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Assessment Report on Ginkgo Biloba L., Folium

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Assessment Report on Ginkgo Biloba L., Folium 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) Final Herbal substance(s) (binomial scientific name of Ginkgo biloba L., folium the plant, including plant part) Herbal preparation(s) Dry extract (DER 35-67:1), extraction solvent: acetone 60% m/m (in accordance with the Ph. Eur. monograph “Ginkgo dry extract, refined and quantified” 04/2008: 1827) Powdered herbal substance Pharmaceutical form(s) Herbal preparations in liquid or solid dosage forms for oral use. Rapporteur Jacqueline Wiesner Assessor Eva-Maria Eibl Peer-reviewer Olga Palomino 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimil +44 (0)20 3660 5555 e Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Introduction ....................................................................................................................... 4 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof .. 4 1.2. Information about products on the market in the Member States ............................... 5 1.3. Search and assessment methodology ................................................................... 28 2. Data on medicinal use ...................................................................................................... 29 2.1. Information on period of medicinal use in the European Union ................................. 29 2.2. Information on traditional/current indications and specified substances/preparations .. 29 2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications ....................................................................................... 30 3. Non-Clinical Data ............................................................................................................. 30 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 31 3.1.1. Primary pharmacodynamic................................................................................ 31 3.1.2. Secondary pharmacodynamic ............................................................................ 33 3.1.3. Safety pharmacology ....................................................................................... 33 3.1.4. Pharmacodynamic interactions .......................................................................... 35 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 35 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof ....................................................................... 37 3.3.1. Single dose toxicity .......................................................................................... 37 3.3.2. Repeated dose toxicity ..................................................................................... 38 3.3.3. Genotoxicity ................................................................................................... 39 3.3.4. Carcinogenicity ................................................................................................ 39 3.3.5. Reproductive and developmental toxicity ............................................................ 40 3.3.6. Local tolerance ................................................................................................ 43 3.3.7. Other special studies ........................................................................................ 44 3.4. Overall conclusions on non-clinical data ................................................................ 44 4. Clinical Data ..................................................................................................................... 47 4.1. Clinical Pharmacology ......................................................................................... 47 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 47 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 49 4.2. Clinical Efficacy .................................................................................................. 57 4.2.1. Dose response studies...................................................................................... 57 4.2.2. Clinical studies (case studies and clinical trials) ................................................... 57 4.3. Clinical studies in special populations (e.g. elderly and children) ............................ 103 4.4. Overall conclusions on clinical pharmacology and efficacy ...................................... 105 5. Clinical Safety/Pharmacovigilance ................................................................................. 107 5.1. Overview of toxicological/safety data from clinical trials in humans ......................... 107 5.2. Patient exposure .............................................................................................. 107 5.3. According to the “Arzneiverordungs-Report 2012” (annual medicines prescription report in Germany published by U. Schwabe and D. Paffrath) the prescription of Ginkgo biloba Assessment report on Ginkgo biloba L., folium EMA/HMPC/321095/2012 Page 2/116 preparations was in total about 5.5 Mio. Adverse events and serious adverse events and deaths ................................................................................................................... 107 5.4. Laboratory findings ........................................................................................... 113 5.5. Safety in special populations and situations ......................................................... 114 5.6. Overall conclusions on clinical safety ................................................................... 114 6. Overall conclusions ........................................................................................................ 115 Annex ................................................................................................................................ 116 Assessment report on Ginkgo biloba L., folium EMA/HMPC/321095/2012 Page 3/116 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 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: (e. g. Chan et al. 2007, van Beek 2000) Terpenes - Triterpenelactones (diterpenes: ginkgolides A, B, C, J (0.06-0.23%) and sesquiterpene: bilobalide (up to 0.26%)) - Triterpenes (steroids, phytosterols) - Carotenoids - Polyprenols (di-trans-poly-cis-octadecaprenol) concentration ranges from 0.04% to 2.0% - Volatile terpenes Flavonoids not less than 0.5% - Flavanols (catechins) - Flavones (aglycones, monoglycosides and biflavones with a concentration of 0.4% to 1.9%) - Flavonols (the aglycones isorhamnetin, kaempferol, quercetin and myricetin have a concentration of 0.2% to 1.4% w/w) Organic acids Polyacetate derived compounds - Alkyl phenolic acids and alkyl phenols (ginkgolic acid, cardanols (approx. 0.1%)) - Long chain hydrocarbons (waxes) - Lipids Others (carbohydrates, miscellaneous organic compounds, inorganic compounds) Assessment report on Ginkgo biloba L., folium EMA/HMPC/321095/2012 Page 4/116 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 22.0-27.0%), represented by quercetin, kaempherol and isorhamnetin and “terpene lactones” (total 5.0-7.0), represented by ginkgolides A, B, C (2.8- 3.4%) and bilobalide (2.6-3.2%). The content of ginkgolic acids is limited with max. 5 ppm. The limit value of 5 ppm was chosen since it complies
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