Ginkgo leaf – Ginkgo folium (Ginkgo biloba L.)

Latin name of the genus: | Ginkgo folium |
Latin name of herbal substance: | Ginkgo biloba l. |
Botanical name of plant: | Herbalref.com |
English common name of herbal substance: | Ginkgo leaf |
Used to: Venous circulatory disorders;
Latin name of the genus: Ginkgo folium
Botanical name of plant: Ginkgo biloba L.
English common name of herbal substance: Ginkgo leaf
5.3. According to the
1. Introduction
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Herbal substance(s)
A monograph on Ginkgo leaf is 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
Synonyms: Fossil tree, Kew tree, Maidenhair Tree, Yin Xing (whole plant), Yin Xing Ye (leaves)
Constituents: (e. g. Chan et al. 2007, van Beek 2000)
Terpenes
–Triterpenelactones (diterpenes: ginkgolides A, B, C, J
–Triterpenes (steroids, phytosterols)
–Carotenoids
–Polyprenols
–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 included in the European Pharmacopoeia. Currently the following monograph exists:
–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
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 European Union monograph is established on Ginkgo folium and preparations thereof.
1.2. Information about products on the market in the Member States
(Information was collected when drafting of the European Union monograph was started.)
Austria:
1.Dry extract of Ginkgo biloba leaves (EGb 761); DER
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 terpene lactones (ginkgolides, bilobalide)
4.Dry extract of Ginkgo biloba leaves, not further specified
5.Dry extract of Ginkgo biloba leaves; DER
6.Dry extract of Ginkgo biloba leaves (EGb 761) standardised to 9.6 mg ginkgoflavonglycosides and
2.4mg terpene lactones (ginkgolides, bilobalide)
7.Dry extract of Ginkgo biloba leaves (EGb 761) standardised to 9.6 mg ginkgoflavonglycosides and
2.4mg terpene lactones (ginkgolides, bilobalide)
8.See 6
9.Dry extract of Ginkgo biloba leaves (EGb 761) standardised to 9.6 mg ginkgoflavonglycosides and
2.4mg terpene lactones (ginkgolides, bilobalide)
10.One coated tablet contains 20 mg dry extract of Ginkgo biloba leaves standardised to 4,8 mg ginkgoflavonglycosides
Indications
1.For the symptomatic treatment of
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
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:
1.Dry extract; DER
2.Dry extract; DER
3.Dry extract; DER
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
3.To delay the pathological symptoms typical of mild to moderate
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:
1.Ginkgo biloba dry extract standardised to
2.Ginkgo biloba dry extract standardised to
3.See 1
4.See 2
5.Ginkgo biloba dry extract standardised to
6.Ginkgo biloba dry extract standardised to
7.Ginkgo biloba dry extract standardised to
8.Ginkgo biloba dry extract standardised to
For all products: In dizziness and tinnitus of vascular or involution character treatment longer than
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
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 headaches; 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). 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:
Additional comments
Preparations 1 – 4
Ginkgo biloba dry extract standardised to
Preparations 5) – 8)
Ginkgo biloba dry extract standardised to
Denmark:
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
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
4.Product with brand name
5.Product with brand name
Indications
1.Herbal medicinal product in
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:
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
Proton pump inhibitors: Ginkgo leaf (multiple doses) decrease AUC for a single dose omeprazole with
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
2.See 1.
Additional comments
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:
1.Dry extract from ginkgo leaf, corresponding to 9.6 mg of flavones glycosides and 2.4 mg terpene lactones (ginkgolides, bilobalide)
2.Dry extract from ginkgo leaf, corresponding to 14.4 mg of flavones glycosides and 3.6 mg terpene lactones (ginkgolides, bilobalide)
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
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
Combination products
Average number of combination substances:
France
One product (ginkgo powder 180 mg) has been on the market as food supplement.
The product is marketed for vertigo, improvement of blood circulation, heavy legs, haemorrhoids, memory deficit.
Germany:
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
Preparations in the following strengths are available:
30 mg/tablet: No. 1
40 mg/tablet or rather 40 mg/ml: No.
50 mg/tablet: No.
60 mg/tablet: No.
80 mg/tablet: No.
120 mg/tablet: No.
240 mg/tablet: No.
Since when are the preparations on the market?
No. 2 since 1986; No.
Pharmaceutical forms
