day for 30 days. Plasma drug concentration was
measured using HPLC. The resulting plasma concentration of donepezil during GBE supplementation
(meanSD [95% CI]; 24.412.6 ng/ml [17.1-31.7 ng/ml]) was not significantly different from that
before ginkgo supplementation (22.710.3 ng/ml [16.8-28.7 ng/ml]) or that 4 weeks after its
discontinuation (25.012.9 ng/ml [17.6-32.4 ng/ml]). In conclusion, the results show that ginkgo
supplementation does not have major impact on the pharmacokinetics of donepezil.
4.2. Clinical Efficacy

4.2.1. Dose response studies
4.2.2. Clinical studies (case studies and clinical trials)

EMA/HMPC/321095/2012
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Study
Treatment
Study and
Number
Diagnosis, inclusion
criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
Herrschaft et
24 weeks
EGb 761
n=410
mild to moderate AD
changes in the SKT
improvement of
119 AE in 91 (44.4%)
al. 2012
randomised,
(240 mg
n=205
or VaD associated
and NPI total score
2.23.5 points on the
EGb 761 treated
double-
once daily)
verum
with neuropsychiatric
SKT in the EGb 761
patients and 126 AEs
blind,
or placebo
n=205
symptoms
group and 0.33.7
for 82 patients (40.0%)
placebo-
placebo
points on placebo, NPI
of the placebo group;
controlled
50
score improved by
no major differences,
years
4.67.1 in the EGb 761
except for dizziness
group and by 2.16.5
with 7.3% in the
in the placebo group,
placebo group and
both drug-placebo
2.0% in the EGb 761
comparisons were
group; three serious AE
significant at p<0.001
in the EGb 761 group

were judged unrelated
to the trial medication
Ihl et al.
2010a
24 weeks
EGb 761
n=404
Mild to moderate
change of the SKT
improvement of SKT
no difference of
randomised,
(240 mg
n=202
dementia with
total score
score in 32% in the
incidence of AE in the
double-
once daily)
verum
neuropsychiatric
(cognitive efficacy)
EGb 761 group and in
treatment groups;
blind,
or placebo
n=202
features, at least 50
and the 12-item NPI
15% in the placebo
seven times more
placebo-
placebo
years, probable AD in
total score
group, improvement of
patients with tinnitus in
controlled,
50
accordance with the
(neuropsychiatric
NPI total score in
the placebo group;
parallel
years
NINCDS-ADRA
efficacy) during trial
45%in the EGb 761
dizziness: 19 (9.2%) in
criteria, possible AD
period

EMA/HMPC/321095/2012
group and 24% in
EGb 761 group and 23
with cerebrovascular
placebo group,
(11.3%) in placebo
disease (CVD) as
significant superiority of
group; serious AE:
Page 59/120
Study
Treatment
Study and
Number
criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
defined by the
EGb 761 over placebo
EGb 761 group
NINDS-AIREN criteria
in both primary
(ischaemic stroke and
or probable VaD
endpoints (p<0.001)
stage IV lung cancer),
age
according to NINDS-
placebo group
AIREN, symptoms of
(ischaemic stroke and
dementia at least for
rapid deteriora-tion of
6 months, CT or MRI
intellectual and motor
scan no more than 1
function)
year old, consistent

with the inclusion
diagnosis and showing
no evidence of other
brain lesions that
could account for the
cognitive deficit
Napryeyenko
22 weeks
EGb 761
n=391
mild to moderate
mean -3.2-point
EGb 761 group: 166
and
randomised,
(120 mg
n=196
dementia with
improvement in the
patients reported 302
Borzenko
double-
twice daily)
verum
neuropsychiatric
SKT on EGb 761 and
AE, placebo group: 178
2007
blind,
or placebo
n=195
features; 50 years,
average deterioration
patients reported 481
placebo-
placebo
probable AD
by +1.3 points on
AE; dizziness: 12 (6%)
controlled,
50
(NINCDS-ADRDA),
placebo (p<0.001);
in EGb 761 group and
parallel
years
possible AD
EGb 761 was
36 (18%) in placebo
(NINCDS/ADRDA),
significantly superior to
group; 7 non-fatal
with CVD (NINDS-
placebo with respect to
serious AE were

EMA/HMPC/321095/2012
SKT
Page 60/120
Study
Treatment
Study and
Number
criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
AIREN), probable VaD
all (primary and
reported on EGb 761
(NINDS-AIREN), CT or
secondary)efficacy
and 13 on placebo; no
MRI scan no more
variables (p<0.001)
event of bleeding
age
than one year old, no

other brain lesions,
TE4D score below 36,
SKT score from 9 to
23, CDT score below
6, score at least 5 on
the 12-item NPI with
at least one item
score being 3 or
higher, score below
20 on the 17-item
HAMD, presence of
caregiver
Yancheva et
al. 2009
22 weeks
EGb 761
n=96
AD and
no primary outcome
improvement in all
AE in 32% of EGb 761
randomised,
(120 mg
n=30
neuropsychiatric
measures were
tests and rating scales
group, 73% in
double-
twice daily),
verum
features, meet
defined, outcome of
in all groups, no
donepezil group and
blind,
or donepizil
n=29
NINCDS/ADRAD
interest were the
statistically significant
56% in combined
donepezil-
(5 mg once
control
criteria, score below
SKT, the CDT and
differences, relatively
treatment group; fewer
controlled,
daily during
n=29
36 on the TE4D,
the Verbal Fluency
consistent but not
AE (related to study
parallel
first 4
verum
below 6 on the Clock-
Test (cognitive
significant, slight
medication) in EGb 761
weeks,
+control
Drawing Test (CDT),
domain), the NPI
superiority of the
group than in the other

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duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
10 mg
50
between 9 and 23 on
and the HAMD
combined treatment
groups (p=0.01); most
during last
years
the SKT, at least
(behavioural and
over the single drugs
frequent: headache,
18 weeks),
score five on the 12-
psychological
insomnia, diarrhoea,
or combined
item NPI
domain), the GBS
and fatigue
treatment
(overall geriatric
(at recom-
assessment)
mended
doses)
Kanowski et
al. 1996
24 weeks
EGb 761
n=156
mild to moderate
psychopathological
responder rates in CGI
122 AE, 63 AE on
randomised,
(120 mg
n=79
primary degenerative
assessment (CGI),
and SKT higher under
EGb 761 and 59 on
double-
twice daily)
verum
dementia of the AH
cognitive
EGb 761 compared to
placebo; gastro-
blind,
or placebo
n=77
type or multi-infarct
performance
placebo (p<0.05), in
intestinal disorders
placebo
placebo
dementia (MID); SKT
assessment (SKT),
NAB tendency in favour
occurred more
controlled,
55
score between 6-18
assessment of
of EGb 761 (p<0.1),
frequently and in higher
parallel
years
(inclusive), MMSE
behaviour (NAB),
frequency of therapy
intensity on placebo; 7
score between 13-25
clinical efficacy
responders differed
serious AE (5 on
(inclusive)
assessment (therapy
significantly in favour of
EGb 761 and 2 on
response defined as
EGb 761 (p<0.005) in
placebo), one serious
response in at least
Fishers Exact Test
AE suspected acute
two of the three
cerebral incident was
primary variables-
related to study drug
Fishers Exact Test)
(investigator declined
to comment)

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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
Heinen-
12 months
EGb 761 (no
n=683
mild to moderate
quality of life of
according to PLC a
14 inpatient stays (5 on
Kammerer et
non-
dose
n=281
dementia;
care-taking relatives
significant improvement
EGb 761, 9 on
al. 2005
randomised,
mentioned)
verum
MMSE score between
and patients on the
in quality-of-life of care
standard) causally
two-armed,
or standard
n=402
12 and 24, 65-80
basis of PLC (quality
taking relatives
determined to dementia
open,
(no Ginkgo
standard
years, family member
of life profile of
(p<0.001) and patients
standard-
biloba
chronically ill
(positive mood
controlled,
extract,
65-80
as caregiver at home,
speak German, no
patients)
p=0.018, negative
parallel
previous
years
standard
aphasia, signed
mood p<0.001) was
informed consent
observed in the ginkgo
therapy
group
could be
continued)
Le Bars et
al. 1997
52 weeks
EGb 761
n=309
mildly to severely
changes in cognitive
50% of EGb 761 group
5 serious AE not related
randomised,
(40 mg three
n=155
demented patients
impairment (ADAS-
completed the study
to the study
double-
times daily)
verum
with AD or multi-
Cog), in daily living
and 38% of placebo
medication; 188 AE, 97
blind,
or placebo
n=154
infarct dementia,
and social behaviour
group; no significant
on EGb 761 and 91 on
placebo
placebo
without other
(GERRI), and in
change in the ADAS-
placebo, majority mild
controlled,
45
significant medical
general
Cog for EGb 761 group,
to moderate intensity
parallel
years
conditions
psychopathology
a significant worsening
(167/188); AE of
(CGIC)
of 1.5 points (p=0.006)
severe intensity (12 for
on placebo; mild
EGb 761 and 9 for
improvement in the
placebo) resulted in
GERRI on EGb 761,
withdrawal in 2 patients
significant worsening on
on EGb 761 and 1 on

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control
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Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
placebo (0.08 points;
placebo;
p=0.02), statistically
gastrointestinal events
significant difference in
more often on EGb 761
favour of EGb 761
(18 of 29 events)
age
(p=0.004); slight
worsening for both
treatment groups on
the CGIC; AD subgroup
analysis: similar results
for both treatments,
differences were
significant on ADASCog (p=0.02) and
GERRI (p<0.001)
Hofferberth
1989
8 weeks
EGb 761
n=36
cerebro-organic
quantitative EEG,
highly significant
after 4 weeks clearly
randomised,
(40 mg three
n=18
Syndrome;
saccadic test,
difference after 4 and
positive attitude in
double-
times daily)
verum
Haschinsky-Score,
Wiener
also 8 weeks in
verum group; 3 AE in
blind,
or placebo
n=18
EEG-theta ratio of
Determination Test,
saccadic test and
EGb 761 and 2 in
placebo-
placebo
70% of the whole
ZVT
psychometric tests
placebo group; no drop
controlled
53-69
spectrum, saccadic
(Wiener Determination
out
years
latency more than
Test and ZVT) on
250 ms, maximum
EGb 761 compared to
saccadic speed of
placebo, saccade
250/s, saccade
duration was shortened

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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
duration more than
and latency reduced,
150 ms, Wiener
number of correct
Determination Test
answers in Wiener
(less than 160 correct
Determination Test and
reactions in level 10,
ZVT increased
168 in level 12, 175 in
significantly on
level 15) and ZVT
EGb 761, marked
(more than 28
reduction in theta
seconds for
proportion of the
completing the test)
theta/alpha ratio, all

parameters tested
largely unaffected
under placebo
Halama et
12 weeks
EGb 761
n=40
mild to medium
SCAG score,
total SCAG score
no drop out; 1 AE in
al. 1988
randomised,
(40 mg three
n=20
cerebrovascular
descriptive: HIV
dropped on average by
verum group (mild to
double-
times daily)
verum
insufficiency;
(Hintergrundinterfer
9 points on EGb 761
moderate headache)
blind,
or placebo
n=20
Hachinski score >7,
enz-Verfahren),
and remained
placebo-
placebo
Crichton scale level 1-
SKT, CCG
unchanged on placebo
controlled
55-85
3 (score 11-21)
(Craniocorpographie
(difference between
), symptom-rating
treatment groups
years
p=0.00005), an effect
in SCAG-items
particularly on
disturbances of short-

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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
term memory and
mental awareness,
specific verum effect on
the SKT, no effect
shown on HIV and CCG,
superior effects were
also shown in the
symptoms of dizziness,
headaches and tinnitus
Eckmann
6 weeks
Ginkgo
n=58
cerebral insufficiency
changes in 12
small but progressive
1990
randomised,
biloba
n=29
and the leading
typical symptoms
improvements on
double-
extract
verum
symptom depressive
after 2, 4 and 6
placebo, overall number
blind,
(solution
n=29
mood
weeks
of improvements
placebo-
Kaveri,
placebo
significantly larger on
controlled
three times
41-71
Ginkgo biloba, after 2
daily, daily
years
weeks differences in
dosage
only a few of the
160 mg or
symptoms, after 4 and
rather 40 mg
6 weeks differences in
ginkgoflavon
11 of the 12 symptoms,
glycosides)
largest number of
or placebo
improvements on
not indicated
ginkgo between week 2

and 4 (2/3 of patients)
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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
Mazza et al.
24 weeks
Ginkgo
n=76
mild to moderate
SKT, CGI, CGI-2,
no significant change
5 drop outs on Ginkgo
2006
randomised,
biloba
n=25
dementia;
MMSE
for MMSE scores,
biloba not imputable to
double-
special
ginkgo
mean score of 3-5 on
EGb 761 and donepezil
AE and 4 drop outs on
blind,
extract E.S.
n=25
the Brief Cognitive
group show significant
donepezil due to AE
placebo-and
(Flavogin,
donepezil
Rating Scale,
difference of SKT and
donepezil
160 mg
n=26
Hachinski Ischemic
CGI scores after
controlled
daily-no
placebo
Score of <4, IQ>80
treatment compared
further
50-80
(global assessment),
with placebo (p=0.01)
details) or
years
SKT score between 8
donepezil
and 23, MMSE score
(5 mg daily-
between 13 and 25
no further
(inclusive)
details) or
placebo
Schneider et
al. 2005
26 weeks
EGb 761
n=513
mild to moderate
ADAS-cog, ADCS-
no differences between
Dizziness cases:
CGIC
the treatment groups in
EGb 761 120 mg group
cognitive endpoint,
17 (10.1%), EGb 761
randomised,
(60 mg or
n=169
dementia of the
double-
120 mg
verum
Alzheimer type
blind,
twice daily)
(120 mg)
ADCS-CGIC did not
240 mg group 11
placebo-
or placebo
n=170
differ significantly
(6.5%) and placebo
controlled,
verum
among treatment
group 12 (6.9%); in 4
parallel
(240 mg)
groups
out of 42 serious AE a

EMA/HMPC/321095/2012
n=174
causal relationship was
placebo
considered unlikely
60
related to the study
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duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
years
drug; no dose effect

was detected; no
systematic changes or
prolongation in
bleeding time and blood
coagulation; no
interaction between
EGb 761 and aspirin or
warfarin in relevant
subjects
Van Dongen
24 weeks
EGb 761 (80
n=214
dementia (either AD
NAI-ZVT-G, NAI-ZN-
no effect on each of the
first part: AE were
et al. 2000
randomised,
or 120 mg
n=84
or VaD; mild to
G, NAI-WL, SCAG,
outcome measures for
56%, 52%, and 44%
double-
twice daily)
verum
moderate degree) or
GDS, self-perceived
patients on ginkgo
for the ginkgo 240 mg,
blind,
or placebo
(160 mg)
age-associated
health and memory
compared to placebo
ginkgo 160 mg, and
placebo-
n=82
memory impairment
status, and
placebo groups,
controlled,
verum
behavioural
respectively; most
parallel,
(240 mg)
assessment
common: dizziness
after 12
n=48
(n=58), nervousness
weeks
placebo
(n=49), headache
ginkgo users
50
(n=32); second part:
were
randomised
years
rates of AE were 46%,

40% and 65%; 35
once again
serious AE during entire
to continued
trial period (one
ginkgo or
possible association

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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
McCarney et
al. 2008
placebo
with study treatment,
treatment
placebo user)
6 months
EGb 761
n=176
mild to moderate
cognitive functioning
no significant effect
total of 63 AE, 29
randomised,
(60 mg twice
n=88
dementia; 55 years,
(ADAS-Cog),
between treatment
(placebo group) and 28
double-
daily) or
verum
presence of a carer,
participant and
groups on any primary
(ginkgo group); one
blind,
placebo
endpoint
fatal cerebral
n=88
informed consent,
carer-rated quality
placebo-
placebo
sufficient command of
of life (QOL-AD)
controlled,
55
English, clinical
parallel
years
diagnosis of dementia,
haemorrhage in ginkgo
group
MMSE score of 12-26

inclusive, living in
Greater London and
adjoining regions
Grass-
12 weeks
EGb 761
n=300
very mild cognitive
efficacy and
EGb 761 improved
most frequently
Kapanke et
randomised,
(240 mg
al. 2011
double-
once daily)
n=150
impairment (vMCI),
tolerability of
cognitive functioning
gastrointestinal
verum
subjective complaints
EGb 761 in subjects,
and aspects of quality
symptoms and
blind,
or placebo
n=150
of impairment, low
(measure of
of life
infections and
placebo-
control
functioning in at least
attention and of
infestations; no serious
controlled,
45-65
one of the cognitive
memory, perceived
AE
parallel
years
tests, perceived
physical health)
impairment for at
least 3 months, total
score above 23 in the

