12 March 2013 EMA/HMPC/321232/2012 Committee on Herbal Medicinal Products (HMPC) Assessment report on Panax ginseng C.A. Meyer, radix 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 Whole or cut dried root, designated white ginseng; of the plant, including plant part) treated with steam and then dried, designated red ginseng, of Panax ginseng C.A.Meyer Herbal preparation(s) White ginseng: A) Comminuted herbal substance B) Powdered herbal substance C) Dry extract (DER 2-7:1), extraction solvent ethanol 34-40% V/V D) Dry extract (DERgenuine 3-7:1), extraction solvent ethanol 40% V/V, containing 4% ginsenosides (sum of Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg2) E) Dry extract (DER 3-7:1), extraction solvent ethanol 57.9% V/V (=50% m/m) - 60% V/V F) Dry extract (DER 3.3-5:1), extraction solvent methanol 60% V/V G) Soft extract (DER 1.7-3.2:1), extraction solvent ethanol 60-70% V/V H) Soft extract (DER 2-6:1), extraction solvent methanol 30% V/V I) Liquid extract (DER 1:0.8-1.2), extraction solvent ethanol 30.5% V/V (=25% m/m) – 34% V/V J) Liquid extract (DER 1:11-13.6), extraction solvent liquor wine Red Ginseng: K) Powdered herbal substance L) Dry extract (DER 2-4.5:1), extraction solvent ethanol 60% V/V 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7051 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Pharmaceutical forms Comminuted herbal substance (herbal preparation A) as herbal tea for oral use. Herbal preparations B, C, E, F, K, L in solid dosage form for oral use. Herbal preparations G, H, I, J in liquid dosage form for oral use. Herbal preparation D in solid and liquid dosage form. Rapporteur Assessor(s) Note: This draft Assessment Report is published to support the release for public consultation of the draft Community herbal monograph on Panax ginseng C.A. Meyer, radix. It should be noted that this document is a working document, not yet edited, and which shall be further developed after the release for consultation of the monograph. Interested parties are welcome to submit comments to the HMPC secretariat, which the Rapporteur and the MLWP will take into consideration but no ‘overview of comments received during the public consultation’ will be prepared in relation to the comments that will be received on this assessment report. The publication of this draft assessment report has been agreed to facilitate the understanding by Interested Parties of the assessment that has been carried out so far and led to the preparation of the draft monograph. Assessment report on Panax ginseng C.A. Meyer, radix EMA/HMPC/321232/2012 Page 2/123 Table of contents Table of contents ................................................................................................................... 3 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 ............................... 6 1.3. Search and assessment methodology ..................................................................... 8 2. Historical data on medicinal use ........................................................................................ 8 2.1. Information on period of medicinal use in the Community ......................................... 8 2.2. Information on traditional/current indications and specified substances/preparations .. 27 2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications ....................................................................................... 29 3. Non-Clinical Data ............................................................................................................. 31 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 31 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 53 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof ....................................................................... 55 3.4. Overall conclusions on non-clinical data ................................................................ 59 4. Clinical Data ..................................................................................................................... 60 4.1. Clinical Pharmacology ......................................................................................... 60 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 60 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 64 4.2. Clinical Efficacy .................................................................................................. 67 4.2.1. Dose response studies...................................................................................... 67 4.2.2. Clinical studies (case studies and clinical trials) ................................................... 67 4.2.3. Clinical studies in special populations (e.g. elderly and children) .......................... 112 4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 112 5. Clinical Safety/Pharmacovigilance ................................................................................. 112 5.1. Overview of toxicological/safety data from clinical trials in humans ......................... 112 5.2. Patient exposure .............................................................................................. 116 5.3. Adverse events and serious adverse events and deaths ........................................ 116 5.4. Laboratory findings ........................................................................................... 118 5.5. Safety in special populations and situations ......................................................... 118 5.6. Overall conclusions on clinical safety ................................................................... 122 6. Overall conclusions ........................................................................................................ 123 Annex ................................................................................................................................ 123 Assessment report on Panax ginseng C.A. Meyer, radix EMA/HMPC/321232/2012 Page 3/123 1. Introduction 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof • Herbal substance(s) Ginseng radix (European Pharmacopoeia): Ginseng radix consists of the whole or cut dried root, designated white ginseng, treated with steam and then dried, designated red ginseng, of Panax ginseng C.A. Meyer and contains not less than 0.40% for the sum of ginsenosides Rg1 and Rb1 (dried drug). Constituents (Wichtl 2009, Hänsel & Sticher 2010) Ginsenosides: 2-3%, Triterpensaponins: Dammarane and Oleanolic acid derivatives More than 200 saponins have been isolated from ginseng species, including roots (processed and native), leaves, stems, flower buds, berries, and seeds. Regarding the chemical structure, ginseng saponins are divided into several groups. The two major groups are protopanaxadiol (PPD)-type saponins with sugar moieties attached to the C3 and/or C20, and the protopanaxatriol (PPT)-group with sugar moieties at C6 and/or C20. Other types include the ocotillol-type with a five-membered epoxy- ring at C20, the oleanane –type with a nonsteroidal structure and the dammarane type with a modified C20 side chain. The nomenclature of the ginsenosides (Ra, Rb, Rc, etc.) is related to the TLC-Rf-value, whereby the polarity is decreasing from Ra to Rf, correlating to the grade of glycosylation. So far, from the roots of Panax ginseng about 50 ginsenosides have been identified, mostly belonging to the neutral, bisdesmosidic type (Rb1, Rc, Re, Rg1), but also monodesmosides are present (Rf, Rg2). In general the sugar chains are not branched. Except Rg3, Rg2, Rh1 and Rs3 all ginsenosides from the unprocessed roots are of 20(S)-PPT or 20(S)-PPD-type. 20(R)-derivatives are characteristic for red ginseng and can be seen as artifacts arising during the treatment with steam. Malonylginsenosides (e.g. mRb1, mRb2) are only present in white ginseng, the malonyl-group is cleaved during the steam processing. (Hänsel & Sticher 2010) Not only red and white ginseng, but also roots and leaves show considerable differences in the ginsenoside spectrum. Especially the small rootlets (“slender tails”) are rich in ginsenosides. Therefore, the qualitative and quantitative composition of and the ratio between certain ginsenosides in ginseng preparations allow conclusions about the