Oral drops, solution: No.
Oral liquid: No. 10, 12,
Capsule, hard: No. 13,
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 tablet 2 times daily
Dementia syndrome
1 tablet 3 times daily or 2 tablets 2 times daily
1 tablet
1 tablet 2 times daily
For the symptomatic treatment of
Peripheral arterial occlusive disease, vertigo, as an adjuvant in tinnitus
25 drops (1,25 ml) 3 times daily or rather 40 drops (2 ml) 2 times daily
20 drops (1 ml) 3 times daily or rather 40 drops (2 ml) 2 times daily
2 pumps (1 ml) 3 times daily or rather 4 pumps (2 ml) 2 times daily
1 tablet 3 times daily (=150 mg): No.
1 tablet 2 times daily
1 tablet 1 time daily (=120 mg): No.
For increasing the
For increasing the
1 capsule 3 times daily or rather 2 capsules 2 times daily
25 drops (1 ml) 3 times daily or rather 50 drops (2 ml) 2 times daily
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
Do not take the
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
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
b)For increasing the
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, b, e: No. 2, 5, 7,
a: No. 3, 52,
a, b: No. 6
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.
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
Interactions
If a preparation containing Ginkgo biloba is taken concomitantly with anticoagulants (e.g. phenprocoumon, warfarin, clopidogrel, acetylsalicylic acid and other
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).
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
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
The herbal substance is not on the market.
Norway:
1.Ginkgo biloba leaf dry extract
2.Ginkgo biloba leaf dry extract
Indications
Used to improve blood circulation in for example cold hands and feet
Poland:
1.Ginkgo biloba leaf dry extract, refined
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
Indications
In mild disorders of peripheral circulation with feeling of cold hands and legs; adjunctively in mild age- linked impairment of intellectual capability
Risks
Adverse drug reaction
Gastrointestinal complaints (nausea, constipation, diarrhoea), headache, sleep disorders, palpitation, vertigo anxiety, hypersensitivity reactions (pruritus, erythema), bleeding
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
The herbal substance is on the market.
Additional comments
Other herbal medicinal products than
1.Ginkgo biloba leaf dry extract
2.Ginkgo biloba leaf dry extract
3.Ginkgo biloba leaf dry extract
4.Ginkgo biloba leaf dry extract containing
5.Ginkgo biloba leaf dry extract
6.Ginkgo biloba leaf dry extract
7.Ginkgo biloba leaf dry extract
8.Ginkgo biloba leaf dry extract
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)
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
4.(b) In disorders of peripheral circulation with accompanying feeling of cold legs or pain
5.(a) In elderly patients manifesting impaired cognitive and neurosensorial functions (except for
Alzheimer’s disease and other states of profound dementia). In cerebral circulation disorders with such symptoms as vertigo and tinnitus, impaired sight and hearing
6.(b) Adjunctively for treatment of symptoms of peripheral circulation disorders – intermittent claudication in chronic peripheral obliterative arterial disease (stage 2)
7.(c) Adjunctively for treatment of Raynaud’s disease symptoms
8.See 3
9.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)
10.(a) In
11.(b) Adjunctively in cerebral circulation disorders with manifestations like vertigo and tinnitus
12.(c) Adjunctively in disorders of peripheral circulation with pain during walking or feeling of cold hands and legs
13.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)
14.In disorders of peripheral circulation ; adjunctively in cerebral circulation disorders
15.In peripheral circulation disorders
Risks (adverse drug effects, literature)
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
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
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
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:
1.Ginkgo biloba standardised extract (EGb 761) containing 24% of ginkgo heterosides and 6% of terpenes (ginkgolides, bilobalide)
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:
1.Dry extract standardised to
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, Raynaud’s syndrome, acrocyanosis); neurosensory disorders of vascular origin (vertigo, tinnitus, acuphenes)
Risks
Patients with known hypersensitivity to Ginkgo biloba preparations or to any of the excipients
The herbal substance is not on the market.
Additional comments
Ginkgo biloba dry extract comply with Ph. Eur. monograph 1827/2008
Spain:
1.1. Ginkgo biloba dry extract standardised to
2.Ph. Eur. monograph
3.Ph. Eur. monograph
Indications
For all products: Symptomatic treatment of cerebrovascular and peripheral vascular disorders