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Study and
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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
MMSE, intact activities
of daily living, no
indication of dementia
DeKosky et
6.1 years
EGb 761
n=3069
normal cognition or
diagnosis of
16.1% in placebo group
no statistically
al. 2008
randomised,
(120 mg
n=1545
MCI, 75 years
dementia by DSM-IV
were diagnosed with
significant differences
double-
twice daily)
verum
criteria
dementia and 17.9% in
in rate of serious AE;
blind,
or placebo
n=1524
EGb 761 group
mortality rate was
placebo-
placebo
similar in the two
controlled,
75
treatment groups
parallel
years
Burle et al.
6 weeks
Ginkgo
n=59
MCI, > 60 years,
DemTect (mental
no significant change in
39 AE; only one
2009
open
biloba fresh
>60
plant extract
years
DemTect score >12,
performance), SF-12
DemTect and SF-12
gastrointestinal
no obvious symptoms
(quality of life), 5-
physical subscore, SF-
disturbances and 18 AE
(90 mg twice
of dementia in the
point scale (change
12 mental subscore
were evaluated as
daily)
judgement of the
in symptoms), 4-
increased significantly
possibly related to the
investigator, signed
point scale
by 3 points to 51.57.9
medication, transient
informed consent, at
(assessing efficacy
(p=0.013), symptoms
and mild to moderate in
least two of the
by the patient and
improved in 41.3%
nature; treatment was
following symptoms:
the investigator),
(forgetfulness), 43.1%
tolerated well to very
forgetfulness,
questioning of
(impaired
well in 83%; 6.8%
impaired
retreatment
concentration), and
were dissatisfied with
concentration, or
(acceptance of
34.5% (impaired
the tolerability
impaired memory,
treatment)
memory), 61% of the

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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
medication for
patients assessed
improvement of
efficacy as good or
mental performance
rather good, 28.8%
was only allowed if it
noticed no effect,
had been taken at a
investigators rated
regular dosage for
tablets as effective or
more than 4 weeks
very effective in 69.4%,
prior to start of the
and as not effective in
study
23.7%, 90% would

take the tablets again
Vellas et al.
2012
5 years
EGb 761
n=2854
spontaneously
conversion to
61 participants (1.2
Death, stroke and
probable AD
randomised,
(120 mg
n=1406
reported memory
cases per 100 person-
incidence of other
double-
twice daily)
verum
complaints to
years) in the Ginkgo
haemorrhagic or
blind,
or placebo
n=1414
primary-care
biloba group and 73
vascular events did not
placebo-
placebo
physician
(1.4 cases per 100
differ between groups
controlled,
70
person-years) in the
parallel
years
placebo group had been

diagnosed with
probable AD (hazard
ratio 0.84, 95% CI 0.61.18; p=0.306)

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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
Brautigam et
24 weeks
Geriaforce,
n=241
Memory and/or
EMCT, Benton Test,
in subjective test,
most frequently side
al. 1998
randomised,
fresh plant
n=77
concentration
Rey Test part 1,
EMCT, Rey 1 and Rey 2
effects were
double-
extract
high dose
complaints
BDI, Rey Test part
no significant
gastrointestinal
blind,
(ethanol
n=82 low
2, subjective
differences in
complaints; no
placebo-
70% V/V,
dose
perception of
improvement between
differences in the
controlled
DER 1:4,
n=82
memory and
groups, in Benton test
number of these side
total flavone
placebo
concentration
increases of 18%, 26%
effects between placebo
glycosides
55-86
and 11% in the HD, LD
and verum group;
0.2 mg/ml,
years
and placebo group,
dizziness: HD group 3,
respectively
LD group 4 and placebo
total
ginkgolides
0 cases; among drop
0.34 mg/ml),
outs 3 cases in the HD
high dose
group, 1 in LD group
(HD): 40
and 3 on placebo
drops ginkgo
extract three
times daily,
low dose
(LD): 40
drops ginkgo
extract 1:1
with placebo
three times
daily or
placebo

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Study
Treatment
Study and
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criteria
duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
Kaschel
6 weeks
EGb 761
n=188
mentally healthy,
assess effects on
significant improvement
low incidence of AE and
2011
randomised,
(240 mg
n=94
aged 45-65, higher-
long-term memory,
in quantity and quality
not significantly
double-
once daily)
verum
level secondary
replicate evidence
of recall of
different between
blind,
or placebo
n=94
education (at least
suggesting that
appointments, no
treatment groups
placebo-
placebo
middle or high
objective
superiority of ginkgo in
controlled,
45-65
school), sufficient
improvement is
another everyday
parallel
years
language skills to
paralleled by
memory test
understand and
changes in
(recognition of a driving
respond to interview
subjective memory
route)
questions and
ratings, link changes
undergo
in objective
neuropsychological
psychometric test
testing without
performance with
difficulties and without
everyday life in
assistance, who had
terms of ecological
provided written
validity
informed consent
Dodge et al.
42 months
Ginkgo
n=118
normal elderly, 85
mild cognitive
14 cases among
GBE group had more
2008
randomised,
biloba
n=60
years, informant
decline (defined as
placebo and 7 cases
stroke or TIA incidences
double-
extract
verum
available, no
CDR from 0 to 0.5),
among GBE group
(p=0.01), all strokes
blind,
(GBE, at
n=58
subjective memory
decline in memory
progressed to
were non-haemorrhagic
placebo-
least 6%
placebo
complaint, normal
function (Word List
CDR=0.5, GBE group
infarcts except one
controlled
terpene
85
memory function,
Delayed Recall test),
showed a tendency of
case, no deaths due to
lactones and
years
MMSE score >23,
adverse events
less decline in memory
stroke; dizziness: GBE

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duration
control
of
Study
drugs, daily
subjects
design
dose
by arms,
Primary endpoints
Efficacy results
Safety results
age
24% flavone
function, no difference
group 2 (3.3%) and
glycosides)
CDR=0, CES-D-10 >4
in adverse events
placebo group 2 (5.2%)
80 mg three
(p=0.44)
times daily
or placebo
The following table summarises relevant data from the table above concerning the age associated meaning of dementia. Most studies are conducted with
patients aged 50 and older. Four studies included patients with a minimum age of 41 (one study) or rather 45 (three studies). No data are given about the
number of patients with corresponding age. To compare the mean age the lowest mean age of the older age studies is 63 years. In comparison to the
studies with patients aged 41 or rather 45 the mean age is in the range of 54-56, except one study by Le Bars et al (1997). In this trial the mean age (69
years) is in the range of the mean age of studies with older aged patients. The three studies, which show no comparable mean age to the rest of the studies,
include a low number of patients or a diagnosis which has no relevance in supporting the monograpf relevant indication.
Study
Patients (No.)
Age
Diagnosis
Efficacy results
Herrschaft et al. 2012
n=410
50 years
Mild to moderate AD or
Improvement of 2.23.5 points on the SKT in the
Mean age: 65 years
VaD associated with
EGb 761 group and 0.33.7 points on placebo, NPI
neuropsychiatric
score improved by 4.67.1 in the EGb 761 group and
symptoms
by 2.16.5 in the placebo group, both drug-placebo

comparisons were significant at p<0.001
Ihl et al. 2010a
n=404

EMA/HMPC/321095/2012
50 years
Mild to moderate dementia
Improvement of SKT score in 32% in the EGb 761
Mean age: 65 years
group and in 15% in the placebo group,
features
improvement of NPI total score in 45%in the
Page 74/120
Study
Patients (No.)
Age
Diagnosis
Efficacy results
EGb 761 group and 24% in placebo group, significant
superiority of EGb 761 over placebo in both primary
endpoints (p<0.001)
Napryeyenko and
n=391
Borzenko 2007
50 years
Mean -3.2-point improvement in the SKT on EGb 761
Mean age: placebo group
and average deterioration by +1.3 points on placebo
63 years, verum group 65
features
(p<0.001); EGb 761 was significantly superior to
years
placebo with respect to all (primary and

secondary)efficacy variables (p<0.001)
Yancheva et al. 2009
Kanowski et al. 1996
n=96
n=156
50 years
AD and neuropsychiatric
Improvement in all tests and rating scales in all
Mean age: verum group 70
features
groups, no statistically significant differences,
years, donepezil group 67
relatively consistent but not significant, slight
years and combined
superiority of the combined treatment over the single
treatment group 69 years
drugs
55 years
Mild to moderate primary
Responder rates in CGI and SKT higher under
Mean age: placebo (male)
degenerative dementia of
EGb 761 compared to placebo (p<0.05), in NAB
66, (female) 72 years,
the AH type or multi-
tendency in favour of EGb 761 (p<0.1), frequency of
verum (male and female)
infarct dementia (MID)
therapy responders differed significantly in favour of
70 years
Heinen-Kammerer et
n=683
al. 2005
Le Bars et al. 1997
n=309
65-80 years
EGb 761 (p<0.005) in Fishers Exact Test

According to PLC a significant improvement in
Mean age: standard group
quality-of-life of care taking relatives (p<0.001) and
patients (positive mood p=0.018, negative mood
years
p<0.001) was observed in the ginkgo group
45 years
Mildly to severely
50% of EGb 761 group completed the study and
Mean age: both groups 69
demented patients with AD
38% of placebo group; no significant change in the
years
or multi-infarct dementia
ADAS-Cog for EGb 761 group, a significant worsening

of 1.5 points (p=0.006) on placebo; mild
improvement in the GERRI on EGb 761, significant

EMA/HMPC/321095/2012
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Study
Patients (No.)
Age
Diagnosis
Efficacy results
worsening on placebo (0.08 points; p=0.02),
statistically significant difference in favour of
EGb 761 (p=0.004); slight worsening for both
treatment groups on the CGIC; AD subgroup
analysis: similar results for both treatments,
differences were significant on ADAS-Cog (p=0.02)
and GERRI (p<0.001)
Hofferberth 1989
n=36
53-69 years
Cerebro-organic Syndrome
Highly significant difference after 4 and also 8 weeks
in saccadic test and psychometric tests (Wiener
years
Determination Test and ZVT) on EGb 761 compared

to placebo, saccade duration was shortened and
latency reduced, number of correct answers in
Wiener Determination Test and ZVT increased
significantly on EGb 761, marked reduction in theta
proportion of the theta/alpha ratio, all parameters
tested largely unaffected under placebo
Halama et al. 1988
n=40
55-85 years
Mild to medium
Total SCAG score dropped on average by 9 points on
cerebrovascular
EGb 761 and remained unchanged on placebo
insufficiency
(difference between treatment groups p=0.00005),
years
an effect in SCAG-items particularly on disturbances

of short-term memory and mental awareness,
specific verum effect on the SKT, no effect shown on
HIV and CCG, superior effects were also shown in the
symptoms of dizziness, headaches and tinnitus
Eckmann 1990
n=58
41-71 years
Cerebral insufficiency and
Small but progressive improvements on placebo,
the leading symptom
overall number of improvements significantly larger
depressive mood
on Ginkgo biloba, after 2 weeks differences in only a
years

EMA/HMPC/321095/2012
few of the symptoms, after 4 and 6 weeks
Page 76/120
Study
Patients (No.)
Age
Diagnosis
Efficacy results
differences in 11 of the 12 symptoms, largest
number of improvements on ginkgo between week 2
and 4 (2/3 of patients)
Mazza et al. 2006
n=76
50-80 years
No significant change for MMSE scores, EGb 761 and
donepezil group show significant difference of SKT
and CGI scores after treatment compared with
years, donepezil group 65
placebo (p=0.01)
years
Schneider et al. 2005
n=513
60 years
No differences between the treatment groups in
Mean age: placebo and
of the Alzheimer type
cognitive endpoint, ADCS-CGIC did not differ
verum group II 78 years,
significantly among treatment groups
verum group I 79 years

Van Dongen et al.
n=214
2000
50 years
Dementia (either AD or
No effect on each of the outcome measures for
Mean age: all groups 83
VaD; mild to moderate
patients on ginkgo compared to placebo
years
degree) or age-associated
memory impairment
McCarney et al. 2008
n=176
55 years
No significant effect between treatment groups on

any primary endpoint

years
Grass-Kapanke et al.
n=300
2011
DeKosky et al. 2008
n=3069
45-65 years
Very mild cognitive
EGb 761 improved cognitive functioning and aspects
Mean age: 55 years
impairment (vMCI)
of quality of life
75 years
Normal cognition or MCI
16.1% in placebo group were diagnosed with
Mean age: 79 years

Burle et al. 2009
n=59
>60 years
Mean age: 72 years

EMA/HMPC/321095/2012
dementia and 17.9% in EGb 761 group

MCI
No significant change in DemTect and SF-12 physical

subscore, SF-12 mental subscore increased
Page 77/120
Study
Patients (No.)
Age
Diagnosis
Efficacy results
significantly by 3 points to 51.57.9 (p=0.013),
symptoms improved in 41.3% (forgetfulness), 43.1%
(impaired concentration), and 34.5% (impaired
memory), 61% of the patients assessed efficacy as
good or rather good, 28.8% noticed no effect,
investigators rated tablets as effective or very
effective in 69.4%, and as not effective in 23.7%,
90% would take the tablets again
Vellas et al. 2012
n=2854
70 years
Spontaneously reported
61 participants (1.2 cases per 100 person-years) in
memory complaints to
the Ginkgo biloba group and 73 (1.4 cases per 100
years
primary-care physician
person-years) in the placebo group had been

diagnosed with probable AD (hazard ratio 0.84, 95%
CI 0.6-1.18; p=0.306)
Brautigam et al. 1998
n=241
55-86 years
Memory and/or
In subjective test, EMCT, Rey 1 and Rey 2 no
Mean age: all three groups
concentration complaints
significant differences in improvement between
69 years
groups, in Benton test increases of 18%, 26% and

11% in the HD, LD and placebo group, respectively
Kaschel 2011
Dodge et al. 2008
n=188
n=118
45-65 years
Mentally healthy
Significant improvement in quantity and quality of
recall of appointments, no superiority of ginkgo in
another everyday memory test (recognition of a
ears
driving route)
85 years
Mean age is not given
Normal elderly
14 cases among placebo and 7 cases among GBE

group progressed to CDR=0.5, GBE group showed a
tendency of less decline in memory function, no
difference in adverse events (p=0.44)

EMA/HMPC/321095/2012
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4.2.2.1. Cognitive decline/Dementia syndrome

The authors conclusion of the English version of the executive summary of the IQWiG final report A0519B: For the therapy goal activities of daily living, there is evidence of a benefit of high-dose
(240 mg daily) ginkgo extract EGb 761. In patients taking this dose, there are also indications of a
benefit for the therapy goals cognitive function and general psychopathological symptoms, as well
as for the caregiver-relevant therapy goal quality of life of caregivers (measured on the basis of
caregivers emotional stress). However, the conclusion that ginkgo has a beneficial effect is based on
very heterogeneous results; therefore no summarising conclusion can be made on the potential effect
size. In addition, there is an indication that this benefit is only present in patients with accompanying
psychopathological symptoms. Moreover, it needs to be considered that the results were strongly
affected by 2 studies conducted in Eastern European health-care setting with specific patient
populations (among other things, patients with a high rate of accompanying psychopathological
symptoms).
Due to the high heterogeneity between studies, no conclusive statement can be made on the benefit of
low-dose ginkgo (120 mg daily). Relevant data on ginkgo extracts other than ginkgo extract EGb 761
were not available.
The benefit of ginkgo compared with other drugs approved for Alzheimers disease (such as
cholinesterase inhibitors or memantine) is unclear, as only one explorative study investigated a direct
comparison (vs. donepezil).
Despite the consideration of the ginkgo dose in the interpretation of results, the considerable
heterogeneity could not be adequately explained. An assessment of the effect size was not possible on
the basis of the available study data. Additional studies designed specifically to investigate individual
subgroups of patients with Alzheimers disease are needed to enable subgroup-specific conclusions to
be drawn. As the results of this benefit assessment were dominated by 2 studies that were not
conducted in the health-care setting of a Western country, future studies should be carried out in such
a setting. If, due to available treatment options (e.g., cholinesterase inhibitors), placebo-controlled
studies seem difficult to conduct, appropriate comparator studies with other antidementiva drugs could
be an alternative option. Data from long-term studies would also be desirable to assess potential
beneficial and adverse effects of long-term therapy with ginkgo (Institute for Quality and Economic
Efficiency in the Healthcare System 2008).
Study
Herrschaft et al. 2012
Indication
mild to moderate AD or VaD associated with neuropsychiatric symptoms
Treatment duration
24 weeks
Test product
EGb 761
Single/Daily dosage
240 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
n=17
number of patients
410 randomised; 205 (EGb 761), 205 (placebo)
age
50 years
wash-out
4 weeks

