Assessment report on Ginkgo biloba L., folium

1 28 January 2014 EMA/HMPC/321095/2012 Committee on herbal Medicinal Products (HMPC) Assessment report on Ginkgo biloba L., folium Based on Article 10a of Directive 2001/83/EC as amended (well-established use) Based on Article 16d(1), Article 16f and Article 16h of Directive 2001/83/EC as amended (traditional use) Draft herbal substance(s) (binomial scientific name of the plant, including plant part) Ginkgo biloba L., folium herbal preparation(s) Dry extract (35-67:1) of Ginkgo biloba leaf is refined and quantified to 22-27% ginkgoflavonglycosides, represented by quercetin, kaempherol and isorhamnetin and 5-7% terpene lactones, represented by ginkgolides A, B, C ( ) and bilobalide ( ). The content of ginkgolic acids is less than 5 ppm. Extraction solvent: acetone 60%.

2 Powdered herbal substance Pharmaceutical form(s) herbal preparation in solid dosage forms for oral use. Rapporteur Dr Jacqueline Wiesner Assessor(s) Eva-Maria Eibl Note: This draft Assessment report is published to support the release for public consultation of the draft Community herbal monograph on Ginkgo biloba L., folium . It should be noted that this document is a working document, not yet fully edited, and which shall be further developed after the release for consultation of the monograph. Interested parties are welcome to submit comments to the HMPC secretariat, which the Rapporteur and the MLWP will take into consideration but no overview of comments received during the public consultation will be prepared in relation to the comments that will be received on this Assessment report .

3 The publication of this draft Assessment report has been agreed to facilitate the understanding by interested parties of the Assessment that has been carried out so far and led to the preparation of the draft monograph. 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom An agency of the European Union Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7051 E-mail Website European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Introduction .. 4 Information about products on the market in the Member States .. 5 Search and Assessment methodology .. 30 2. Historical data on medicinal use .. 30 Information on period of medicinal use in the Community .. 30 Information on traditional/current indications and specified substances/preparations.

4 31 Specified strength/posology/route of administration/duration of use for relevant preparations and indications .. 32 3. Non-Clinical Data .. 32 Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof .. 33 Primary 33 Secondary pharmacodynamic .. 34 Safety pharmacology .. 35 Pharmacodynamic interactions .. 37 Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof .. 37 Absorption .. 37 Distribution .. 37 Metabolism .. 37 Elimination .. 38 Pharmacokinetic interactions with other medicinal products .. 38 Overview of available toxicological data regarding the herbal substance(s)/ herbal preparation(s) and constituents thereof.

5 39 Single dose toxicity .. 39 Repeated dose toxicity .. 40 Genotoxicity .. 40 Carcinogenicity .. 40 Reproductive and developmental toxicity .. 42 Local tolerance .. 45 Other special studies .. 45 Overall conclusions on non-clinical data .. 46 4. Clinical Data .. 48 Clinical Pharmacology .. 48 Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents .. 48 Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents .. 50 Clinical Efficacy .. 58 Dose response 58 Clinical studies (case studies and clinical trials) .. 58 Clinical studies in special populations ( elderly and children) .. 107 Overall conclusions on clinical pharmacology and efficacy.

6 109 Assessment report on Ginkgo biloba L., folium EMA/HMPC/321095/2012 Page 2/120 5. Clinical Safety/Pharmacovigilance .. 111 Overview of toxicological/safety data from clinical trials in humans .. 111 Patient exposure .. 111 Adverse events and serious adverse events and deaths .. 111 Laboratory findings .. 118 Safety in special populations and situations .. 118 Overall conclusions on clinical safety .. 118 6. Overall conclusions .. 119 Annex .. 120 List of references .. 120 Assessment report on Ginkgo biloba L., folium EMA/HMPC/321095/2012 Page 3/120 1. Introduction Description of the herbal substance(s), herbal preparation(s) or combinations thereof herbal substance(s) There is a monograph on Ginkgo leaf published in the European Pharmacopoeia (Ph.)

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

8 Bilobalide (up to )) - Triterpenes (steroids, phytosterols) - Carotenoids - Polyprenols (Di-trans-poly-cis-octadecaprenol) concentration ranges from to - Volatile terpenes Flavonoids not less than - Flavanols (catechins) - Flavones (Aglycones, monoglycosides and biflavones with a concentration of to ) - Flavonols (the aglycones isorhamnetin, kaempferol, quercetin and myricetin have a concentration of to w/w) Organic acids Polyacetate derived compounds - Alkyl phenolic acids and alkyl phenols (ginkgolic acid, cardanols (approx. )) - Long chain hydrocarbons (waxes) - Lipids Others (Carbohydrates, miscellaneous organic compounds, inorganic compounds) herbal preparation(s) 1. Ginkgo biloba dry extract is a component part of the European Pharmacopoeia.

9 Actually the following monograph exists: Assessment report on Ginkgo biloba L., folium EMA/HMPC/321095/2012 Page 4/120 - Ginkgo dry extract, refined and quantified (Ph. Eur. 7th edition 2012 ( ), ref. 04/2008:1827) This extract contains several chemical constituents, among which the two main constituents flavones glycosides (total ), represented by quercetin, kaempherol and isorhamnetin and terpene lactones (total ), represented by ginkgolides A, B, C ( ) and bilobalide ( ). The content of ginkgolic acids is limited with max. 5 ppm. The limit value of 5 ppm was chosen since it complies with the detection limit recordable by routine methods, thus allowing to assure to a maximum degree removal of these compounds from therapeutically used extracts.

10 2. Powdered herbal substance Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable. The monograph is established on Ginkgo folium and preparations thereof. Information about products on the market in the Member States Austria: Well-established use 1. Dry extract of Ginkgo biloba leaves (EGb 761); DER 35-67:1; quantified to mg ginkgoflavonglycosides and mg terpene lactones (ginkgolides, bilobalide); extraction solvent acetone 2. Dry extract of Ginkgo biloba leaves standardised to mg ginkgoflavonglycosides and mg terpene lactones (ginkgolides, bilobalide) 3. Dry extract of Ginkgo biloba leaves standardised to mg ginkgoflavonglycosides and mg terpene lactones (ginkgolides, bilobalide) 4.