Spain: Traditional use
Indications
For all products: Vertigo, heavy legs, haemorrhoids
Sweden: Traditional use
1.Ginkgo biloba, dried leaf, dry extract (DER
2.Ginkgo biloba, dried leaf, dry extract (DER
3.Ginkgo biloba, dried leaf, dry extract (DER
4.Ginkgo biloba, dried leaf, dry extract (DER
5.Ginkgo biloba, dried leaf, dry extract (DER
Indications
For all products: Traditional herbal medicinal product for the treatment of
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
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
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
One interaction study has indicated that the Cmax of nifedipine may be increased by Ginkgo 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.
The herbal substance is on the market.
There were pharmacovigilance actions taken on the medicinal product containing the herbal substance.
Additional comments
The following products have been registered according to a previous national registration scheme (so called registered ‘naturmedel’):
Brandname 80 mg (30:1) 2×2, reg Naturmedel 1986
Brandname 40 mg (EGb 761)
Brandname 250 mg 1×3, reg Naturmedel 1989
Slovenia:
1.Ginkgo biloba leaf dry extract
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:
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
3.Ginkgo biloba leaf dry extract; 40 mg standardised to 24% ginkgoflavonglycosides and 6% ginkgolides and bilobalide
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 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.
1.3. Search and assessment methodology
Available literature on Ginkgo biloba at the “Bundesinstitut für 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
Only articles found to be relevant for establishment of a monograph and assessment are included in the list of references.
2. Data on medicinal use
2.1. Information on period of medicinal use in the European Union
According to the information specified above the most frequent authorised herbal preparation on Ginkgo biloba leaves with
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
The tincture of Ginkgo biloba leaves is less than 30 years on the market and was consequently not considered for the monograph.
For a herbal preparation reported to be marketed in Poland (Ginkgo biloba leaf dry extract, refined
2.2. Information on traditional/current indications and specified substances/preparations
For the traditional powdered herbal substance reference was made to the medicinal use in France and Spain. The following indication is reflecting this part of the traditional indications which is complying with the legal requirements: “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
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 35- 67:1) described the use for the symptomatic treatment of
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
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,
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
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
See also 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 overall approach to have relatively short periods for duration of use (e.g. described for a related indication in the European Union monograph for Melilotus).
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
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
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
Free
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
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
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
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) 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
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
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 PAF- antagonistic activities of individual ginkgolides and EGb 761 were evaluated in rabbit platelets. PAF- mediated aggregation of human platelets was
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 PAF
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,
3.1.3. Safety pharmacology
In vitro studies
Auguet et al. (1982a) EGb 761 (100 µg/ml) that did not provoke contractions of rabbit aorta, potentiated the contractile effect of norepinephrine (EC50 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 concentration- dependent contractile response with an EC50 of about 1.0 mg/ml. This action was antagonised by phentolamine. Inhibitors of catecholamine
Hellegouarch et al. (1985) showed that EGb 761 elicited in a
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 µg/15ml (=0.8 and 2.7 µg/ml) Ginkgo biloba flavonoid preparation to 50 and 100%, respectively. The same effect was observed with 120 µg/15 ml (=8 µg/ml) kaempferol and 200 µg/15 ml (=13 µg/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 µg/ml, EGb 761 was either inactive, or produced a slight relaxation. At 100 µg/ml a distinct relaxation was produced, and at 200 µg/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 µg/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
In vivo studies
Peter et al. (1966) examined further the influence of Ginkgo biloba flavonoid preparation (diluted in Cremophor EL and
Cats received consecutively in approx.
Oppositional results were observed in rats and guinea pigs. In rats, at the low (330 µg/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 10- fold 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
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 (5- HT), acetylcholine (ACh) and the metabolites 3,4- dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and
HIAA were not affected. The same treatment regimen was used in a subsequent study with the aim of investigating the effects of two
3.1.4. Pharmacodynamic interactions
No specific data on pharmacodynamic interactions in animals are reported here, as there are various clinical data on this topic available and presented in section 4.
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.
Absorption
Moreau et al. (1986) studied the absorption of radiolabelled 14C EGb 761 in rats. They let Ginkgo plants grow under supply of
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
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
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 (Ki>900 µg/ml). The activity of CYP2C9 was the most affected by EGb 761 (Ki=14±4 µg/ml). CYP1A2 (106±24 µg/ml), CYP2E1 (127±42 µg/ml), and CYP3A4 (155±43 µg/ml) were also inhibited but to a lesser extent. The terpenoidic fraction inhibited only CYP2C9 (Ki =15±6 µg/ml) whereas the flavonoidic fraction of EGb 761 showed high inhibition of CYP2C9, CYP1A2, CYP2E1, and CYP3A4 (Ki’s between 4.9 and 55 µg/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,
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
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 N-
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
Hellum and Nilsen (2008) investigated Ginkgo biloba (solubilised in ethanol) for its in vitro inhibitory potential of CYP3A4 mediated metabolism and
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 LD50 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. LD50 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 LD50 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 µg of ginkgotoxin in a recommended maximum daily dose
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 B6 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
hepatocytes. Consequentially, pretreament with selective CYP inducers,
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.
Hitzenberger (1992) 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
and 4.6 mg/l, respectively. A concentration dependent release of LDH was observed when cells were incubated in the presence of ginkgolic acids
lysosomal enzymes, while morphological evaluation of
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.
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 dose- dependent 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
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
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 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.
Maeda et al. (2014) published an in vivo study of a Ginkgo biloba extract and reported about a reporter gene mutation assay using gpt delta mice and also a combined liver comet assay and bone marrow micronucleus assay using constitutive androstane receptor knockout and
3.3.5. Reproductive and developmental toxicity
Monograph relevant extract
Eimazoudy and Attia (2012) evaluated potential
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, oestrous cycle, reproduction hormones, ovarian follicle counts, resorption index, implantation index, foetal viability and foetuses, and placenta mean weights were evaluated. There was a
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
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 significant reduction in the rate of oocyte maturation, fertilisation, and in vitro embryonic development. Treatment of oocytes with
Chan (2005) showed that ginkgolide A and ginkgolide B treatment (both 5 and 10 µM) of mouse blastocysts induces apoptosis, decreases cell numbers, retards early postimplantation blastocyst development, and increases
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 LD50 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 LD50 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
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 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.
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; maternal’s liver, kidney and ovary weights; resorption index;
14 mg/kg/day to rats in the organogenic and fetogenic periods can lead to fetal
Amin et al. (2012) assessed the protective effects of Ginkgo biloba extract (GBE, purchased from General Nutrition Corporation, Pittsburgh, USA) against
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
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
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.
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
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 µg/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
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
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
The Ginkgo biloba extract EGb 761 contains standardised amounts of flavonoids and ginkgolides. In animal models of Alzheimer’s disease (AD), these antioxidants and neuroprotectants inhibit amyloid
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 rates 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.
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
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
The results show LD50 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
In vitro and in vivo studies conducted with single components of Ginkgo biloba (ginkgolide A and B with a HED of
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
per daily dose) given from day
Further, a protective effect of ginkgo containing extracts against
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 above- mentioned pharmacological data, clinical findings and derived indications, a
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
Primary pharmacodynamics
Effect on cognition
Geßner et al. (1985): In a
Elsabagh et al. (2005) conducted a
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
Santos et al. (2003) performed a
Effect on blood flow
Guinot et al. (1989): An open study was conducted to examine the antagonistic activity of EGb 761 on
15 ml liquid extract (dose not indicated). Ex vivo platelet aggregation was determined by aggregometry on
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:
Secondary pharmacodynamics
No data available.
Safety pharmacology
No data available.
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,
Wolf (2006) suggests that coadministration of aspirin and EGb 761 to 50 healthy male volunteers
Jiang et al. (2005) analysed the effect of EGb 761 (80 mg three times daily) on clotting status and pharmacodynamics of warfarin in an
affect clotting status or pharmacodynamics of warfarin in healthy subjects.
Jiang et al. (2006) investigated