EMA/HMPC/321095/2012
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Outcome
Patients treated with EGb 761 improved by 2.23.5 points (mean sd) on
the SKT total score, whereas those receiving placebo changed only slightly
by 0.33.7 points. The NPI composite score improved by 4.67.1 in the
EGb 761-treated group and by 2.16.5 in the placebo group. Both drugplacebo comparisons were significant at p<0.001. Patients in the EGb 761
group also showed a more favourable course in most of the secondary
efficacy variables (ability to cope with the demands of everyday living,
quality of life and clinicians global judgement).
Authors conclusion: Treatment with EGb 761 at a once daily dose of
240 mg was safe and resulted in a significant and clinically relevant
improvement in cognition, psychopathology, functional measures and
quality of life of patients and caregivers.
Study
Ihl et al. 2010a
Indication
Mild to moderate dementia with neuropsychiatric features (probable

Alzheimers disease (AD) according to National Institute of Neurological and
Communicative Disorders and Stroke/ AD and Related Disorders
Association (NINCDS-ADRDA), possible AD with cerebrovascular disease
(CVD) according to National Institute of Neurological Disorders and
Stroke/Association Internationale pour la Recherche et l`Enseignement en
Neurosciences (NINDS-AIREN) or probable vascular dementia (VaD)
according to (NINDS-AIREN)); scoring 35 or lower in the Test for Early
Detection of Dementia with Discrimination from Depression (TE4D),
between 9 and 23 on the Syndrom Kurz Test (SKT), at least 5 on the
Neuropsychiatric Inventory (NPI), with at least on item score of 3 or more,
but below 20 on the Hamilton Rating Scale for Depression (HAMD)
Treatment duration
24 weeks
Test product
EGb 761
Single/Daily dosage
240 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
n=20
number of patients
202 (EGb 761); 202 (placebo)
age
50 years
wash-out
up to 4 weeks
Outcome
Patients treated with EGb 761 improved by -1.4 (95% CI -1.8; -1.0) points
on the SKT and by -3.2 (-4.0; -2.3) on the NPI total score, whereas those
receiving placebo deteriorated by +0.3 (-0.1; 0.7) on the SKT and did not
change on the NPI total score (-0.9; 0.9). Both drug-placebo comparisons
were significant at p<0.001. EGb 761 was significantly superior to placebo
with respect to Alzheimers Disease Cooperative Study Clinical Global
Impression of Change (ADCS-CGIC), Activities of Daily Living International
Scale (ADL-IS), NPI distress score, DEMQOL-Proxy quality-of-life scale and
Verbal Fluency Test. Averse event rates were similar for both treatment
groups.

EMA/HMPC/321095/2012
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Authors conclusion: EGb 761, 240 mg once daily, was found significantly
superior to placebo in the treatment of patients with dementia with
neuropsychiatric symptoms.
Study
Ihl et al. 2010b

Retrospective analysis of data from the above mentioned trial
Outcome
Correlations between changes from baseline and NPI baseline scores were
weak to modest, but conspicuously different between active drug and
placebo groups. The slopes of the regression lines for the EGb 761 and the
placebo groups showed qualitative and statistically significant differences:
With increasing NPI baseline scores there was faster deterioration in the
placebo group and thus more net benefit from treatment for the EGb 761
group. EGb 761 was effective in the treatment of dementia irrespective of
the severity of neuropsychiatric symptoms.
Study
Ihl et al. 2011

Subgroup analyses of the above mentioned study
Outcome
EGb 761 treatment was superior to placebo with respect to the SKT total
score (drug-placebo differences: 1.7 for AD, p<0.001, and 1.4 for VaD,
p<0.05) and the NPI total score (drug-placebo differences: 3.1 for AD,
p<0.001 and 3.2 for VaD, p<0.05). Significant drug-placebo differences
were found for most secondary outcome variables (ADCS-CGIC, ADL-IS,
the DEMQOL-proxy quality of life scale, and the Verbal Fluency Test) with
no major differences between AD and VaD subgroups. Rates of adverse
effects were essentially similar in both groups.
Authors conclusion: EGb 761 improved cognitive functioning,
neuropsychiatric symptoms and functional abilities in both types of
dementia.
Study
Bachinskaya et al. 2011

Secondary analyses of data from the above mentioned study
Outcome
Primary outcome: NPI composite score improved by -3.2 (95% CI -4.0 to 2.3) in patients taking EGb 761, no change (-0.9; 0.9) in those receiving
placebo
Secondary outcome: NPI distress score (evaluate caregivers distress)
revealed similar baseline pattern and improvements
Authors conclusion: Treatment with EGb 761, at once-daily dose of
240 mg, was safe, effectively alleviated behavioural and neuropsychiatric
symptoms in patients with mild to moderate dementia, and improved the
wellbeing of their caregivers.

EMA/HMPC/321095/2012
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Study
Napryeyenko and Borzenko 2007
Indication
Mild to moderate dementia with neuropsychiatric features (probable AD

(NINCDS-ADRDA), possible AD (NINCDS/ADRDA) with CVD (NINDS-AIREN)
or probable VaD (NINDS-AIREN))
Treatment duration
22 weeks
Test product
EGb 761
Single/Daily dosage
120 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
n=16
number of patients
400 randomised; study completed: 196

(EGb 761), 195 (placebo)
Outcome
age
50 years
wash-out
up to 4 weeks
There was a mean -3.2-point improvement in the SKT upon EGb 761
treatment and an average deterioration by +1.3 points on placebo
(p<0.001, two sided, ANOVA). EGb 761 was significantly superior to
placebo on all secondary outcome measures, including the NPI and an
activities-of-daily-living scale. Treatment results were essentially similar for
AD and VaD subgroups. The drug was well tolerated; adverse events were
no more frequent under drug than under placebo treatment.
Authors conclusion: The data add further evidence on the safety and
efficacy of EGb 761 in the treatment of cognitive and non-cognitive
symptoms of dementia.
Study
Napryeyenko et al. 2009

Secondary analyses of the above mentioned trial
Outcome
Under EGb 761 treatment the SKT total score improved by -3.02.3 and 3.42.3 points in patients with AD and VaD, respectively, whereas the
patients on placebo deteriorated by +1.22.5 and 1.52.2 points,
respectively (p<0.01 for both drug-placebo differences). Significant drugplacebo differences were found for all secondary outcome variables with no
major differences between AD and VaD subgroups. The rate of adverse
events tended to be higher for the placebo group.
Authors conclusion: The subgroup analyses demonstrated that EGb 761
was safe and effective in the treatment of both major types of dementia,
AD and VaD.
Study
Scripnikov et al. 2007

Detailed description of the effects of EGb 761 on the various
neuropsychiatric symptoms of dementia of data from the above mentioned
trial
Outcome
The mean composite score (frequency x severity) and the mean caregiver

EMA/HMPC/321095/2012
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distress score of the NPI dropped from 21.39.5 to 14.79.5 and from
13.56.7 to 8.75.5, respectively, in the EGb 761-treated patients, but
increased from 21.69.9 to 24.112.8 and 13.46.4 to 13.97.2,
respectively, under placebo (p<0.001). The largest drug-placebo
differences in favour of EGb 761 were found for apathy/indifference,
anxiety, irritability/lability, depression/dysphoria and sleep/nighttime
behaviour.
Authors conclusion: EGb 761 was safe and effective in the treatment of
dementia with neuropsychiatric symptoms.
Study
Kanowski et al. 1996
Indication
Mild to moderate primary degenerative dementia of the Alzheimer type or

multi-infarct dementia (MID); SKT score: 6-18; MMSE score: 13-25
Treatment duration
24 weeks
Test product
EGb 761
Single/Daily dosage
120 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
n=41
number of patients
216 (ITT: 205; per-protocol (PP):156)
age
55 years
wash-out
4 weeks
Outcome
The frequency of therapy responders in the two treatment groups differed

significantly in favour of EGb 761, with p<0.005 in Fishers Exact Test. The
intent-to-treat analysis led to similar efficacy results.
Authors conclusion: The clinical efficacy of EGb 761 in dementia of the
Alzheimer type and multi-infarct dementia was confirmed. The
investigational drug was found to be well tolerated.
Study
Kanowski and Hoerr 2003

Detailed ITT analysis of all patients and for the subgroup of probable
dementia of the Alzheimer type (DAT) patients of data from the above
mentioned study
Outcome
ITT analysis of the total population: The ITT analysis of the SKT and
estimated AD Assessment Scale-cognition (ADAS-cog) scores revealed a
mean decrease in the total score by -2.1 (95% CI: -2.7; -1.5) points and 2.7 (95% CI: -3.5; -1.9) points, respectively, for the EGb 761 group, which
indicates an improvement in cognitive function. On the contrary, the
placebo group exhibited only a minimal change of -1.0 (95% CI: -1.6; 0.3) and -1.3 (95% CI: -2.0; -0.4) points, respectively. The changes from
baseline differed significantly between treatment groups by 1.1 (SKT) and
1.4 (estimated ADAS-cog) points, respectively (p=0.01). The Clinical
Global Impression of Change favoured the EGb 761 group with a mean

EMA/HMPC/321095/2012
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difference of 0.4 points (p=0.007). Changes in the rating related to

activities of daily living (Nrnberger-Alters-Beobachtungs-Skala, NAB)
showed a favourable trend for EGb 761.
ITT analysis of patients with DAT: Using a decrease of at least 4 points on
the estimated ADAS-cog scores as cutoff criterion for treatment response,
35% of EGb 761-treated patients were considered responders versus only
19% for the placebo group (p=0.01)
Authors conclusion: The results substantiate the outcomes previously
obtained with a responder analysis of the PP population and confirm that
EGb 761 improves cognitive function in a clinically relevant manner in
patients suffering from dementia.
Study
Heinen-Kammerer et al. 2005
Indication
Mild to moderate dementia; MMST: 12-24
Treatment duration
12 months
Test product
EGb 761
Single/Daily dosage
no dose mentioned
Study design
randomised
no
double-blind
no (open)
controlled
yes (standard)
parallel group
yes
multicentre
yes
number of patients
281 (Ginkgo-cohort), 402 (Standard-cohort)
age
65-80 years
wash-out
Outcome
According to Profile of quality of life of chronically ill (PLC) a significant

improvement in quality-of-life of care-taking relatives (p<0.001) and
patients (positive mood p=0.018, negative mood p<0.001) was only
observed in the ginkgo-cohort. Barthel-Index indicated an improvement in
the ginkgo-cohort (p<0.001). MMST-scores increased in significantly only
in the ginkgo-cohort (p<0.001).
Authors conclusion: EGb 761 attributes to a higher quality of life for both
care-takers and patients and the progression of disease is slowed down.
Study
Le Bars et al. 1997
Indication
Mildly to severely demented patients with AD or multi-infarct dementia,

without other significant medical conditions
Treatment duration
52 weeks
Test product
EGb 761
Single/Daily dosage
40 mg/120 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
n=6

EMA/HMPC/321095/2012
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Outcome
number of patients
309 (ITT); 202 (end point analysis)
age
45 years
wash-out
2 weeks
ITT analysis: The EGb 761 group had an ADAS-cog score 1.4 points better
than the placebo group (p=0.04) and a Geriatric Depression Scale (GERRI)
score 0.14 points better than the placebo group (p=0.004).
End point analysis: The same patterns were observed with the evaluable
data set in which 27% of patients treated with EGb 761 achieved at least a
4-point improvement on the ADAS-cog, compared with 14% taking placebo
(p=0.005); on the GERRI, 37% were considered improved with EGb 761,
compared with 23% taking placebo (p=0.003). No difference was seen in
the Clinical Global Impression of Change (CGIC). No significant differences
compared with placebo were observed in the number of patients reporting
adverse events or in the incidence and severity of these events.
Authors conclusion: EGb 761 was safe and appears capable of stabilising
and, in a substantial number of cases, improving the cognitive performance
and the social functioning of demented patients for 6 months to 1 year.
Although modest, the changes induced by EGb 761 were objectively
measured by the ADAS-cog and were of sufficient magnitude to be
recognised by the caregivers in the GERRI.
Study
Hofferberth 1989
Indication
Classical symptoms of organic syndrome such as dizziness, memory and

concentration loss, and orientation disorders
Treatment duration
8 weeks
Test product
EGb 761
Single/Daily dosage
40 mg/120 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
number of patients
36 (18 each group)
age
53-69 years
wash-out
2 weeks
Outcome
A highly significant difference could be seen in the results of the saccadic

test and the psychometric tests compared to the placebo control group.
Saccade duration was shortened and the latency reduced. In parallel, the
number of correct answers given in the Wiener Determination Test and
Number Connection Test increased significantly compared to the control
group. A marked reduction in the theta proportion of the theta/alpha ratio
was found. All the parameters tested remained largely unaffected under
placebo therapy.
Authors conclusion: EGb 761 is significantly more effective than placebo
and confirms the favourable results obtained to date in this indication area.

EMA/HMPC/321095/2012
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Study
Halama et al. 1988
Indication
Mild to medium cerebrovascular insufficiency; Hachinski score: >7;

Crichton: level 1 to 3
Treatment duration
12 weeks
Test product
EGb 761
Single/Daily dosage
40 mg/120 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
no
number of patients
40
age
55-85 years
wash-out
Outcome
In the EGb 761 group, the values for total Sandoz Clinical AssessmentGeriatric (SCAG) score dropped on average by 9 points, whereas they
remained unchanged in the placebo group (p=0.00005, one-sided, Xtest). Evaluation of the separate items showed an effect particularly on
disturbances of short-term memory and mental awareness as well as on
dizziness as a symptom.
Study
Eckmann 1990
Indication
Cerebral insufficiency and the leading symptom depressive mood
Treatment duration
6 weeks
Test product
Ginkgo biloba extract (drops, not further specified)
Single/Daily dosage
53.33 mg/160 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
no
number of patients
58 (29 each group)
age
41-71 years
wash-out
Outcome
In the group receiving placebo, small, but progressive improvements were

observed. In the Ginkgo biloba group, the overall number of improvements
was significantly larger. After 2 weeks the differences were marked for only
a few of the symptoms; after 4 and 6 weeks in contrast, in 11 of the 12
symptoms. The largest number of improvements (two-thirds) in the Ginkgo
biloba group was observed between the second and fourth weeks of
treatment.
Study
Mazza et al. 2006
Indication
Treatment duration
24 weeks
Test product
Ginkgo biloba special extract E.S. (Flavogin)
Single/Daily dosage
160 mg daily dose

EMA/HMPC/321095/2012
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Study design
Outcome
randomised
yes
double-blind
yes
controlled
yes (donepezil; placebo)
parallel group
multicentre
number of patients
76
age
50-80 years
wash-out
An improvement of MMSE scores was observed in the ginkgo group: mean

value was from 18.803.622 (SD) at baseline to 19.403.485 (SD) at 24
weeks period. As regard SKT we observed an improvement of scores in the
ginkgo group: mean values passed from 16.453.05 (SD) at baseline to
13.152.9 (SD) at 24 weeks. A statistical significance was observed for
Ginkgo biloba extract and donepezil group in a t-test comparison; both
groups show also a significant difference when compared with placebo
group in an ANOVA. There was a significant difference in Clinical Global
Impression (CGI) scores changes for donepezil and Ginkgo biloba group
from baseline to the end of 24 weeks of treatment. Mean values passed
from 4.650.87 (SD) to 3.750.96 (SD) for Ginkgo biloba group.
Authors conclusion: The study suggests that there is no evidence of
relevant differences in the efficacy of Ginkgo biloba extract and donepezil
in the treatment of mild to moderate AD, so the use of both substances can
be justified. In addition, this study contributes to establish the efficacy and
tolerability of the Ginkgo biloba special extract E.S. in the dementia of the
Alzheimer type with special respect to moderately severe stages.
Korczyn (2007) commented some important aspects on the above mentioned article. The first two
parameters he was missing were that it was not stated who supported the study (industry?) and who
made the statistical calculations. Secondly, the primary and secondary end-points of the study were
not mentioned and the main conclusions (the MMSE) were negative, which was not reflected in the
paper. Also, results a long the way of the study are not shown, at which this is surprisingly as in
studies of cholinesterase inhibitors the strongest effect is seen at 6-12 weeks. In the placebo 4-week
run-in period it was not stated how placebo responders were determined and how many were rejected.
The time point for baseline values was not stated. Last but not least the commentator was missing an
analysis from the completers of the study as there were about 20% dropouts.
Mazza et al. (2007) replied as follows: The study was not supported by any pharmaceutical industry.
The aim of the study was to assess the efficacy of Ginkgo biloba in moderately severe stages of AD.
The results suggested an efficacy of ginkgo comparable with donepezil. Therefore the main conclusions
were not negative, considering that patients treated with ginkgo showed an improvement in attention,
memory and cognitive performance. Results after 6 and 12 weeks showed a significant efficacy and
tolerability of ginkgo compared with donepezil.
Corrao et al. (2007) commented methodological matters on the article by Mazza et al. (2006): There
was a small population sample studied and no effort was made to calculate sample size. Trials with
small population samples have scare sensitivity and can bring to negative results (no differences
between groups). Besides, a drop-out at follow-up 20% comprises the overall quality of a trial. In
this case there was a drop-out of about 21%. Because there exist a lot of different types of ANOVA, it

