European Medicines Agency London, 12 November 2009 Doc. Ref.: EMA/HMPC/330383/2008 COMMITTEE ON HERBAL MEDICINAL PRODUCTS (HMPC) ASSESSMENT REPORT ON SALVIA OFFICINALIS L., FOLIUM AND SALVIA OFFICINALIS L., AETHEROLEUM Superseded 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 75 23 70 51 E-mail: [email protected] http://www.emea.europa.eu © European Medicines Agency, 2010. Reproduction is authorised provided the source is acknowledged. TABLE OF CONTENTS I. REGULATORY STATUS OVERVIEW........................................................................................ 3 II. ASSESSMENT REPORT................................................................................................................. 4 II.1 INTRODUCTION............................................................................................................................... 5 II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof ........ 5 II.1.2 Specified products on the market in the European Member States ......................................... 7 II.1.3 Search and assessment methodology....................................................................................... 8 II.2 HISTORICAL DATA ON MEDICINAL USE .......................................................................................... 9 II.2.1 Information on period of medicinal use in the Community ..................................................... 9 II.2.2 Information on traditional/current indications and specified substances/preparations ......... 9 II.2.3 Specified strength/posology/route of administration/duration of use for relevant preparations and indications ...................................................................................................................................... 9 II.3 OVERVIEW OF AVAILABLE PHARMACOLOGICAL DATA REGARDING THE HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) AND RELEVANT CONSTITUENTS THEREOF .......................................... 12 II.3.1 Composition........................................................................................................................... 12 II.3.2 Non-clinical pharmacology ................................................................................................... 15 II.3.3 Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ................................................................................ 19 II.3.4 Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof .............................................................................................. 20 II.3.5 Overall conclusions on non-clinical data.............................................................................. 23 II.4 CLINICAL DATA ........................................................................................................................... 24 II.4.1 Clinical Pharmacology.......................................................................................................... 24 II.4.1.1 Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................................... 24 II.4.1.2 Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................................... 27 II.4.2 Clinical Efficacy .................................................................................................................... 28 II.4.2.1 Dose response studies............................................................................................... 32 There are no dose response studies available .................................................................................. 32 II.4.2.2 Clinical studies (case studies and clinical trials) ...................................................... 32 II.4.2.3 Clinical studies in special populations (e.g. elderly and children) ........................... 32 II.4.3 Overall conclusions on clinical pharmacology and efficacy................................................. 32 II.5 CLINICAL SAFETY/PHARMACOVIGILANCE................................................................................... 32 II.5.1 Overview of toxicological/safety data from clinical trials in humans ................................... 32 II.5.2 Patient exposure .................................................................................................................... 32 II.5.3 Adverse events and serious adverse events and deaths ......................................................... 33 II.5.4 Laboratory findings ............................................................................................................... 33 II.5.5 Safety in special populations and situations.......................................................................... 33 II.5.6 Overall conclusions on clinical safety................................................................................... 37 II.6 OVERALL CONCLUSIONS.............................................................................................................. 38 III. ANNEXES........................................................................................................................................ 39 III.1 COMMUNITY HERBAL MONOGRAPH ON SALVIA OFFICINALIS L., FOLIUM , ................................... 39 III.2 LITERATURE REFERENCES ........................................................................................................... 39 Superseded EMA/HMPC/330383/2008 © EMEA 2010 Page 2/39 I. REGULATORY STATUS OVERVIEW1 MA: Marketing Authorisation; TRAD: Traditional Use Registration; Other TRAD: Other national Traditional systems of registration; Other: If known, it should be specified or otherwise add ’Not Known’ Member State Regulatory Status Comments Austria MA TRAD Other TRAD Other Specify: Belgium MA TRAD Other TRAD Other Specify: Only combinations Bulgaria MA TRAD Other TRAD Other Specify: Only combinations Cyprus MA TRAD Other TRAD Other Specify: No reply Czech Republic MA TRAD Other TRAD Other Specify: Denmark MA TRAD Other TRAD Other Specify: Estonia MA TRAD Other TRAD Other Specify: Finland MA TRAD Other TRAD Other Specify: No MA France MA TRAD Other TRAD Other Specify: No reply Germany MA TRAD Other TRAD Other Specify: Greece MA TRAD Other TRAD Other Specify: No reply Hungary MA TRAD Other TRAD Other Specify: Iceland MA TRAD Other TRAD Other Specify: No MA Ireland MA TRAD Other TRAD Other Specify: No reply Italy MA TRAD Other TRAD Other Specify: Only combination Latvia MA TRAD Other TRAD Other Specify: Only combinations Liechtenstein MA TRAD Other TRAD Other Specify: No reply Lithuania MA TRAD Other TRAD Other Specify: No reply Luxemburg MA TRAD Other TRAD Other Specify: No MA Malta MA TRAD Other TRAD Other Specify: No MA The Netherlands MA TRAD Other TRAD Other Specify: No MA Norway MA TRAD Other TRAD Other Specify: Poland MA TRAD Other TRAD Other Specify: Portugal MA TRAD Other TRAD Other Specify: No MA Romania MA TRAD Other TRAD Other Specify: Slovak Republic MA TRAD Other TRAD Other Specify: No MA Slovenia MA TRAD Other TRAD Other Specify: Spain MA TRAD Other TRAD Other Specify: Only combinations Sweden MA TRAD Other TRAD Other Specify: Only combination United Kingdom MA TRAD Other TRAD Other Specify: Only combinations 1 This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned. EMA/HMPC/330383/2008 © EMEA 2010 Page 3/39 II. ASSESSMENT REPORT SALVIA OFFICINALIS L., FOLIUM and SALVIA OFFICINALIS L., AETHEROLEUM BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS AMENDED (TRADITIONAL USE) Herbal substance(s) (binomial scientific name of Salvia officinalis L., folium ; the plant, including plant part) [Salvia officinalis L., aetheroleum] Comminuted herbal substance. Liquid extract (1:1), ethanol 70% V/V Dry extract (4-7:1), extraction solvent: water Liquid extract (1:3.5-5), extraction solvent: ethanol 31.5% V/V Herbal preparation(s) Liquid extract (1:4-5) extraction solvent: ethanol 50% V/V Liquid extract (1:7.2), extraction solvent: liquor wine : ethanol 96% V/V (38.25 : 61.75 m/m) Tincture (1:10) extraction solvent: ethanol 70% V/V Herbal substance as herbal tea for oral and topical use. Herbal preparations in liquid or solid dosage Pharmaceutical forms forms for oral use. Liquid or semi-solid preparations for oromucosal use. Rapporteur Gro Anita Fossum Karl Egil Malterud Assessors SupersededAnne-Cecilie Østensvig EMA/HMPC/330383/2008 © EMEA 2010 Page 4/39 II.1 INTRODUCTION II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof Herbal substance(s): Sage leaf consists of the whole or cut dried leaves of Salvia officinalis L. It contains not less than 15 ml/kg of essential oil for the whole drug and minimum 10 ml/kg of essential oil for the cut drug, both calculated with reference to the anhydrous drug. Sage leaf oil is rich in thujone (Ph. Eur., 2008). Sage tincture produced from 1 part of comminuted sage leaf and 10 parts of ethanol (70% V/V) is a separate monograph in the European Pharmacopoeia. The tincture produced from sage leaf should contain minimum 0.1% m/m essential