Duche et al. (1989) found that EGb 761 showed no effect on the hepatic microsomal drug oxidation system. 24 healthy male volunteers
400 mg/day of EGb 761 (group 1), 300 mg/day phenytoin (group 2) or placebo (group 3). The elimination
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
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.
Table 1. Pharmacokinetic parameters of terpene lactones in 12 healthy volunteers after single oral administration of 120 mg EGb 761 (Kressmann et al. 2002)
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)
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 Tmax.
Biber (2003): In a
Table 3. Pharmacokinetic parameters after oral administration of EGb 761 in healthy volunteers
(Biber 2003)
As reported in the German monograph of the Commission E, the absolute oral bioavailability was 98- 100% for ginkgolide A,
Chan et al. (2007): After an oral dose of EGb 761 (80 mg) maximum plasma levels of ginkgolide A (Cmax=15 ng/ml) and ginkgolide B (Cmax=4 ng/ml) were attained at
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,
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)
Wójcicki 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 (Wójcicki et al. 1995)
Distribution
No data available.
Metabolism
Chang et al. (2006): In the following in vitro study the effect of Ginkgo biloba extract constituents on
Elimination
No data available.
Pharmacokinetic interactions with other medicinal products
Studies with defined Ginkgo biloba extract (EGb 761)
Robertson et al. (2008): Evaluation of an
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.
Markowitz et al. (2003) assessed in normal volunteers (n=12) aged
Greenblatt et al. (2006): The study shows that
ginkgo tablet contained 6.6 µg of amentoflavone and 61.2 µg 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
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
Blonk et al. (2012) studied the effect of EGb 761 on the pharmacokinetics of raltegravir in an open- lable, randomised,
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.
In the article by
Jiang et al. (2005) analysed the effect of EGb 761 (80 mg three times daily) on pharmacokinetics of warfarin in an
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
Kudolo et al. (2006): A study is described which was designed as a
Gardner et al. (2007): The purpose of this randomised,
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 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
Yoshioka et al. (2004b): The effects of Ginkgo biloba leaf extract (manufactured in Chiba, Japan) on the pharmacokinetics of nifedipine (NFP), a
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
respectively, whereas t½ and tmax indicated no alteration. The results suggest that Ginkgo biloba extract significantly inhibited
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
Yin et al. (2004) designed this study to investigate the potential
Kim et al. (2010) evaluated the potential pharmacokinetic interactions between ticlopidine and Ginkgo biloba extract (not further specified). 24 healthy Korean male volunteers (24±4.3 years) participated in this
Mauro et al. (2003): An open label, randomised, crossover investigation was conducted in 8 healthy volunteers aged
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 single- dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CYP2C19 extensive
or poor metabolisers. In a randomised,
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, N- demethyldiazepam, 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
Mohutsky et al. (2006) conducted two
Gurley et al. (2005) noted no effect of Ginkgo biloba on cytochrome P450 activity in this
4.2. Clinical Efficacy
4.2.1.Dose response studies
4.2.2.Clinical studies (case studies and clinical trials)