EMA/HMPC/321095/2012
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must be stated what kind of ANOVA was used. Differences in resulting scores of SKT and MMSE
(obviously not normally distributed) should be evaluated by distribution-free (non-parametric)
statistical methods, like in this case, the Kruskal-Wallis test (a non-parametric ANOVA). The study had
three groups and in no case pair-wise comparisons can be made by a t-test (only used if the study
groups are exclusively two), hence comparison between the study groups need a post hoc evaluation
test like Dwass-Steel-Critchlow-Fligner or Conover-Inman procedures. For all these reasons, no
statements could be made on the efficacy of the two treatments. Moreover, this study cannot evaluate
tolerability of Ginkgo biloba due to the small sample size and the short-time follow-up. Having pointed
out these aspects, this study has scientific value, but readers should be advised of all these
considerable limitations.
Reply by Mazza et al. (2007): It was already outlined in the Discussion and conclusions section
that larger samples of patients should be considered to confirm these results. In the authors opinion
this drop-out rate clearly reflects peculiar clinical features of enrolled patients, as psychiatrists and
neurologists working in the field of dementia know. As for considerations regarding the statistical
analysis section, a preliminary analysis of the data was conducted using the Shapiro-Wilk normality
test (W), which checks of normal distribution. In the present case W was not significant, so the
scientists were not obliged to use non-parametric methods. The authors do not assume that the results
of this test is clear evidence of normality or non-normality, but, in such perspective, we used t-test
comparing each group in two different times (baseline and after 24 weeks).
Study
Yancheva et al. 2009
Indication
AD and neuropsychiatric features (NINCDS/ADRDA, score below 36 on the

TE4D, score below 6 on the CDT and between 9 and 23 on the SKT; at
least 5 on the 12-item NPI)
Treatment duration
22 weeks
Test product
EGb 761, donepezil or both
Single/Daily dosage
120 mg/240 mg (EGb 761); 5 mg/5 mg (donepezil, first 4 weeks);

5 mg/10 mg (donepezil, remaining 18 weeks), and combined treatment
(recommended doses)
Study design
randomised
yes
double-blind
yes
controlled
yes (donepezil)
parallel group
yes
multicentre
n=4
number of patients
96 randomised; completed study: 30 (EGb 761),

29 (donepezil), and 29 (combined treatment)
Outcome
age
50 years
wash-out
8 weeks
Changes from baseline to week 22 and response rates were similar for all
three treatment groups with respect to all outcome measures (SKT, NPI,
total score and ADL sub-score of the GBS, HAMD, CDT and Verbal Fluency
Test). An apparent tendency in favour of combination treatment warrants
further scrutiny. Compared to donepezil mono-therapy, the adverse event
rate was lower under EGb 761 treatment and even under the combination
treatment.
Authors conclusion: Three hypotheses were developed that will have to be

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proven in further studies. First, there is no significant difference in the

efficiency between EGb 761 and donepezil, second, a combination therapy
will be superior to a mono-therapy with one of both substances and third,
there will be fewer side effects under a combination therapy than under
mono-therapy with donepezil.
Study
Schneider et al. 2005
Indication
Mild to moderate dementia of the Alzheimer type (probable AD

(NINCDS/ADRDA); dementia symptoms for at least 6 months; modified
Hachinski ischemic score less than 4; MMSE score of 10 to 24
Treatment duration
26 weeks
Test product
EGb 761
Single/Daily dosage
60 mg/120 mg or 120 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
n=44
number of patients
513 randomised; study completed: 135 (placebo),

135 (120 mg EGb 761), 140 (240 mg EGb 761)
Outcome
age
56-98 years (randomised patients)
wash-out
4 weeks
There were no significant between-group differences for the whole sample.

There was little cognitive and functional decline of the placebo-treated
patients, however. For a subgroup of patients with neuropsychiatric
symptoms there was a greater decline of placebo-treated patients and
significantly better cognitive performance and global assessment scores for
the patients on EGb 761.
Authors conclusion: The trial did not show efficacy of EGb 761, however,
the lack of decline of the placebo patients may have compromised the
sensitivity of the trial to detect a treatment effect. Thus, the study remains
inconclusive with respect to the efficacy of EGb 761.
Study
Van Dongen et al. 2000
Indication
Dementia (either AD or VaD; mild to moderate degree) or age-associated

memory impairment (AAMI)
Treatment duration
24 weeks
Test product
EGb 761
Single/Daily dosage
120 mg/240 mg or 80 mg/160 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
yes
number of patients
214; 48 (placebo), 84 (160 mg EGb 761), 82

(240 mg EGb 761)

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Outcome
age
50 years
wash-out
3 weeks (run-in period)
An ITT analysis showed no effect on each of the outcome measures for

participants who were assigned to EGb 761 (n=79) compared with placebo
(n=44) for the entire 24-week period. After 12 weeks of treatment, the
combined high dose and usual dose EGb 761 groups (n=166) performed
slightly better with regard to self-reported ADL but slightly worse with
regard to self-perceived health status compared with the placebo group
(n=48). No beneficial effects of a higher dose or prolonged duration of
EGb 761 treatment were found. There was no subgroup detected that
benefited from EGb 761. EGb 761 use was also not associated with the
occurrence of (serious) adverse events.
Authors conclusion: The results of the trial suggest that EGb 761 is not
effective as a treatment for older people with mild to moderate dementia or
AAMI.
Study
Van Dongen et al. 2003
Outcome
There were no statistically significant differences in mean change of scores
Analysis of the primary outcome measures of the above mentioned study

between EGb 761 and placebo. The differences were for SKT: +0.4 (90%
CI -0.9-1.7), for CGI-2: +0.1 (90% CI -0.3-0.4), and for NAI-NAA: -0.4
(90% CI -1.9-1.2). A positive difference is in favour of EGb 761. Neither
the dementia subgroup (n=36) nor the AAMI subgroup (n=87) experienced
a significant effect of EGb 761 treatment. There was no dose-effect
relationship and no effect of prolonged EGb 761 treatment.
Authors conclusion: The trial did not support the view that EGb 761 has a
beneficial effect for patients with dementia or AAMI.
Study
McCarney et al. 2008
Indication
Treatment duration
6 months
Test product
EGb 761
Single/Daily dosage
60 mg/120 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
number of patients
176
age
55 years
wash-out
Outcome
Ginkgo biloba did not have a significant effect after 6 months on either the
ADAS-cog score (p=0.392), the participant-rated QOL-AD score (p=0.787)
nor the carer-rated QOL-AD score (p=0.222).

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Authors conclusion: There was no evidence found that a standard dose of

EGb 761 benefits in mild-moderate dementia over 6 months.
Study
Grass-Kapanke et al. 2011
Indication
Very mild cognitive impairment (vMCI)
Treatment duration
12 weeks
Test product
EGb 761
Single/Daily dosage
240 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
n=5
number of patients
300
age
45-65 years
wash-out
Outcome
ITT analysis: Significant improvement (p<0.025, one-sided) beyond

practice effects for EGb 761 in a measure of attention (WTS-ALS), trends in
favour of EGb 761 in measures of memory (WMC III Faces I), and
perceived physical health (SF-36); cognitive effects were more pronounced
and more consistent (p<0.025 in 4 of 5 tests) in subjects with lower
memory function at baseline; specifically, practice effects in the more
demanding tests were attenuated or absent in these subjects
Authors conclusion: EGb 761 improved cognitive functioning and aspects
of quality of life in subjects with vMCI.
Study
DeKosky et al. 2008
Indication
Normal cognition or mild cognitive impairment (MCI)
Treatment duration
6.1 years (2002-2008)
Test product
EGb 761
Single/Daily dosage
120 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
yes (n=5)
number of patients
2587 (normal cognition); 482 (MCI)
age
75 years
wash-out
Outcome
523 individuals developed dementia (246 receiving placebo and 277

receiving EGb 761) with 92% of the dementia cases classified as possible
or probable AD, or AD with evidence of vascular disease of the brain. The
overall dementia rate was 3.3 per 100 person-years in participants
assigned to EGb 761 and 2.9 per 100 person-years in the placebo group.
The hazard ratio for EGb 761 compared with placebo for all-cause dementia
was 1.12 (95% CI, 0.94-1.33; p=0.21) and for AD, 1.16 (95% CI, 0.97-

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1.39; p=0.11). EGb 761 also had no effect on the rate of progression to
dementia in participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; p=0.39).
Authors conclusion: EGb 761 at 120 mg 2 times daily was not effective in
reducing either the overall incidence rate of dementia or AD incidence in
elderly individuals with normal cognition or those with MCI.
Study
Burle et al. 2009
Indication
Mild cognitive impairment
Treatment duration
6 weeks
Test product
Ginkgo biloba fresh plant extract (DER 3-5:1; extractant 65% ethanol V/V;
produced in Switzerland)
Single/Daily dosage
90 mg/180 mg
Study design
randomised
double-blind
no (open)
controlled
parallel group
multicentre
n=11
number of patients
59
age
>60 years
wash-out
Outcome
After 6 weeks the SF-12 mental score had increased significantly from
48.310.1 to 51.37.9, whereas the sf-12 body score (44.59.2 to
45.38.1) and the DemTect score (15.92.0 to 16.02.3) had not
changed significantly. About half of all patients experienced an
improvement in their memory and their ability to concentrate, as well as a
decrease in symptoms of forgetfulness. The majority of investigators and
patients judged the treatment to be effective.
Authors conclusion: This newly developed, holistic fresh leaf extract of
Ginkgo biloba is a safe, effective, and, at least, adjuvant treatment option
for patients with mild cognitive impairments.
Study
Vellas et al. 2012
Indication
Spontaneously reported memory complaints
Treatment duration
5 years
Test product
EGb 761
Single/Daily dosage
120 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
n=13
number of patients
2854 randomised, 1406 (EGb 761), 1414

(placebo)
age
70 years
wash-out

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Outcome
Over 5 years, 61 participants in the ginkgo group had been diagnosed with
probable Alzheimers disease (1.2 cases per 100 person-years) compared
with 73 participants in the placebo group (1.4 cases per 100 person-years;
hazard ratio [HR] 0.84, 95% CI 0.6-1.18; p=0.306), but the risk was not
proportional over time. Incidence of adverse events was much the same
between groups. Death and stroke rate also incidence of other
haemorrhagic or cardiovascular events did not differ between groups.
Authors conclusion: Long-term use of standardised Ginkgo biloba extract
in this trial did not reduce the risk of progression to Alzheimers disease
compared with placebo.
Study
Brautigam et al. 1998
Indication
Memory and/or concentration complaints
Treatment duration
24 weeks
Test product
Ginkgo biloba alcohol/water extract (Geriaforce)
Single/Daily dosage
high dose (HD):

40 drops (1.9 ml) undiluted ginkgo extract/120 drops (5.7 ml);
low dose (LD):
40 drops (1.9 ml) ginkgo extract 1:1 with placebo/120 drops (5.7 ml)
Study design
Outcome
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
n=22
number of patients
241; 197 completed
age
55-86 years
wash-out
4 weeks
In the subjective test, the EMCT, the Rey 1 and Rey 2 no significant
differences in improvement in time between the groups were observed. In
the Benton test increases of 18%, 26% and 11% (expressed as percentage
of baseline scores) were observed in the HD, LD and placebo, respectively
(MANOVA; p=0.0076). No substantial correlation was observed between
subjective perception of the severeness of memory complaints and the
objective test results. There were no differences in the amount of side
effects between groups.
Authors conclusion: It was demonstrated that a Ginkgo biloba
alcohol/water extract is effective in elderly individuals with cognitive
impairment.
Study
Kaschel 2011
Indication
To investigate the effects of EGb 761 on memory and the specificity of such
effects on distinct memory functions
Treatment duration
6 weeks
Test product
EGb 761
Single/Daily dosage
240 mg/240 mg

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Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
no
number of patients
188 randomised; full analysis set: 177, PP set:

159
Outcome
age
45-56 years
wash-out
at least 8 weeks
EGb 761-treated subjects improved significantly in quantity of recall (list of

appointments; drug-placebo differences: p=0.038 for immediate and
p=0.008 for delayed recall). Effects on qualitative recall performance were
similar (drug-placebo differences: p=0.092 for immediate and p=0.01 for
delayed recall). No superiority of ginkgo was evident in another everyday
memory test which asked for recognition of a driving route (drug-placebo
differences: p>0.1). The incidence of adverse events was low and not
significantly different between treatment groups.
Authors conclusion: EGb 761 (240 mg once daily) improves free recall of
appointments in middle-aged healthy volunteers, which requires high
demands on self-initiated retrieval of learned material. This function is
known to be sensitive to normal aging, i.e., reduced in healthy middle-aged
subjects. No effects are seen in a less demanding everyday memory task
which does not tap this critical function.
Study
Dodge et al. 2008
Indication
No subjective memory complaint; normal memory function (Wechsler

Memory Scale revised, WMS-R); Mini Mental State Examination (MMSE)
score>23.6; Clinical Dementia Rating (CDR)=0; Center for Epidemiological
Studies Depression Scale (CES-D-10)<4
Treatment duration
42 months
Test product
Ginkgo biloba extract (Thorne Research, Inc., Sandpoint, ID)
Single/Daily dosage
80 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
number of patients
118
age
85 years
wash-out
Outcome
Intention-to-treat analysis: No reduced risk of progression from CDR=0 to

CDR=0.5 (log-rank test, p=0.06) among the Ginkgo biloba group; there
was no less of a decline in memory function among the ginkgo group
(p=0.05)
Control of the medication adherence level: Ginkgo biloba group had a lower
risk of progression from CDR=0 to CDR=0.5 (Hazard ratio (HR)=0.33,
p=0.02), and a smaller decline in memory scores (p=0.04)

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Authors conclusion: In unadjusted analyses, Ginkgo biloba extract neither

altered the risk of progression from normal to CDR=0.5, nor protected
against a decline in memory function. Secondary analysis taking into
account medication adherence showed a progression effect of Ginkgo
biloba on the progression to CDR=0.5 and memory decline. Results of
larger prevention trials taking into account medication adherence may
clarify the effectiveness of Ginkgo biloba extract.
Reviews and meta-analyses:

Gertz and Kiefer (2004) concluded in the review of the, at that time, current and past literature that
Ginkgo biloba extract has reproducible effects on cognitive functions in AD. There was no convincing
evidence of beneficial effects in VaD, however methodologically sound studies are lacking in this field.
The extremely low rate of side effects together with the knowledge of interesting mechanisms of action
make Ginkgo biloba extract a promising substance for further clinical studies in AD and other
dementing disorders.
Kaschel (2009) concluded that this review suggested evidence for a specific pattern of improvements
achieved in randomised controlled group-studies using Ginkgo biloba extract. In spite of possible
biases which cannot be ruled out in some trials, predominantly complex measures of memory,
attention and intelligence improved. Significant changes occurred more often than expected by chance
even after adjustment for number of comparisons and after correction for possible correlations
between scores. Thus, the most influential factors which tend to produce -errors could be controlled
in this manner in this review. In contrary, -errors are less discussed in other reviews though we can
show that they occur frequently in the trials included and these -errors seem to be the main source of
the rather heterogeneous results. Therefore, ginkgo might not have had a fair chance to demonstrate
specific effects in its chronic administration to non-demented subjects, as selection of psychometric
tests was rarely theoretically or empirically grounded, samples were small, treatment duration was
short and reliable and modern psychometric tests sensitive to deficits and sensitive to monitor change
are often lacking. Replications are missing and researchers tend to use their own measures thus
lowering the comparability and the number of replications available to date. If replications are
reported, these yield rather consistent results (Mix and Crews, 2000, 2002). The specific pattern
identified encourages future research and respective trials should not only concentrate on JADAD
scores as the only index for methodological quality but take into account psychometric standards.
Birks (2009): Authors conclusion in the abstract of the Cochrane Review on Ginkgo biloba for
cognitive impairment and dementia (Review) is as follows: Ginkgo biloba appears to be safe in use
with no excess side effects compared with placebo. Many of the early trials used unsatisfactory
methods, or were small, and publication bias cannot be excluded. The evidence that Ginkgo biloba has
predictable and clinically significant benefit for people with dementia or cognitive impairment is
inconsistent and unreliable.
Wang et al. (2010): Meta-analysis of clinical studies of the effectiveness of standardised Ginkgo
biloba extract on cognitive symptoms of dementia

