25 March 2014 EMA/HMPC/680615/2013 Committee on Herbal Medicinal Products (HMPC) Assessment report on Eleutherococcus senticosus (Rupr. et Maxim.) Maxim., radix 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 Eleutherococcus senticosus (Rupr. et Maxim.) the plant, including plant part) Maxim., radix Herbal preparation(s) Comminuted herbal substance Powdered herbal substance Liquid extract (DER 1:1, extraction solvent ethanol 30-40% v/v) Dry extract (DER 13-25 : 1, extraction solvent ethanol 28-40% v/v) Dry extract (DER 17-30 : 1, extraction solvent ethanol 70% v/v) Dry aqueous extract (DER 15-17:1) Tincture (ratio of herbal substance to extraction solvent 1:5, extraction solvent ethanol 40% v/v) Liquid extract (DER 1:11), extraction solvent sweet wine Liquid extract (DER 1:20), extraction solvent sweet wine Pharmaceutical forms Comminuted herbal substance as herbal tea for oral use Herbal preparations in solid or liquid dosage forms for oral use. Rapporteur Dace Kaļķe Assessor(s) Dace Kaļķe 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ................................................................................................................... 2 1. Introduction ....................................................................................................................... 3 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof .. 3 1.2. Information about products on the market in the Member States ............................... 5 1.3. Search and assessment methodology ..................................................................... 6 2. Historical data on medicinal use ........................................................................................ 6 2.1. Information on period of medicinal use in the Community ......................................... 6 2.2. Information on traditional/current indications and specified substances/preparations .. 11 2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications ....................................................................................... 12 3. Non-Clinical Data ............................................................................................................. 14 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 14 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 32 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof ....................................................................... 33 3.4. Overall conclusions on non-clinical data ................................................................ 34 4. Clinical Data ..................................................................................................................... 35 4.1. Clinical Pharmacology ......................................................................................... 35 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 35 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 38 4.2. Clinical Efficacy .................................................................................................. 39 4.2.1. Dose response studies...................................................................................... 39 4.2.2. Clinical studies (case studies and clinical trials) ................................................... 39 4.2.3. Clinical studies in special populations (e.g. elderly and children) ............................ 43 4.3. Overall conclusions on clinical pharmacology and efficacy ........................................ 44 5. Clinical Safety/Pharmacovigilance ................................................................................... 45 5.1. Overview of toxicological/safety data from clinical trials in humans ........................... 45 5.2. Patient exposure ................................................................................................ 45 5.3. Adverse events and serious adverse events and deaths .......................................... 46 5.4. Laboratory findings ............................................................................................. 46 5.5. Safety in special populations and situations ........................................................... 47 5.6. Overall conclusions on clinical safety ..................................................................... 49 6. Overall conclusions .......................................................................................................... 50 Annex .................................................................................................................................. 51 Assessment report on Eleutherococcus senticosus (Rupr. et Maxim.) Maxim., radix EMA/HMPC/680615/2013 Page 2/51 1. Introduction 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof • Herbal substance(s) Eleutherococcus root (Eleutherococci root) is a dried, whole or cut underground organs of Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. with a content of a minimum 0.08% for the sum of eleutheroside B and eleutheroside E (European Pharmacopoeiea, 2013). The correct binomial botanic name is Eleutherococcus senticosus (Rupr. et Maxim.) Maxim., syn. Acanthopanax senticosus (Rupr. et Maxim.) Harms. Eleutherococcus was formerly known as Acanthopanax senticosus (Rupr. et Maxim.) Harms and this name is still widely used by Chinese scientists (Li et al., 2005; Frodin, 2006). The first English name, created in the USA for Eleutherococcus, was “Eleuthero” (Baranov, 1979). "Siberian Ginseng" has been used in the USA as a second name since 1971, but the name has been banned by the Ginseng Labelling Act of 2002 (Farnsworth et al., 1986; Israelsen, 1993). Fifteen names that are based on the abbreviated Latin generic name “Eleuthero” are currently used in various EU official languages; in 4 languages variants from name “Siberian Ginseng”, in 4 languages – variants from “Russian root” or “Russian ginseng root”, and in German and in Hungarian variants from “Taiga root” - “Taigawurzel” and “tajga gyökér” are used. In this assessment report the names “Eleutherococcus” or latin “Eleutherococcus senticosus” are used although both synonyms may be found in the original articles. Constituents Although over 35 compounds have been identified from the Eleutherococcus root, the search for active substances is not finished yet. Eleutherococcus senticosus is characterised by the co-existence of pentacyclic and tetracyclic triterpenoidal saponins and their prosapogenins, lignans, coumarins, phenylcarbonic acids and xanthones (Jeljakov et al., 1972; Sandberg, 1973; Anetai et al., 1987; Sonnenborn et al., 1993; Deyama et al., 2001). The main constituents are: − phenyl propane compounds: eleutheroside B (or syringin) – 0.5% (Ovodov et al., 1967), chlorogenic acid – up to 0.3% (Deyama et al., 2001), coniferyl aldehyde and its glucoside (Deyama et al., 2001), caffeic acid derivates (Wagner et al., 1982; Liu et al. 2012a); − lignanes: (+)-syringaresinol –O-β-D-glucoside (or eleutheroside E) – 0.1% (Ovodov et al., 1967; Deyama et al., 2001), episyringaresinol-4’’-O-β-D-glucoside (or Eleutheroside E2 ) (Li et al., 2001), ((-)-sesamin ( or eleutheroside B4 ) – 0.023% (Suprunov et al., 1971; Bladt et al., 1990; Li et al., 2001), (-)-Syringaresinol-4-4’-O-β-D-diglucosid (or Eleutherosid D) – 0.10%, (Ovodov et al., 1967) , (-)-Syringaresinol-4-O-β-D-monoglucosid (or Eleutherosid E1) (Aicher et al., 2006, 2012), (-)-Syringaresinol (Aicher et al., 2006, 2012); (+)-pinoresinol di-O- β-D- glucoside (Deyama et al., 2001); − coumarins: isofraxidin (6,8-dimethoxy-7-hydroxycumarin) (Wagner et al., 1982; Deyama et al., 2001) and its O-glucoside eleutherosid B1 (Nörr, 1993; Deyama et al., 2001), 7-ethyl- umbelliferone (Barnes et al., 2007). Assessment report on Eleutherococcus senticosus (Rupr. et Maxim.) Maxim., radix EMA/HMPC/680615/2013 Page 3/51 − triterpensaponines: daucosterol (eleutheroside A), β -hederin (Eleutheroside K) (Farnsworth et al., 1985),2-protoprimulagenin A-glycoside – 0.125% (Segiet-Kujawa et al., 1991; Evans et al., 2002). − polysaccharides (heteroglycans and eleutherans) (Fang et al., 1985; Wagner et al., 1984; Wagner et al., 1985; Shen et al., 1991). Other constituents comprise steroids, carbohydrates and essential oil 0.8% (Barnes et al., 2007). • Herbal preparation(s) − Comminuted herbal substance − Powdered herbal substance − Liquid extract (DER 1:1, extraction solvent ethanol