The following table summarises relevant data from the table above concerning the relevance of association with age from studies on 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




Cognitive decline/Dementia syndrome
The author’s conclusion of the English version of the executive summary of the IQWiG final report A05- 19B: For the therapy goal “activities of daily living”, there is evidence of a benefit of
(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
Due to the high heterogeneity between studies, no conclusive statement can be made on the benefit of
The benefit of ginkgo compared with other drugs approved for Alzheimer’s 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 Alzheimer’s disease are needed to enable






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
Mazza et al. (2007b) 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
three groups and in no case
Reply by Mazza et al. (2007a): It was already outlined in the “Discussion and conclusions” section that larger samples of patients should be considered to confirm these results. In the author’s opinion this







Reviews and
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
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 and Grimley Evans (2009): Author’s 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):

Author’s conclusion: The bivariate random effect
Weinmann et al. (2010):
ITT/LOCF change scores for cognition outcomes
ITT/LOCF change scores for ADL outcomes:
Author’s 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 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):
Author’s 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 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 withdrawn from development.
Lüders 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
Healthy participants

that the extract has a demonstrable effect in improving mood and the self- assessed performance of the tasks of everyday living.
Peripheral arterial occlusive disease (intermittent claudication)
Reviews and
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
(95% CI: 1.16, 1.31) and demonstrates the efficacy of EGb 761 over placebo as well.
Ratio theta of the increase in
Author’s 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).
Nicolaï 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
Forest plot of clinical studies comparing the absolute claudication distance (expressed as kilocalories) at the end of the study

Author’s conclusion: There is no evidence that Ginkgo biloba has a clinically significant benefit for patients with PAD.
Pittler and Ernst (2000) included eight randomised,
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.