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Authors conclusion: The bivariate random effect meta-analysis of 6 clinical studies demonstrated that
standardised Ginkgo biloba extract could significantly improve the cognitive function of dementia
disorders with the treatment period of 6 months when baseline risk was considered in assessing the
efficacy of standardised Ginkgo biloba extract.
Weinmann et al. (2010): Meta-analysis of clinical studies of the effects of Ginkgo biloba in dementia
ITT/LOCF change scores for cognition outcomes (ADAS-cog, SKT):
ITT/LOCF change scores for ADL outcomes:
Authors conclusion: A statistically significant advantage of Ginkgo biloba compared to placebo in

improving cognition for the whole group of patients with AD, vascular or mixed dementia was found.
Regarding ADL, there was no significant difference for the whole group. However, in the subgroup of
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patients with AD, there was a statistically significant advantage of Ginkgo biloba compared to placebo.
In a situation, where the clinical significance of the moderate effects of cholinesterase inhibitors and
memantine as symptomatic treatments is increasingly been questioned, Ginkgo biloba may not be an
inferior treatment option for a considerable number of people with mild to moderate dementia.
However, direct comparisons are lacking. A major multicenter study to compare the relative
effectiveness of Ginkgo biloba and cholinesterase inhibitors for different dementia subgroups appears
justified.
Yang et al. (2011): Meta-analysis of Ginkgo biloba extract for the treatment of AD
Meta-analysis of MMSE scores:
Meta-analysis of SKT scores:
Meta-analysis of ADAS-cog score:
Authors conclusion: Ginkgo biloba extract shows good therapeutic effects for mild and moderate AD.
Solomon and Michalczuk (2009) discussed the conflicting results of Ginkgo biloba studies emerged
from the fact that there is no agreed upon set of standards by which to judge the efficacy of
complementary and alternative medicines (CAM). On the basis of having no generally accepted
guidelines to standardise the types of studies that are conducted in the field of cognition enhancement
in both healthy elderly and patients with AD and other dementing disorders, the authors suggested a
roadmap for establishing guidelines for the evaluation of CAM in cognition. They applied these
guidelines to the conflicting literature on Ginkgo biloba to determine whether they might help resolve
the conflicting results. The criteria suggested in the guidelines of this article are the generally accepted
standards by both United States [draft guideline for the evaluation of antidementia compounds (Leber
1990) of the Division of Pharmacologic Drug Actions of the U.S. FDA] and European regulatory
agencies [guidelines for evaluating the efficacy (and safety) of treatments for AD and other dementias]
for clinical research. Applying the proposed guidelines to some of the literature that have led to the
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controversy results invites the conclusion that Ginkgo biloba has no discernable benefits on cognition in
either patients with AD, in preventing AD, or in the healthy elderly. The clinical implications of this
conclusion are that Ginkgo biloba should not be recommended to healthy elderly or patients with AD.
The authors themselves make assumptions about the criteria suggested in this article (which are the
generally accepted standards by both U.S. and European regulatory agencies for clinical research) used
to judge studies. A second and related question is whether the evidence regarding ginkgo on cognition
is sufficient to conclude that the compound is not effective, and further research is unlikely to change
this conclusion and therefore not necessary. In summary the authors would suggest that if Ginkgo
biloba had to meet present regulatory guidelines to be marketed, it would be with drawn from
development.
Lders et al. (2012) summarised the increasing knowledge that has been obtained from clinical
studies about the impact that vascular factors have on cognitive function and dementia (vascular
dementia). Due to demographic reasons and still insufficient control of all vascular risk factors,
dementia and associated problems are of increasing importance and will have impact on economical
and social develpoment in most countries. The incidence of cognitive impairment and dementia will
increase exponentially. As long as no causal therapy for dementia exists, diagnosis and control of risk
factors for dementia will need much more attention. Hypertension is not only the most important risk
factor for stroke that often leads to dementia but also for silent brain infarcts, which are also
associated with onset of dementia. Uncontrolled hypertension is associated with cognitive impairment
and sufficient control of hypertension in middle-aged patients can reduce the risk of dementia in older
ages. Nevertheless, treatment of all other risk factors, such as diabetes mellitus, smoking,
hyperlipidemia, aterial fibrillation, is important to reduce the onset of not only vascular but also
Alzheimer dementia.
Healthy participants:
Study
Trick et al. 2004
Indication
To investigate the effects of continuing treatment with Ginkgo biloba

extract (GBE) on the ADL and mood
Treatment duration
4 months pretreatment; 6 months follow-up (study period)
Test product
LI 1370
Single/Daily dosage
120 mg/120 mg
Study design
randomised
no
double-blind
no
controlled
yes (no treatment: NT)
parallel group
yes
multicentre
number of patients
1570; 4 groups: GBE-GBE (111), GBE-NT (314),

NT-BGE (407) and NT-NT (738)
Outcome
age
>60 years
wash-out
no
There were significant differences in the mean overall line analogue rating
scale (LARS) and self-rating activities of daily living scale (SR-ADL) scores
between the four treatment combination groups at the end of the follow-up
period. A factor analysis of the LARS revealed two factors, mood and
alertness. When scores from each of the treatment groups were
examined over the whole 10 month period it was evident that the ratings
of overall competence in the SR-ADL and both factors of the LARS were
diminished on the cessation of treatment with LI 1370, and improved when

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LI 1370 treatment was initiated. The magnitude of the improvement on all

scales was revealed to the overall duration of LI 1370 supplementation.
Authors conclusion: Significant differences between the groups of subjects
treated with LI 1370 for different periods of time (4-10 months) suggests
that the extract has a demonstrable effect in improving mood and the selfassessed performance of the tasks of everyday living.
4.2.2.2. Peripheral arterial occlusive disease (intermittent claudication)

Horsch and Walther (2004) stated in a review that in the majority of the studies there was an
advantage of EGb 761 in the increase of pain-free walking distance compared to placebo. For 7
studies, the advantage was found to be statistically significant. Testing the relevant superiority showed
a significant result in 6 of the selected 9 studies. The pooled estimator of the ratio amounts to =1.23
(95% CI: 1.16, 1.31) and demonstrates the efficacy of EGb 761 over placebo as well.
Ratio theta of the increase in pain-free walking distance under EGb 761 and placebo with 95% CI
(theta >1 means superiority of EGb 761; Horsch and Walther 2004).
Authors conclusion: The reviewed studies confirm the efficacy of EGb 761. In 6 of 9 studies, a relevant
superiority compared to placebo could be demonstrated. The pooled evaluation of all studies showed
the clinical relevance of the therapeutic effects of EGb 761 as well. With a good to very good
tolerability, the benefit/risk ratio is consequently in favour of a therapy with EGb 761 in patients with
PAOD stage II (according to Fontaine).
Nicola et al. 2009: In the abstract of the Cochrane Review on Ginkgo biloba for intermittent
claudication (Review) the results are as follows: Fourteen trials with a total of 739 participants were
included. Eleven trials involving 477 participants compared Ginkgo biloba with placebo and assessed
the absolute claudication distance. Following treatment with Ginkgo biloba at the end of the study the
absolute claudication distance increased with an overall effect size of 3.57 kilocalories (CI -0.10 to
7.23, p=0.06), compared with placebo. This translates to an increase of just 64.5 (CI -1.8 to 130.7)
meters on a flat treadmill with an average speed of 3.2 km/h. Publication bias leading to missing data
or negative trials is likely to have inflated the effect size.
Forest plot of clinical studies comparing the absolute claudication distance (expressed as kilocalories)
at the end of the study

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Authors conclusion: There is no evidence that Ginkgo biloba has a clinically significant benefit for
patients with PAD.
Pittler and Ernst (2000) included eight randomised, placebo-controlled, double-blind trials in a
meta-analysis. In three of these trials EGb 761 was applied. There is no concrete information on the
other extracts. A significant difference in the increase in pain-free walking distance in favour of Ginkgo
biloba (weighed mean difference: 34 meters, 95% confidence interval [CI]: 26 to 43 meters) was
determined. In studies using similar methodological features (ergometer speed: 3 km/h, inclination:
12%) this difference was 33 meters in favour of Ginkgo biloba (95% CI: 22 to 43 meters). Concerning
to the authors these results suggest that Ginkgo biloba extract is superior to placebo in the
symptomatic treatment of intermittent claudication. However, the size of the overall treatment effect is
modest and of uncertain clinical relevance.
Letzel and Schoop (1992): Clinical trials on the efficacy of EGb 761 and pentoxifylline were
assessed. On average an increase of 45% (EGb 761) or 57% (pentoxifylline) in relation to initial values
was found.
Study
Gardner et al. 2008
Indication
Claudication symptoms of peripheral artery disease
Treatment duration
4 months
Test product
EGb 761
Single/Daily dosage
60 mg/300 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
number of patients
62
age
708 years (meanSD)
wash-out
at least one month
Outcome
Maximal treadmill walking time increased by 2080 and 91242 seconds

in the placebo and the EGb 761 groups, respectively (p=0.12). Pain-free
walking time increased by 1531 and 2143 seconds, respectively
(p=0.28). No significant differences were detected between groups for any
of the secondary outcomes.

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Authors conclusion: In older adults with PAD, Ginkgo biloba produced a

modest but insignificant increase in maximal treadmill walking time and
flow-mediated vasodilation. These data do not support the use of Ginkgo
biloba as an effective therapy for PAD, although a longer duration of use
should be considered in any future trials.
Study
Thomson et al. 1990
Indication
Fontaine stage 2 peripheral vascular disease
Treatment duration
24 weeks
Test product
EGb 761 (Tanakan)
Single/Daily dosage
Three tablets daily
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
number of patients
37; 20 (EGb 761), 17 (placebo)
age
wash-out
6 weeks
Outcome
Severity of pain using a 10 cm linear analogue scale was significantly

improved in the EGb 761 group, but not in the placebo group. Claudication
distance increased significantly by EGb 761, but not in the placebo group.
A/B ratio and Doppler ankle responses to exercise did not show any
significant change in either group, nor did the post exercise recovery time.
Authors conclusion: EGb 761 is a safe and effective method of improving
walking distance and reducing pain severity in patients with intermittent
claudication, although Doppler studies have failed to suggest any gross
improvement in the perfusion of the ischaemic leg.
Study
Wang et al. 2007
Indication
PAD
Treatment duration
24 weeks
Test product
Ginkgo biloba tablets
Single/Daily dosage
120 mg/240 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (controlled)
parallel group
yes
multicentre
number of patients
17; 8 (ginkgo), 9 (placebo)
age
50-80 years
wash-out
Outcome
Of the measured variables only the maximal walking time increased

significantly in the ginkgo group after the combined treatment of Ginkgo
biloba tablets and exercise training (from 236112 seconds to
557130 seconds, p=0.001). Similar change was also found in the placebo

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group after exercise training (from 384125 seconds to 820146 seconds,

p=0.001).
Authors conclusion: Supervise exercise training combined with Ginkgo
biloba treatment did not produce greater beneficial effects than exercise
training alone in patients with PAD.
Study
Wu et al. 2007
Indication
Coronary artery disease (CAD)
Treatment duration
one-time administration
Test product
Ginkgo biloba extract (GBE) injectable solution (Ginaton, manufactured in

China)
Single/Daily dosage
intravenous 0.7 mg/min GBE for 120 min
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
number of patients
80; 42 (GBE), 38 (placebo)
age
6212 years (GBE), 5813 years (placebo)
wash-out
Outcome
GBE significantly increased distal left anterior descending coronary artery

(LAD) blood flow in maximal diastolic peak velocity (MDPV), maximal
systolic peak velocity (MSPV) and diastolic time velocity integral (DTVI)
compared with the control group (16.1410.93% vs. 0.282.14%,
9.148.23% vs. 0.792.56%, and 15.237.28% vs. 0.422.43%,
respectively, p<0.01). Increased brachial artery flow-mediated dilation
(FMD) by 69.75% (from 3.951.49% to 6.552.51%, p<0.01). A linear
correlation was found between the percentage changes in MDPV, MSPV, or
DTVI of LAD blood flow and the percentage change in brachial artery FMD
following treatment with GBE (r=0.612, 0.486, or 0.521, respectively,
p<0.01).
Authors conclusion: GBE treatment in CAD patients leads to an increase of
LAD blood flow in MDPV, MSPV and DTVI. The increased response might
relate to the improved endothelium-dependent vasodilatory capacity.
Healthy participants:
Study
Galdurz et al. 2007
Indication
To compare the effects of age and gender on blood viscosity and to

appraise the effectiveness of Ginkgo biloba extract in reducing blood
viscosity
Treatment duration
6 months
Test product
EGb 761 (produced by Maze Productos Quimicos e Farmaceuticos Ltda. and

prepared by Magister Medicamentos Ltda.)
Single/Daily dosage
80 mg/80 mg
Study design
randomised

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yes
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double-blind
controlled
yes (placebo and Allium sativum)
parallel group
multicentre
no
number of patients
Stage 1: 80 male and 80 female; Stage 2: 60

male; Stage 3: 25 male
age
Stage 1: 80 aged 18-60 and 80 aged 61 (same

age profile for male and female)
wash-out
Outcome
Significant differences were found when considering age; measures of

blood viscosity in the younger group was significantly lower than in the
senior group; in both groups (3.790.07 and 4.190.3, younger and older
males, respectively; p<0.01; and 3.370.3 and 4.360.3, young and old
females, respectively; p<0.001). Comparing the measured blood viscosity
of the younger men and women, a significant difference was found
(3.790.07 and 3.370.3, men and women, respectively; p<0.01),
whereas no significant difference was found in the older group (4.190.3
and 4.360.3, men and women, respectively; p=0.2). Also found was a
positive correlation between age and blood viscosity (r=0.32; p<0.05),
with viscosity increasing with age. EGb 761 led to the highest reduction in
blood viscosity compared with placebo and A. sativum. In relation to the
use of the two substances, Ginkgo biloba and A. sativum, dry extract of
Ginkgo biloba proved to be more effective in reducing blood viscosity.
Study
Wu et al. 2008
Indication
To test the effects of Ginkgo biloba extract (GBE) on LAD blood flow and
endothelium-dependent brachial artery FMD
Treatment duration
one-time administration
Test product
GBE injectable solution (Ginaton, manufactured in China)
Single/Daily dosage
intravenous 0.7 mg/min GBE for 120 min
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
number of patients
60; 30 (GBE), 30 (placebo)
age
5410 years (GBE), 568 years (placebo)
wash-out
Outcome
GBE significantly increased LAD blood flow in MDPV, MSPV and DTVI
compared with the placebo group (19.1613.91% vs. 0.302.55%,
17.7614.56% vs. 0.532.32%, and 21.7316.13% vs. 0.812.33%,
MDPV, MSPV, and DTVI improvement from baseline, respectively,
p<0.01).Brachial artery FMD was also increased by 56.03% (from
7.212.52% to 11.283.95%, p<0.01). A linear correlation was found
between the percentage change in MDPV, MSPV, or DTVI of LAD blood flow
and the percentage change in brachial artery FMD following treatment with
GBE (r=0.538, 0.366, or 0.573, respectively, p<0.01, p<0.05, or p<0.01).

