30 May 2017 EMA/HMPC/424584/2016 Committee on Herbal Medicinal Products (HMPC) Assessment report on Echinacea purpurea (L.) Moench, radix Final Based on Article 16d(1), Article 16f and Article 16h of Directive 2001/83/EC (traditional use) Herbal substance(s) (binomial scientific name of Echinacea purpurea (L.) Moench, radix the plant, including plant part) Herbal preparation(s) Dry extract (DER 5.5-7.5:1), extraction solvent ethanol 45% (V/V) Dry extract (DER 4:1); extraction solvent water Pharmaceutical form(s) Herbal preparation in solid dosage forms for oral and oromucosal use Rapporteur(s) S. Kreft, B. Razinger Assessor(s) S. Läer, D. Janeš Peer-reviewer I. Chinou 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom elephone +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, 2017. Reproduction is authorised provided the source is acknowledged. Table of contents 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof .. 4 1.2. Search and assessment methodology ..................................................................... 6 2. Data on medicinal use ........................................................................................................ 7 2.1. Information about products on the market .............................................................. 7 2.1.1. Information about products on the market in the EU/EEA Member States ................. 7 2.1.2. Information on products on the market outside the EU/EEA .................................. 12 2.2. Information on documented medicinal use and historical data from literature ............ 12 2.3. Overall conclusions on medicinal use .................................................................... 13 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 3.1.1. Primary pharmacodynamics .............................................................................. 14 3.1.2. Secondary pharmacodynamics .......................................................................... 31 3.1.3. Safety pharmacology ....................................................................................... 34 3.1.4. Pharmacodynamic interactions .......................................................................... 34 3.1.5. Conclusions .................................................................................................... 34 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 34 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. Repeat dose toxicity ......................................................................................... 37 3.3.3. Genotoxicity ................................................................................................... 37 3.3.4. Carcinogenicity ................................................................................................ 37 3.3.5. Reproductive and developmental toxicity ............................................................ 37 3.3.6. Local tolerance ................................................................................................ 37 3.3.7. Other special studies ........................................................................................ 37 3.3.8. Conclusions .................................................................................................... 37 3.4. Overall conclusions on non-clinical data ................................................................ 37 4. Clinical Data ..................................................................................................................... 38 4.1. Clinical pharmacology ......................................................................................... 38 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 38 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 41 4.2. Clinical efficacy .................................................................................................. 44 4.2.1. Dose response studies...................................................................................... 44 4.2.2. Clinical studies (case studies and clinical trials) ................................................... 46 4.3. Clinical studies in special populations (e.g. elderly and children) .............................. 54 4.4. Overall conclusions on clinical pharmacology and efficacy ........................................ 54 5. Clinical Safety/Pharmacovigilance ................................................................................... 54 5.1. Overview of toxicological/safety data from clinical trials in humans ........................... 54 5.2. Patient exposure ................................................................................................ 60 5.3. Adverse events, serious adverse events and deaths ................................................ 60 Assessment report on Echinacea purpurea (L.) Moench, radix EMA/HMPC/424584/2016 Page 2/67 5.4. Laboratory findings ............................................................................................. 61 5.5. Safety in special populations and situations ........................................................... 61 5.5.1. Use in children and adolescents ......................................................................... 61 5.5.2. Contraindications ............................................................................................. 62 5.5.3. Special warnings and precautions for use ........................................................... 62 5.5.4. Drug interactions and other forms of interaction .................................................. 62 5.5.5. Fertility, pregnancy and lactation ....................................................................... 64 5.5.6. Overdose ........................................................................................................ 65 5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability ...... 65 5.5.8. Safety in other special situations ....................................................................... 65 5.6. Overall conclusions on clinical safety ..................................................................... 66 6. Overall conclusions (benefit-risk assessment) ................................................................. 66 Annex .................................................................................................................................. 67 Assessment report on Echinacea purpurea (L.) Moench, radix EMA/HMPC/424584/2016 Page 3/67 Introduction 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof • Herbal substance(s) Echinaceae purpureae radix (European Pharmacopoeia monograph reference 01/2008: 1824) Echinaceae purpureae radix consists of the whole or cut, dried underground parts of Echinacea purpurea (L.) Moench. It contains not less than 0.5% for the sum of caftaric acid (C13H12O9; Mr 312.2) and cichoric acid (C22H18O12; Mr 474.3) in dried drug. Constituents (Barnes et al., 2005; Barnes et al., 2007; Bauer and Remiger, 1989; Bradley, 2006; ESCOP, 2009; Bauer and Liersch, 1993; Mazza and Cottrell, 1999; Wolters Kluwer Health, 2004; PDR, 2007): − Alkamides (0.01-0.7%): mainly isobutylamides of straight-chain fatty-acids with olefinic and/or acetylenic bonds e.g. isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamide. Undeca-2Z,4E- diene-8,10-diynoic acid isobutylamide is also prominent. Isobutylamides contain mainly 2,4- dienoic units. − Caffeic acid derivatives (2.0-2.8%): principally cichoric acid (2,3-O-dicaffeoyltartaric acid, 1.7- 2.4%) and caftaric acid (2-O-caffeoyltartaric acid, ca. 0.2-0.8%) also echinacoside, verbascoside, caffeoylechinacoside, chlorogenic and isochlorogenic acids. − Polysaccharides and glycoproteins: arabinogalactans, and an arabinogalactan-containing glycoprotein with a sugar component consisting of arabinose (64-84%), galactose (2-5%) and galactosamine (6%). − Volatile oil (0.1%): caryophyllene, caryophyllene oxide, humulene, α-phellandrene, limonene, camphene, aldehydes and dimethyl sulphide. − Other constituents: small amounts of polyacetylenic compounds polyynes (0.01 mg/100 g including trideca-1-en-3,5,7,9,11-pentaine, trideca-1,11-dien-3,5,7,9,-tetraine, trideca-8,10,12- triene-2,4,6-triine) − Non toxic pyrrolizidine alkaloids: tussilagine, isotussilagine. Baiciunaite et al. (2015) evaluated the protein content in dried roots of Echinacea purpurea