Reviews and
Von Boetticher (2011) concluded that EGb 761, a standardised Ginkgo biloba extract, is an
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 author’s 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
Vertigo

Reviews and
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.
4.3. 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
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
Szczurko et al. (2011): A pilot clinical trial concerning vitiligo vulgaris was performed in 12 participants aged

by 3.9 (p<0.001) from 2.7 to
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 PAF. 119
Usai et al. (2011): Another study investigated the effect of ginkgolide B as preventive treatment to confirm the
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
Cala et al. (2003) examined the use of herbal therapy in children or adolescents receiving care for a depressive disorder or
years (mean age 10.9±3.1 years). The mean age at onset of a psychiatric condition was 8.1±3.3 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 ADHD in a randomised,
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,
4.4. 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
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
54 ng/ml when given as tablets. The corresponding
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 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
was studied in healthy volunteers. The observed increase of Cmax by 33% and AUC by 21% without any significant alterations in Tmax and T1/2 of talinolol supports the hypothesis of Blonk et al. (2012): that a
possible explanation for the increase in Cmax and bioavailability of a drug when combined with EGb 761

could be the inhibition of
One study examining clinical pharmacokinetic interactions of Ginkgo biloba extract and nifedipine, a
From two reviews clinical pharmacological interactions of Ginkgo biloba with alprazolam, haloperidol, trazodone, omeprazole, aspirin, ibuprofen, nifedipine, warfarin, antiepileptics, antidiabetics, diuretics and nonsteroidal
Clinical efficacy
The EMA “Guideline on Medicinal Products for the Treatment of Alzheimer’s 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 (Patterson et al. 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
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

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
Currently, at EMA the “Guideline on Medicinal Products for the Treatment of Alzheimer’s Disease and Other Dementias” is under discussion (“Concept paper on 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
Also the long standing use with ginkgo containg products has to be taken into account.
In summary, clinical trials investigating indications in the therapeutic area of tinnitus and claudication intermittens are not convincing to support
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
5.2.Patient exposure
5.3.
According to the prescription of Ginkgo biloba preparations was in total about 5.5 Mio. 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

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 only the
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 participant’s medical record after
Biggs et al. (2010): In a secondary analysis of the 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,

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
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
Halil et al. (2005) conducted the study to assess the effects of EGb 761 on
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
Naccarato et al. (2012): described a case report of a potential
Granger (2001) describes two patients with
Healthy participants
Keheyan et al. (2011) randomised 14 young healthy men in a

improve vascular function. The arterial stiffness 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, peripheral augmentation index, blood pressure and heart rate.
Köhler 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
Kudolo et al. (2004) examined the effect of EGb 761 administration on arachidonic acid (AA) metabolism in platelets. In this randomised,
Dodge et al. (2008): In the primary analysis the overall and event specific proportion of subjects who reported adverse events were compared between 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
Reviews and
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, diarrhoea, 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 and Kloft. (2011) was to undertake a systematic review and
Forest plots of
Blood flow:
Blood viscosity:
Adenosine
Fibrinogen concentration:
Activated partial thromboplastin time:

Prothrombin time:
Author’s conclusion: Based on
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 and Freeman 2002, Gilbert 1997, Rowin and Lewis 1996)
The majority of the used preparations in the above mentioned case reports were of unknown origin and quality. These were
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
Only 8 of the 16 cases specifically noted that ginkgo was stopped. None of these cases had recurrent bleeding by a
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 kept in mind that these are suspected cases of adverse events and a causal link on an individual basis is not proven with certainty. 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
5.4. Laboratory findings
Jung et al. (1990) conducted a randomised,

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.
According to the Ärzte Zeitung (09.03.2009) acetylsalicylic acid should be discontinued 3 days prior to surgical interventions with an increased risk of bleeding. 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 labelled based on information of case reports, clinical studies and pharmacovigilance data with respect to the dry extract of Ginkgo biloba: bleeding of individual organs (eye, nose, cerebral 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 (EFV), being a substrate, an inhibitor and an inducer of CYPs, exhibits multiple interactions with the P450 system. Evaluation of drug interactions with EFV is further complicated because EFV 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
Criteria for a traditional use are fulfilled for a powder usually administered in a capsule. 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”. The safe use of the powder is based on

the Rapporteur considered it questionable, if the safety profile of Ginkgo in general is suitable to establish a list entry.