EMA/HMPC/321095/2012
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Authors conclusion: GBE treatment in healthy elderly adults leads to the

increase of LAD blood flow in MDPV, MSPV and DTVI, and the increased
response might relate to the improved endothelium-dependent vasodilatory
capacity.
4.2.2.3. Adjuvant therapy in tinnitus of vascular and involutive origin

Study
Drew and Davies 2001
Indication
Tinnitus that was comparatively stable
Treatment duration
12 weeks
Test product
LI 1370
Single/Daily dosage
50 mg/150 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
number of patients
1121; 978 were matched (489 pairs)
age
18-70 years
wash-out
Outcome
There were no significant differences in primary or secondary outcome

measures between the groups. 34 of 360 participants receiving active
treatment reported that their tinnitus was less troublesome after 12 weeks
of treatment compared with 35 of 360 participants who took placebo.
Authors conclusion: 50 mg Ginkgo biloba extract LI 1370 given 3 times
daily for 12 weeks is no more effective than placebo in treating tinnitus.
Study
Holgers et al. 1994 (only the second part is stated below)
Indication
Persistent severe tinnitus
Treatment duration
2 weeks
Test product
Ginkgo biloba extract (GBE) (Seredrin, Farmaflor)
Single/Daily dosage
14.6 mg/29.2 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
no (but crossover)
multicentre
number of patients
20
age
41-77 years
wash-out
1 week (between crossover application)
Outcome
Statistical group analysis gives no support to the hypothesis that GBE

treatment has any effect on tinnitus, although it is possible that GBE has
an effect on some patients due to several reasons, e.g. the diverse etiology
of tinnitus.

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Study
Morgenstern and Biermann 2002
Indication
Chronic tinnitus aurium
Treatment duration
12 weeks (open 10-day EGb 761 infusion pretreatment)
Test product
EGb 761
Single/Daily dosage
80 mg/160 mg (pretreatment: 1 infusion (200 mg)/day)
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
yes
multicentre
number of patients
60
age
median age: 45 (EGb 761), 47 (placebo)
wash-out
Outcome
For the primary outcome measure, significant superiority of EGb 761 over
placebo was demonstrated in the ITT analysis data set after 4, 8 and 12
weeks of out-patient treatment (p<0.05, 1-tailed), although the absolute
treatment group difference was moderate. The results were supported by
the secondary outcome measures for efficacy (e.g. decreased hearing loss,
improved self-assessment of subjective impairment). During out-patient
treatment, there were no adverse events under EGb 761.
Authors conclusion: A combination of infusion therapy followed by oral
administration of EGb 761 appears to be effective and safe in alleviating
the symptoms associated with tinnitus aurium.
Study
Halama et al. 1988
Indication
Mild to medium cerebrovascular insufficiency
Treatment duration
12 weeks
Test product
EGb 761
Single/Daily dosage
40 mg/120 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
no
number of patients
40
age
55-85 years
wash-out
Outcome
The symptom of tinnitus was specifically asked for and their specification
was documented with the aid of a four-stage rating scale.
In the group receiving active substance superior effect was shown in the
symptom of tinnitus (p=0.035).

Von Boetticher (2011) concluded that EGb 761, a standardised Ginkgo biloba extract, is an
evidenced-based treatment option in tinnitus.

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Rejali et al. (2004): In the review it was concluded that there is now level 1a evidence that Ginkgo
biloba does not benefit patients with tinnitus.
Hilton and Stuart (2010): The authors conclusion in the abstract in the Cochrane review Ginkgo
biloba for tinnitus is: The limited evidence did not demonstrate that Ginkgo biloba was effective for
tinnitus which is a primary complaint. There was no reliable evidence to address the question of
whether Ginkgo biloba is effective for tinnitus associated with cerebral insufficiency.
Smith et al. (2005) concluded in the review: Although there are some clinical trials that have yielded
positive results from the use of Ginkgo biloba extracts (), these studies are few and have been
limited either by design flaws (), the small size of the significant effect (), or else the results have
not been published in peer-reviewed journals () and therefore the quality of the research is not
proven. On the other hand, the two most systematic clinical trials, both of which are double-blind and
placebo-controlled, and are published in respected peer-reviewed journals, have yielded negative
results and suggest that Ginkgo biloba extracts are of little more use in the treatment of tinnitus than
placebo. This is an important conclusion because treatments that do not have therapeutic efficacy not
only waste money but can prevent patients from seeking therapy that is efficacious. Furthermore,
the unsupervised use of Ginkgo biloba extracts with other medications could lead to adverse side
effects (e.g. haemorrhagic effects of concurrent use of aspirin) which are unnecessary and not justified
in terms of therapeutic benefit.
4.2.2.4. Vertigo
Study
Issing et al. 2005
Indication
Atherosclerosis-related vertigo
Treatment duration
8 weeks
Test product
standardised Ginkgo biloba extract
Single/Daily dosage
40 mg/120 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (vertigoheel)
parallel group
yes
multicentre
n=13
number of patients
170; 87 (vertigoheel), 83 (ginkgo)
age
60-80 years
wash-out
Outcome
Both treatments improved vertigo status. From a baseline mean value of

26.15.2 (on a 50-point scale) in the Vertigoheel group, the dizziness
questionnaire score improved by -10.610.0, and by -10.79.0 from
25.84.7 in the Ginkgo biloba group. Statistical analysis of this endpoint
showed that Vertigoheel was not inferior to Ginkgo biloba. The 95% CI for
the difference between treatment did not reach the inferiority threshold of
0.36 at any of the time points tested. The results were supported by the
results of a line walking test, Unterbergers stepping test, and patient and
physician global assessments of therapeutic effect. Both treatments were
well tolerated.
Authors conclusion: Vertigoheel is an appealing alternative to established
Ginkgo biloba therapy for atherosclerosis-related vertigo.

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Study
Haguenauer et al. 1986
Indication
Vertiginous syndrome of recent onset and undetermined origin
Treatment duration
3 months
Test product
EGb 761
Single/Daily dosage
80 mg/160 mg
Study design
randomised
yes
double-blind
yes
controlled
yes (placebo)
parallel group
multicentre
n=3
number of patients
67; 34 (EGb 761), 33 (placebo)
age
522.5 (EGb 761), 46.42.4 (placebo)
wash-out
Outcome
The results show that effectiveness of Ginkgo biloba extract on the

intensity, frequency, and duration of the vertigo was statistically
significant. At the end of the trial, 47% of the treated patients were free of
their symptoms, as against 18% of those who received placebo (student ttest: p<0.05).

Hamann (2007): The results in the review show a beneficial effect of EGb 761 on vestibular
compensation that has been demonstrated in preclinical and clinical studies. In conclusion, evidence of
the efficacy of EGb 761 for the treatment of vertiginous syndromes is presented in the available
studies.
4.2.3. Clinical studies in special populations (e.g. elderly and children)

Most of the studies mentioned in the chapter Clinical Data are conducted in elderly due to the range
of indications of medicinal products containing Ginkgo biloba. Only a few studies were conducted in
patients under the age of 18 years. Some of these studies are listed in the following.
Donfrancesco and Ferrante (2007) collected preliminary information on the possible efficacy and
tolerability of EGb 761 as a treatment of dyslexia in school-aged children. 15 children aged between 5
and 16 years with dyslexia participated in an open-label trial of EGb 761 given as a single dose of
80 mg in the morning. Standardised tests for dyslexia were administered at baseline and at the end of
the study. All children completed the trial. The score of the standardised tests for dyslexia decreased.
On the list of words the score decreased from mean 4.33 (SD=2.37) at baseline to 2.66 (SD=1.58) at
the end of the study (p<0.01), on the list of non-words from mean 3.39 (SD=1.5) at baseline to 2.26
(SD=0.92) at the end of the study (p<0.02) and on the reading piece from mean 3.52 (SD=2.11) to
2.13 (SD=1.25) at the end of the study (p<0.05). At the end of the study 9 children did not perform
below the -2 SD on the list of words and 7 on reading text and so they no longer fulfilled the DSM-IVTR criteria for dyslexia. A brief period of headache was reported by the parents of two children.
Szczurko et al. (2011): A pilot clinical trial concerning vitiligo vulgaris was performed in 12
participants aged 12-35 years (8 participants under 18). Patients received 60 mg of Ginkgo biloba
(standardised to 15 mg (25%) ginkgoflavonglycosides and 4 mg (6.67 %) terpene lactones per pill,
manufactured by Seroyal) two times per day for 12 weeks. Effectiveness was assessed using the
Vitiligo Area Scoring Index (VASI) and the Vitiligo European Task Force (VETF), which are measures
evaluating the extent of depigmentation and the area of vitiligo lesions, staging, and disease activity,
EMA/HMPC/321095/2012
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respectively. The total VASI score improved by 0.5 (p=0.021) from 5.0 to 4.5, which indicated an
average repigmentation of vitiligo lesions of 15%. The progression of vitiligo stopped in all participants.
VETF total vitiligo lesion area decreased 0.4% (p=0.102) from 5.9 to 5.6 from baseline to week 12.
VETF staging score improved by 0.7 (p=0.10) from 6.6 to 5.8, and the VETF spreading score improved
by 3.9 (p<0.001) from 2.7 to -1.2. There were no statistically significant changes in safety assessed by
serum coagulation factors (platelets, PTT, INR).
Esposito and Carotenuto (2011): The study has investigated administration of ginkgolide B as
preventive treatment in primary headache in young patients. Ginkgolide B was considered as a
pharmacological aid for the treatment of migraine in adult patients because its peculiar modulation of
the glutamatergic transmission in the CNS and on platelet activating factor (PAF). 119 school-aged
patients (mean age 9.71.42) received ginkgolide B/Coenzyme Q10/Riboflavin/Magnesium complex
(not further specified) twice a day for 3 months. At the end of the study the mean frequency per
month of migraine was significantly decreased (9.714.33 vs. 4.533.96 attacks; p<0.001).
Usai (2011): Another study investigated the effect of ginkgolide B as preventive treatment to confirm
the long-term utility on a group of young patients suffering from primary headache such as migraine
without aura. In an open-label trial 30 patients aged between 8 and 18 (mean age 13.52.2) were
treated orally with a combination of ginkgolide B 80 mg, coenzyme Q10 20 mg, vitamin B2 1.6 mg and
magnesium 300 mg twice per day for 3 months. The number of monthly migraine attacks was reduced
after 3 months of treatment in relation to pre study baseline. At 1-year follow-up mean number of
days of headaches per month decreased significantly from 7.24.3 to 1.61.7 (p 0.000).
Cala et al. (2003) examined the use of herbal therapy in children or adolescents receiving care for a
depressive disorder or Attention-Deficit-Hyperactivity Disorder (ADHD) (with or without comorbidities).
The main outcome measure was primary caregivers self-report of the use of herbal therapy in their
children using a 23-item questionnaire on 117 parents or caregivers of patients younger than 18
years (mean age 10.93.1 years). The mean age at onset of a psychiatric condition was 8.13.3
years. 110 patients (94.0%) were being treated with prescription drugs at the time of the study. The
overall lifetime prevalence of herbal therapy in patients was 23 (19.6%) of the 117 patients.
Recommendations from a friend or relative resulted in the administration of herbal medicines by 61%
of 23 caregivers. No caregivers reported that a recommendation from a health care professional or that
an adverse effect from conventional drug was the primary reason herbal therapy was tried in their
children. Herbal medicines were given most frequently for a behavioural condition as reported by 8 of
23 caregivers, with Ginkgo biloba (not further specified) most prevalent (26%). 15 caregivers (65%) of
23 who gave their children herbal medicines thought they were effective, and of these, all perceived
herbal therapy to be at least somewhat if not very effective. None of the 23 caregivers reported any
adverse effects in their children from herbal medicines. However, decreased effectiveness or
ineffectiveness was the most common reported reason for stopping herbal therapy.
Salehi et al. (2010) evaluated their hypothesis that Ginkgo biloba would be beneficial for treatment
of Attention-Deficit-Hyperactivity Disorder (ADHD) in a randomised, double-blind, parallel group
comparison of Ginkgo biloba (Ginko T.D. Tolidaru, Iran) and methylphenidate. Fifty outpatients (39
boys and 11 girls) aged between 6-14 years with DSM-IV-TR diagnosis of ADHD were randomly
assigned to receive treatment using tablet of ginkgo T.D. at a dose of 80-120 mg/day depending on
weight (80 mg/day for <30 kg and 120 mg/day for >30 kg) (group 1) or methylphenidate at a dose of
20-30 mg/day depending on weight (20 mg/day for <30 kg and 30 mg/day for >30 kg) (group) for
6 weeks. The principal measure of outcome was the Teacher and Parent ADHD Rating Scale-IV.
Patients were assessed at baseline and at 21 and 42 days of treatment. Significant differences were
observed between the two groups. The changes at the end of the studycompared to baseline were: 6.5211.43 (meanSD) and -15.9211.44 (meanSD) for Ginko T.D. and methylphenidate,

EMA/HMPC/321095/2012
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respectively for Parent ADHD Rating Scale. The changes at the endpoint compared to baseline were: 0.846.79 (meanSD) and -14.048.67 (meanSD) for Ginko T.D. and methylphenidate, respectively
for Teacher ADHD Rating Scale. The difference between the two groups in the frequency of side effects
was not significant except for decreased appetite, headache and insomnia that were observed more
frequently in the methylphenidate group.
Biggs et al. (2010): In a secondary analysis of the Ginkgo Evaluation of Memory (GEM) study Ginkgo
biloba and risk of cancer was analysed. Evidence from in vitro and in vivo studies suggests that Ginkgo
biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. 3069 subjects
(75 years) participated in the GEM study which had a randomised, double-blind and placebocontrolled design. Participants received 120 mg EGb 761 two times daily or placebo. The results show
there were 148 cancer hospitalisations in the placebo group and 162 in the EGb 761 group (HR, 1.09;
95% CI, 0.87-1.36; p=0.46). Among the site-specific cancers analysed, we observed an increased risk
of breast (HR, 2.15; 95% CI, 0.97-4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92-2.87;
p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43-1.17; p=0.18). In
conclusion, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the
risk of cancer.
4.3. Overall conclusions on clinical pharmacology and efficacy

Clinical pharmacology
In clinical studies pharmacodynamic effects on brain function, memory and blood flow were mentioned
in healthy subjects. Chronic treatment with Ginkgo biloba resulted in an improvement of cognitive
deficits in older subjects, whereas in young subjects there were no effects. The exact mechanism is not
known. Human pharmacologiacal data show increased EEG vigilance in geriatric subjects, reduction in
blood viscosity and improved cerebral perfusion in specific areas in healthy men (60-70 years) and
reduction in platelet aggregation. Additionally, vasodilating effects on forearm blood vessels causing
increased regional blood flow are shown.
The examined coadministration of Ginkgo biloba with aspirin, warfarin and antipyrine revealed no
pharmacodynamic interactions. However, the combination of Ginkgo biloba and cilostazol caused
prolongation of bleeding time without enhancing antiplatelet activity, thus increasing the risk of
haemorrhage.
Pharmacokinetic parameters show a high bioavailability of terpene lactones given as a solution (80%
for ginkgolide A, 88% for ginkgolide B and 79% for bilobalide). Peak plasma concentrations of terpene
lactones were in the range of 16-22 ng/ml for ginkgolide A, 8-10 ng/ml for ginkgolide B and 2754 ng/ml when given as tablets. The corresponding half-lifes of ginkgolide A and B and bilobalide were
3-4, 4-6 and 2-3 hours, respectively. 120 mg Ginkgo biloba extract given as solution peak plasma
concentrations were 25-33 ng/ml, 9-17 ng/ml and 19-35 ng/ml for ginkgolide A, B and bilobalide,
respectively. The related half-life for ginkgolide A was 5 hours, for ginkgolide B 9-11 hours and for
bilobalide 3-4 hours.
A lot of clinical pharmacokinetic interaction studies were conducted in which an interaction potential of
Ginkgo biloba extract with other medicinal products and an effect on drug metabolising enzymes was
supposed. The influence of Ginkgo biloba on drug metabolising CYPs has been demonstrated with
various probe substrates for the corresponding CYPs. Both, an inducing and an inhibitory effect were
suggested for Ginkgo biloba on CYP3A4 by results of interaction studies, depending on the study
design. Whereas a daily dose of 240 mg EGb 761 and extracts other than EGb 761 supposed an
inducing effect, a higher daily dose of EGb 761 assumed an inhibitory effect. An induction of CYP2C9

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was assumed at a daily dose of 360 mg of EGb 761. Also inducing effects for Ginkgo biloba extracts
other than EGb 761 on CYP2C19 were observed.
The inhibitory effect of Ginkgo biloba extract on the pharmacokinetics of the P-gp substrate talinolol
was studied in healthy volunteers. The observed increase of C max by 33% and AUC by 21% without
any significant alterations in T max and T 1/2 of talinolol supports the hypothesis of Blonk et al. (2012):
that a possible explanation for the increase in C max and bioavailability of a drug when combined with
EGb 761 could be the inhibition of P-gp by EGb 761. These findings could also be a reflection of
individual variation in the inhibitory potential of P-gp by Ginkgo biloba. The expression and transport
activities may differ between individuals due to genetic variation in the highly polymorphic MDR1 gene.
Therefore, the extent of the inhibition of P-gp may vary accordingly.
One study examining clinical pharmacokinetic interactions of Ginkgo biloba extract and nifedipine, a
calcium-channel blocker, indicated individual increase in C max by concomitant administration. The two
subjects had severer and longer-lasting headaches with dizziness or hot flushes in combination.
From two reviews clinical pharmacological interactions of Ginkgo biloba with alprazolam, haloperidol,
trazodone, omeprazole, aspirin, ibuprofen, nifedipine, warfarin, antiepileptics, antidiabetics, diuretics
and nonsteroidal anti-inflammatory drugs were mentioned.
Clinical efficacy
The EMA Guideline on Medicinal Products for the Treatment of Alzheimers Disease and Other
Dementias (2009) focuses on the development of new medicinal products for the treatment of
dementia and its subtypes. Other guidelines focus more on clinical aspects and care of people with
dementia. Recommendations from the article Management of dementing disorders, conclusions from
the Canadian consensus conference on dementia (1999) have been developed with particular
attention to the context of primary care, and are intended to support family physicians in their ongoing
assessment and care of patients with dementia. Also the German guideline on dementia (S3-Leitlinie
Demenzen [2009]) gives statements to prevention, diagnostic and therapy of dementia as well as to
mild cognitive impairment. The aim is to give assistance to persons who treat and care patients with
dementia and their relatives in decision making of diagnostic, therapy, care and consultation. Besides
pharmacological therapy special emphasis was placed on psychosocial intervention. A British National
Institute for Health and Clinical Excellence (NICE) guideline dementia (2012) makes
recommendations for the identification, treatment and care of people with dementia and the support of
carers. Settings relevant to these processes include primary and secondary healthcare, and social care.
In addition the Scottish Intercollegiate Guidelines Network (SIGN) published a national clinical
guideline Management of patients with dementia (2006). It covers also diagnosis, nonpharmacological interventions, and pharmacological interventions in people with dementia. The
obligation for medicinal products with indications in the field of neurological disorders to apply for a
marketing authorisation via the centralised procedure is addressing new substances.
The results of the IQWIG report 2008 support the use of ginkgo containing products in patients with
mild, moderate, or severe dementia, which includes AD and mixed-type dementia (AD and VaD). The
following studies were analysed in the report: Schwabe (2008), Napryeyenko and Borzenko (2007),
Yancheva et al. (2006), Schneider et al. (2005), LeBars et al. (1997), Kanowski et al. (1996), Digger
(2007). It was evidenced that 240 mg ginkgo extract EGb 761 has a benefit on activities of daily
living. Further, hints of a benefit on cognitive function and general psychopathological symptoms
are mentioned. However, the conclusion that ginkgo has a beneficial effect is based on very
heterogeneous results. Therefore no summarising conclusion was made on the potential effect size.
Additionally there is a sign that this benefit is only present in patients with accompanying
psychopathological symptoms. Moreover, it needs to be considered that results were strongly affected

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by 2 studies conducted in an Eastern European health-care setting with specific patient populations
(among other things, patients with a high rate of accompanying psychopathological symptoms).
Meanwhile two recent studies are published by Herrschaft et al. (2012) and Ihl et al. (2010) that are
supportive for the monograph relevant indication as well. These studies include patients with mild to
moderate dementia (AD or VaD) with neuropsychiatric symptoms.
According to the complexity of the disease partial aspects should be considered in the therapeutical
concept of dementia. Besides others the factor quality of life of patients and caregivers should be
included in these considerations. The IQWIG report 2008 and two more recent studies (Grass-Kapanke
et al. (2011) and Heinen-Kammerer et al. (2005)) addressed this parameter of improving the patients
and caregivers condition.
On the part of the EMA it is noticed that the Guideline on Medicinal Products for the Treatment of
Alzheimers Disease and Other Dementias is under discussion (Concept paper on no need for revision
of the guideline on medicinal products for the treatment of Alzheimer's disease and other dementias).
It is said in the guideline, that despite the rapid progress in understanding of the neurobiology and
pathophysiology of AD, the most common form of dementia, only cholinesterase-inhibitors and
memantine have been approved for the symptomatic treatment with overall limited clinical
improvement and no product has been approved for disease modification in any neurodegenerative
disorder. Furthermore, it is stated that new diagnostic criteria and choice of outcome parameters
should be revised according to the complex pathomechanism of dementia diseases.
Also the long standing use with ginkgo containg products should be kept in mind.
In summary, clinical trials investigating indications in the therapeutic area of tinnitus and claudication
intermittens are not convincing to support well-established use of this application. There are
appropriate studies which support the usage of Ginkgo biloba preparations in the therapeutic area of
mild dementia demonstrating improvement of cognitive impairment and of quality of life. The most
relevant clinical trials have been performed including patients of 50 years and above. The data
particularly indicate that improvements were observed in patients with neuropsychiatric diagnostics.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
See section 4.1. and 4.2.
Furthermore, as reviewed by Oberpichler-Schwenk (1995) no case of overdose has been reported
so far. The available data prove a low toxicity of Ginkgo biloba extract, whereby it should be keep in
mind that these toxicological data were identified with the special extract EGb 761.
5.2. Patient exposure

According to the Arzneiverordungs-Report 2012 (published by U. Schwabe and D. Paffrath) the long
lasting effect of prescription decline of Ginkgo biloba preparations continued onwards in 2011. In 2011
the prescribed daily doses dropped by 8.8% to 5.5 Mio. compared to the year 2010.
5.3. Adverse events and serious adverse events and deaths

Adverse events
In the WEU part of the monograph, the given frequencies of adverse events were pooled and
estimated from the above-mentioned clinical trials (see section 4.2.). No assessment of the quality of
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studies regarding adverse event reporting was done. Only those trials which mentioned the specific
adverse event have been considered when calculating the frequencies. A frequency calculation was
performed for the most reported adverse events which are: headache, dizziness, respiratory tract
infection, hypertension/blood pressure increased, gastrointestinal complaints (diarrhoea, abdominal
pain and nausea), angina pectoris and tinnitus. It should be keep in mind that the adverse events
profiles for the Ginkgo extract preparations and placebo groups were similar or even higher rates exist
in the placebo group.
For the adverse events mentioned in the monograph in the traditional use part, data based on
information of the extract are given. There are no reports of adverse events regarding the traditionally
used powder. Therefore the possible adverse events are transferred from the WEU part without the
given frequencies.
In Germany currently (June 20, 2012) over 400 adverse reactions reports in nearly all organ systems
are labelled according to the Federal Institute for Drugs and Medical devices (BfArM) database
for adverse events. The following adverse events were most frequently mentioned (more than 20
reports for each adverse event): dizziness, headache, pruritus, vomiting, nausea, diarrhoea, chills,
rash and erythema.
Snitz et al. (2009) stated in their analyses of the GEM study: The adverse event profiles for the
Ginkgo biloba and placebo groups were similar and the rates of serious adverse events, including
mortality and incidence of coronary heart disease, stroke of any type, and major bleeding, did not
differ significantly.
Kuller et al. (2010): In the GEM study cardiovascular disease (CVD) was a secondary outcome. The
identification and classification of CVD was based on methods used in the Cardiovascular Health Study.
Differences in time to event between Ginkgo biloba and placebo were evaluated using Cox proportional
hazards regression adjusted for age and sex. There were 355 deaths in the study, 87 due to coronary
heart disease with no differences between Ginkgo biloba and placebo. There were no differences in
incident myocardial infarction (n=164), angina pectoris (n=207), or stroke (151) between Ginkgo
biloba and placebo. There were 24 haemorrhagic strokes, 16 on Ginkgo biloba and 8 on placebo (not
significant). There were only 35 peripheral vascular disease events, 12 (0.8%) on Ginkgo biloba and
23 (1.5%) on placebo (p=0.004, exact test). Most of the peripheral vascular disease cases had either
vascular surgery or amputation. In conclusion, there was no evidence that Ginkgo biloba reduced total
or CVD mortality or CVD events. There were more peripheral vascular disease events in the placebo
arm. Ginkgo biloba cannot be recommended for preventing CVD. Further clinical trials of peripheral
vascular disease outcomes might be indicated.
DeKosky et al. (2008): Secondary objectives in the GEM study were to evaluate the effect of Ginkgo
biloba among other things on total mortality and incidence of cardiovascular disease (CVD) (defined as
the combined incidence of confirmed coronary heart disease, angina, stroke, transient ischemic attack,
coronary artery bypass surgery, or angioplasty; incidence was confirmed by review of the participants
medical record after self-report). There were 379 deaths from any cause. The adverse event profiles
for EGb 761 and placebo were similar and there were no statistically significant differences in the rate
of serious adverse events. The mortality rate was similar in the 2 treatment groups (HR, 1.04; 95% CI,
0.85-1.26; p=0.72). There were no differences in the incidence of coronary heart disease (myocardial
infarction, angina, angioplasty, or coronary artery bypass graft) or stroke of any type by treatment
group. Of particular note rates of major bleeding did not differ between the treatment groups (HR,
0.97; 95% CI, 0.77-1.23; p=0.81), and bleeding incidence did not differ for individuals taking aspirin
and assigned to either EGb 761 or placebo (rates of 1.98 and 1.76 per 100 person-years, respectively,
p=0.44). Although there were twice as many haemorrhagic strokes in the EGb 761 group compared
with the placebo group (16 vs. 8), the number of cases was small and nonsignificant in the analysis.
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Biggs et al. (2010): In a secondary analysis of the Ginkgo Evaluation of Memory (GEM) study Ginkgo
biloba and risk of cancer was analysed. Evidence from in vitro and in vivo studies suggests that Ginkgo
biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. 3069 subjects
(75 years) participated in the GEM study which had a randomised, double-blind and placebocontrolled design. Participants received 120 mg EGb 761 two times daily or placebo. The results show
there were 148 cancer hospitalisations in the placebo group and 162 in the EGb 761 group (HR, 1.09;
95% CI, 0.87-1.36; p=0.46). Among the site-specific cancers analysed, we observed an increased risk
of breast (HR, 2.15; 95% CI, 0.97-4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92-2.87;
p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43-1.17; p=0.18). In
conclusion, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the
risk of cancer.
Brinkley et al. (2010) based the article on data from the GEM study. The GEM study included 3069
participants with a mean age of 79 years. The effects of EGb 761 on blood pressure and incident
hypertension were determined. It was also examined whether the treatment effects are modified by
baseline hypertension status. At baseline, 54% of the study participants were hypertensive, 28% were
prehypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were
similar changes in blood pressure and pulse pressure in the Ginkgo biloba and placebo groups.
Although baseline hypertension status did not modify the antihypertensive effects of Ginkgo biloba, it
did influence the changes in blood pressure variables observed during follow-up, with decreases in
hypertensives, increases in normotensives and no changes in prehypertensives. Among participants
who were not on antihypertensive medications at baseline, there were no differences between
treatment groups in medication use over time, as the odds ratio (95% CI) for being a never-user in the
Ginkgo biloba group was 0.75 (0.48-1.16). The rate of incident hypertension also did not differ
between participants assigned to Ginkgo biloba vs. placebo (HR, 0.99, 95% CI, 0.84-1.15). In
conclusion, the data indicate that Ginkgo biloba does not reduce blood pressure or the incidence of
hypertension in elderly men and women.
Halil et al. (2005) conducted the study to assess the effects of EGb 761 on PFA-100 in vitro bleeding
time in elderly patients with mild cognitive impairment. 40 patients aged 65-79 years received 80 mg
EGb 761 three times daily for 7 days. There was no statistically significant prolongation in PFA-100 in
vitro bleeding time or coagulation parameters in patients receiving EGb 761 after 7 days. The data
about the safety of EGb 761 from the point of primary haemostasis in our elderly patient population
with mild cognitive impairment casts hope for the future management of this difficult-to-treat
population with the promising ginkgo extracts.
Naccarato et al. (2012): described a case report of a potential drug-herbal interaction between
Ginkgo biloba (supplement of 300 mg daily) and Efavirenz (EFV), an antiretroviral drug, which is
metabolised by CYP3A and CYP2B, in a patient that was maintained on the same regimen for 10 years.
Using the Drug Interaction Probability Scale proposed by Horn et al. to evaluate drug interaction cases,
the proposed causal relationship of virological breakthrough due to a drug interaction between Ginkgo
biloba and EFV was calculated as probable. The authors suggested an inducing effect of Ginkgo biloba
on EFV metabolism leading to virological breakthrough, based on the influence of Ginkgo biloba on the
CYP450 biotransformation.
Granger (2001) describes two patients with well-controlled epilepsy, compliant with their antiepileptic medication (1200 mg sodium valproate daily), who developed seizures within two weeks of
using Ginkgo biloba products (not further specified, 120 mg daily). Both patients took other
medications. Other medications from one patient were temazepam, aspirin and ramipril and from the
other one aspirin, rivastigmine and thioridazine. After cessation of the herbal remedy, both the

EMA/HMPC/321095/2012
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patients remained seizure-free without any increase in the dosage of antiepileptic medication or
change of the other medications.
Healthy participants
Keheyan et al. (2011) randomised 14 young healthy men in a placebo-controlled and crossover trial.
Participants received EGb 761 and placebo to investigate whether a single dose of EGb 761 can
improve vascular function. The arterial stiffness (DVP-SI) was slightly higher 2 hours after EGb 761
administration compared to placebo (p<0.05). There was no effect of either EGb 761 or placebo on
pressure wave reflection (DVP-RI), peripheral augmentation index (pAIx), blood pressure and heart
rate.
Khler et al. (2004): This randomised, crossover trial was conducted to investigate the influence of
EGb 761 on bleeding time, coagulation parameters, and platelet activity. 50 healthy male volunteers
received 120 mg two times daily EGb 761 and placebo. The two treatment phases were separated by
an at least 3 weeks wash-out period. The study did not reveal any evidence to substantiate a causal
relationship between the administration of EGb 761 and haemorrhagic complication. As regards
treatment tolerability, there were no interpretable differences between EGb 761 and placebo except for
slight increase of gastrointestinal complaints during administration of the herbal extract.
Kudolo et al. (2004) examined the effect of EGb 761 administration on arachidonic acid (AA)
metabolism in platelets. In this randomised, double-blind, placebo-controlled and crossover study 12
healthy volunteers ingested 120 mg EGb 761 or placebo daily for 3 months. After 3 months the groups
switched to the other test substance for the next 3 months. In the placebo cycles, AA-stimulated
thromboxane B 2 (TXB 2 ) production was 25811337 pg/106 platelets (range 897-5485) compared to
1668992 pg/106 platelets (range 6-1668) in the EGb 761 cycles (p<0.005). Incubation of platelet-rich
plasma with EGb 761 (150 g/ml) completely inhibited platelet aggregation accompanied by inhibition
of TXB 2 synthesis in all subjects both in the placebo (<200 pg TXB 2 /106 platelets) and EGb 761 cycles
(<120 TXB 2 /106 platelets) (p<0.0001). These results support EGb 761-mediated inhibition of platelet
TXB 2 synthesis in vivo.
Dodge et al. (2008): In the primary analysis the overall and event specific proportion of subjects
who reported adverse events were compared between the Ginkgo biloba extract (GBE) and placebo
groups using Fisher exact test. There was no overall difference in adverse events reported by subjects
in the GBE group, compared to subjects in the placebo group (difference in proportions, p=0.44).
However, the GBE group had more stroke or TIA incidences (7 reports, 11.7%) compared with the
placebo group (0 report) (p=0.01, uncorrected for multiple comparisons). All strokes were nonhaemorrhagic infarcts except one case; the subject with haemorrhagic infarct continues to participate
in the study after the event. There were no deaths due to stroke. Four out of seven participants with
stroke incidence continued to participate in the study. There was no difference in the incidence of
haemorrhagic events such as gastrointestinal ulcer, epistaxis, or ecchymoses. Mortality was not
different between the groups (five subjects among each group). It was concluded that the increased
stroke risk will require further close scrutiny in other GBE prevention trials.
Getov et al. (2007) performed the study by a literature search for safety profile assessment in
clinical studies examining the effect of the standardised extract EGb 761. Safety profile of Ginkgo
biloba products is rarely assessed in comparison with efficacy. Only five studies focus on product safety
(Kanowski 1997, Le Bars 1997, Hofferberth 1994, 1989 and Schmidt 1991). Out of them, four studies
state the product is well tolerated and one study, in addition, proves its safety. Safety assessment
indicates the following adverse drug reactions (ADR): hypersensitivity reactions, skin reactions
(erythema, edema, and itching), and gastrointestinal disorders including abdominal pain, diarrhea,
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nausea and headache. From safety requirements point of view, the ADRs could be characterised as
predominantly mild, with low occurrence, and presenting permissible (acceptable) risk.
IQWiG (2008): Overall, the results on adverse drug effects were inconsistent. With regard to serious
adverse events and overall adverse events, there was no indication of harm caused by ginkgo.
However, evidence was available that with ginkgo, more patients discontinued the study due to
adverse events than with placebo.
The purpose of the study by Kellermann et al. (2011) was to undertake a systematic review and
meta-analysis of 18 randomised controlled trials to assess the impact of Ginkgo biloba leaf extract as
single therapy compared with placebo on risk of bleeding, determined by assessing parameters of
haemostasis.
Forest plots of meta-analysis for the outcome parameters of haemostasis
Blood flow:
Blood viscosity:
Adenosine 5-diphosphate-induced platelet aggregation:
Fibrinogen concentration:

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Activated partial thromboplastin time:
Prothrombin time:
Authors conclusion: Based on meta-analysis of haemostasis outcomes, comparison of mean difference

or baseline change between treatment and placebo groups did not indicate a higher bleeding risk
associated with standardised Ginkgo biloba leaf extract. This finding ultimately contributes to an
informed evaluation of Ginkgo biloba leaf extract use, including patient self-medication.
Serious adverse events and deaths
Referring to published case reports the use of Ginkgo biloba has been associated with different
bleeding incidents:
Spontaneous bleeding of the nose, ecchymosis and haemorrhoidal bleeding (Bent et al.
2005)
Postoperative bleeding (Bebbington et al. 2005, Yagmur et al. 2005, Fessenden et al.
2001, Norred and Finlayson 2000)
Bleeding complications after liver transplantation (Hauser et al. 2002)
Retrobulbar haemorrhage (Fong and Kinnear 2003)
Hyphema (Schneider et al. 2002, Rosenblatt and Mindel 1997)
Cerebral haemorrhage (Meisel et al. 2003, Benjamin et al. 2001)
Subarachnoid haemorrhage (Vale 1998)
Parietal lobe haemorrhage (Matthews 1998)
Subdural haematoma (Miller 2002, Gilbert 1997, Rowin et al. 1996)
The majority of the used preparations in the above mentioned case reports were of unknown origin
and quality. These were over-the-counter ginkgo products marketed in the American and UK markets.
The monograph relevant preparation was only involved in two of the case reports. Since these reports

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were compiled under conditions of routine medical care and not under the controlled conditions of a
clinical trial, they often lacked substantial background information and, in particular, central
coagulation parameters were either not available at all, or were measured under non-standardised
conditions. The technical difficulties commonly associated with the standardisation of bleeding time and
coagulation parameter measurement are well known.
In the absence of relevant data from controlled studies, an evaluation of case reports for evidence of a
causal association between ginkgo use and bleeding includes different causality assessment elements.
Besides timing of event relative to ginkgo exposure, the presence of other factors that might have
caused bleeding, dechallenge and rechallenge are widely accepted elements to establish causality.
In 10 of the 13 cases providing information about duration of use exist. It was reported that ginkgo
was taken for more than 6 months before the bleeding event. Two cases, one with hyphema and one
with cerebral haemorrhage, had used ginkgo for 2 months. In the other case of hyphema, ginkgo was
used for only 1 week.
In addition, other risk factors were reported in most cases that could have caused the bleeding event.
The most common risk factor was age. In 13 of the 16 cases patients were aged 59-78. Another risk
factor was coadministration of medications known to increase the risk of bleeding (aspirin, warfarin,
ibuprofen or vitamin E). Other risk factors for bleeding included a fall or an operation.
Only 8 of the 16 cases specifically noted that ginkgo was stopped. None of these cases had recurrent
bleeding by a follow-up time of 10 days to 4 years. Only one case reintroduced ginkgo after the
bleeding event. The measured bleeding time after reintroducing ginkgo increased to >15 min (normal
range 2.5 to 9.5).
Some of the authors of these case reports therefore admitted that a causal relationship between
Ginkgo biloba and the haemorrhagic complications could not be established definitively; albeit, it could
not be excluded as well. For most of the case reports a possible causal association between ginkgo and
bleeding events was suggested.
According to the pharmacovigilance database of the BfArM 74 cases of haemorrhage during the
intake of Ginkgo biloba medicinal products are reported in Germany (June 20, 2012). It should be keep
in mind that these are suspected cases of adverse events and a causal link on an individual basis is not
certainly proved. The specific location of bleeding incidences of reported adverse events (with 5 or
more than 5 cases mentioned) are as followed: epistaxis, cerebral haemorrhage, gastrointestinal
haemorrhage, gastric ulcer haemorrhage, haematoma, eye haemorrhage, melaena and decreased
haemoglobin value. Included in the 74 reported adverse events are five cases of deaths. The deceased
aged between 71 and 76 (one is unknown), where age is the most common risk factor that might have
caused bleeding in these patients. Another risk factor known to increase the risk of bleeding was that
four patients took at least one additional medicinal product that also has an influence on the
characteristics of blood (anticoagulants in 4 out of 5 cases).
Kupiec and Raj (2005) presented a case report of a 55-year-old male who suffered a fatal
breakthrough seizure, loss of consciousness and death, with no evidence of non-compliance with his
anticonvulant medications. The autopsy report revealed subtherapeutic serum levels for both ingested
anticonvulsants (Depakote and Dilantin). Concomitant with his prescribed medications, the decedent
was also self-medicating with a cornucopia of herbal supplements and nutraceuticals a year prior to his
death, prominent among which was Ginkgo biloba. Herbal drug interactions of Ginkgo biloba and CYPs
metabolised drugs are known. Both anticonvulants are metabolised by CYP2C9 and CYP2C19. The
proposed inducing effect of Ginkgo biloba on CYP2C19 activity could be a plausible explanation for the
subtherapeutic levels of the two anticonvulsants, whereas these fluctuations in the concentrations
could not be definitively attributed to the herb-drug interactions. However, without a qualifying lable or
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a standardised quality control process, use of some nutriceutical products may prove to have
hazardous consequences in individuals with a history of convulsive disorders.
5.4. Laboratory findings

Jung et al. (1990) conducted a randomised, placebo-controlled, single-blind, cross-over study in 10
healthy subjects to investigate the influence of 45 ml LI 1370 (dose not indicated) on blood fluidity and
cutaneous microcirculation. No significant changes in blood pressure or heart rate were found in the
two treatment groups. There was also no influence on haematocrit, plasma viscosity, erythrocyte
rigidity, platelet and leukocyte count as well as platelet aggregation and the number of circulating
platelet aggregates. In contrast, a remarkable influence on the erythrocyte aggregation was observed:
a significant decrease by 15.6% (p<0.0001) with regard to the initial value was observed after 2 hours
in the active treatment group. The blood flow in the nail fold capillaries increased significantly by about
57% (p<0.004) 1 hour after administration of Ginkgo biloba extract. In conclusion, these results
indicate an improvement in blood viscosity as well as an increase in the erythrocyte flow in skin
capillaries after administration of Ginkgo biloba extract.
5.5. Safety in special populations and situations

Dugoua et al. (2006): The article was prepared to systematically review the literature for evidence
on the use, safety, and pharmacology of Ginkgo focusing on issues pertaining to pregnancy and
lactation. There is some very weak scientific evidence from animal and in vitro studies that Ginkgo leaf
has anti-platelet activity, which may be of concern during labour as Ginkgo use could prolong bleeding
time. Low-level evidence based on expert opinion shows that Ginkgo leaf may be an emmenagogue
and have hormonal properties. The safety of Ginkgo leaf during lactation is unknown. Patients and
clinicians should be aware of past reports of Ginkgo products being adulterated with colchicine. The
authors concluded that Ginkgo should be used with caution during pregnancy, particularly around
labour where its anti-platelet properties could prolong bleeding time. During lactation the safety of
Ginkgo leaf is unknown and should be avoided until high quality human studies are conducted to prove
its safety.
Ang-Lee et al. (2001) reviewed literature from 1966 to 2000 on commonly used herbal medications
in the context of the perioperative period to check if these drugs could be an endanger in surgeries.
There are no randomised controlled studies on this topic. The authors recommended discontinuing the
intake of Ginkgo biloba, particularly in the surgical population, at least 36 hours prior to surgery. The
advice is based on pharmacokinetic data showing a half life of terpenoids between 3 and 10 hours. Also
case reports with the perioperative concern of the potential to increase risk of bleeding, especially
when combined with other medications that inhibit platelet aggregation, led to the authors advice.
According to the rzte Zeitung (09.03.2009) acetylsalicylic acid should be discontinued 3 days prior
to surgical interventions with an increased risk of bleeeding. The scientists could show that platelet
function normalises faster: After 3 days already, platelets react normal in different functional tests.
5.6. Overall conclusions on clinical safety

In summary the safety analysis of the adverse event profiles of Ginkgo biloba and placebo were similar
and there were no statistically significant differences in the rate of serious adverse events in the
mentioned studies.
The following adverse events should be labeled based on information of case reports, clinical studies
and of the pharmacovigilance database of the BfArM: bleeding of individual organs (eye, nose, cerebral

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and gastrointestinal haemorrhage), headache, dizziness, mild gastrointestinal complaints (such as

diarrhoea, abdominal pain, nausea and vomiting), hypersensitivity reactions (allergic shock) and
allergic skin reactions (erythema, oedema, itching and rash).
The following adverse events were additionally reported in clinical studies: angina pectoris,
hypertension, respiratory tract infection and tinnitus. The observation of the adverse event angina
pectoris is contradictory to the above mentioned clinical studies of Kuller et al. (2010) and DeKosky et
al. (2008). Both studies analysed the secondary results of the GEM study and stated that there were
no differences in incident myocardial infarction (n=164), angina pectoris (n=207), or stroke (151)
between Ginkgo biloba and placebo. Regarding hypertension the study by Brinkley et al. (2010)
determined the effects of EGb 761 on incident hypertension. It was shown that the rate of incident
hypertension did not differ between participants assigned to Ginkgo biloba vs. placebo.
Efavirenz, being a substrate, an inhibitor and an inducer of CYPs, exhibits multiple interactions with the
P450 system. Evaluation of drug interactions with efavirenz is further complicated because efavirenz is
reported to enhance its own metabolism during repeated administration. Thus the exact underlying
mechanism remains unresolved. Ginkgo biloba preparations may lower EFV plasma levels by the
induction of CYP3A4, an EFV metabolising enzyme. In conclusion an intake of Ginkgo biloba containing
medicinal products can decrease human plasma EFV levels, may result in virological failure and should
be discouraged.
It is recommended to avoid the use of Ginkgo biloba containing products in epileptic patients and those
on medications known to lower seizure threshold. The risk of onset of further seizures is addressed in
the special warning section.
Laboratory findings support the effect of Ginkgo biloba on blood flow and therefore advice for patients
with a pathologically increased bleeding tendency and concomitant anticoagulant and antiplatelet
treatment is included in the special warning section.
Usually, pregnant women are not in an age with major relevance of dementia. However isolated cases
of dementia disease in younger patients may not be excluded. Ginkgo biloba extracts may impair the
ability of platelets to aggregate, which may be of concern during labour because ginkgo use could
prolong bleeding time thereby increasing the disposition for bleeding. Therefore, use in pregnancy is
contraindicated.
Concerning lactation, it is unknown whether Ginkgo biloba/metabolites are excreted in human milk. A
risk to the newborns cannot be excluded. A decision must be made whether to discontinue breast
feeding or to discontinue from Ginkgo biloba containing medicinal product therapy taking into account
the benefit of breast feeding for the child and the benefit of therapy for the woman.
In consideration of a similar mode of action of Ginkgo biloba and acetyl salicylic acid, preparations
containing Ginkgo should be discontinued as a precaution 3 to 4 days prior to surgery.
6. Overall conclusions
A specified preparation of Ginkgo biloba fulfils the requirements of well-established use. There are
different clinical studies which demonstrate benefits of Ginkgo biloba in patients with mild dementia
especially above the age of 50 years, which are displayed in the indication: Herbal medicinal product
for the improvement of (age-associated) cognitive impairment and of quality of life in mild dementia.
The results are supported by meta-analysis of several clinical trials. Overall, there is a reasonable
safety profile of Ginkgo biloba preparations. With respect to side effects bleeding events have been
observed. This signal can be adequately addressed by appropriate labelling. Existing data on
interactions are as well adequately addressed in the respective section. The evaluation of the NTP
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technical report, which was addressing toxicological concerns, led to the conclusion that at present
there is no proof for an increased cancer risk identified for patients taking Ginkgo folium medicinal
products at their approved posology. Overall the benefit-risk-ratio is considered positive.
Criteria for a traditional use are fulfilled for a powder usually administered in a capsule. The discussion
finally concluded that the following indication reflects the traditional use and complies with the
requirements of traditional herbal medicinal products: Traditional herbal medicinal product for the
relief of heaviness of legs and the sensation of cold hands and feet associated with minor circulatory
disorders, after serious conditions have been excluded by a medical doctor. All safety relevant
labelling for traditional use are based on data reported for extracts of Ginkgo biloba on the wellestablished use part of the monograph. It cannot be excluded that they may occur with the powder. A
Community list entry was not established due to lack of specific data on genotoxicity. Moreover, it is
questionable, if the safety profile of Ginkgo in general is suitable to establish a Community list entry.
Annex
List of references

EMA/HMPC/321095/2012
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Assessment Report On Ginkgo Biloba L., Folium D

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Assessment report on Ginkgo biloba L., folium

Ginkgo biloba L., folium

the plant, including plant part)

Dry extract (35-67:1) of Ginkgo biloba leaf is

Herbal preparation in solid dosage forms for oral

An agency of the European Union

2.1. Information on period of medicinal use in the Community ....................................... 30

4.1. Clinical Pharmacology ......................................................................................... 48

Assessment report on Ginkgo biloba L., folium

5. Clinical Safety/Pharmacovigilance ................................................................................. 111

List of references .................................................................................................... 120

Assessment report on Ginkgo biloba L., folium

Triterpenelactones (Diterpenes: ginkgolides A, B, C, J (0.06-0.23%) and sesquiterpene:

Triterpenes (steroids, phytosterols)

Polyprenols (Di-trans-poly-cis-octadecaprenol) concentration ranges from 0.04% to 2.0%

Flavonoids not less than 0.5%

Flavones (Aglycones, monoglycosides and biflavones with a concentration of 0.4% to 1.9%)

Flavonols (the aglycones isorhamnetin, kaempferol, quercetin and myricetin have a

Long chain hydrocarbons (waxes)

Others (Carbohydrates, miscellaneous organic compounds, inorganic compounds)

Assessment report on Ginkgo biloba L., folium

Combinations of herbal substance(s) and/or herbal preparation(s) including a description of

1.2. Information about products on the market in the Member States

2-3 times daily

The amount of tablets per day is not stated

Assessment report on Ginkgo biloba L., folium

2 times daily 1 tablet; if required the dosage can be

increased to 3 times daily 1 tablet

2 times daily 1 ml; if required the dosage can be

increased to 3 times daily 1 ml

3 times daily 1 tablet; duration of treatment comply

containing 50 mg dry extract

with the disease pattern; should last min. 6-8

2 times daily 1 teaspoon; duration of treatment

100 ml solution contain

comply with the disease pattern; should last 6-8

3 times daily 1 tablet during 8-12 weeks

initial treatment: 3 times daily 1 ml for 8-12 weeks

follow-up treatment: if required 2 times daily 1 ml

drops) solution contains

dementia syndrome: 3 times daily 1-2 ml

3 times daily 1 tablet during 8-12 weeks

3 times daily 1 ml during 8-12 weeks

2-3 times daily 1-2 coated tablets

Assessment report on Ginkgo biloba L., folium

Belgium: Well-established use

Adults (> 16 years) 1 capsule 2 times daily;

max. 6 capsules per day; intake longer than

a) 1 tablet 3 times daily; max. 9 tablets per day;

no use in children below 12 years; min. period of

treatment: 8 weeks; intake longer than 3 months:

under medical supervision

3 months: under medical supervision

b) 1-2 tablets once daily, max 2 tablets per day

a) Adults: 1-2 tablets 3 times daily

Venous insufficiency: 1 tablet 3 times daily;

b) Adults: 1-2 ml 3 times daily

Assessment report on Ginkgo biloba L., folium