European Medicines Agency Evaluation of Medicines for Human Use London, 12 November 2009 Doc. Ref.: EMA/HMPC/101303/2008 COMMITTEE ON HERBAL MEDICINAL PRODUCTS (HMPC) ASSESSMENT REPORT ON HYPERICUM PERFORATUM L., HERBA 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, 2009. Reproduction is authorised provided the source is acknowledged TABLE OF CONTENTS I. REGULATORY STATUS OVERVIEW...................................................................................4 II. ASSESSMENT REPORT............................................................................................................5 II.1 INTRODUCTION..........................................................................................................................6 II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof 6 II.1.1.1 Herbal substance:........................................................................................................ 6 II.1.1.2 Herbal preparation(s): ................................................................................................ 7 II.1.1.3 Combinations of herbal substance(s) and/or herbal preparation(s)........................... 9 Not applicable. ................................................................................................................................9 II.1.1.4 Vitamin(s) .................................................................................................................... 9 Not applicable. ................................................................................................................................9 II.1.1.5 Mineral(s).................................................................................................................... 9 Not applicable. ................................................................................................................................9 II.1.2 Information on period of medicinal use in the Community regarding the specified indication......................................................................................................................................... 9 II.1.2.1 Type of tradition, where relevant ................................................................................ 9 II.1.2.2 Bibliographic/expert evidence on the medicinal use................................................... 9 II.1.2.2.1 Evidence regarding the indication/traditional use ................................................ 9 II.1.2.2.2 Evidence regarding the specified posology........................................................ 15 II.2 NON-CLINICAL DATA .............................................................................................................16 II.2.1 Pharmacology ............................................................................................................... 16 II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof .................................................................................................. 16 II.2.1.1.1 Effects associated with depression ..................................................................... 16 II.2.1.1.2 Antidepressant activity in animal models........................................................... 18 II.2.1.1.3 Anxiolytic effects ............................................................................................... 18 II.2.1.1.4 Neuroprotection, memory impairment, nootropic effects .................................. 19 II.2.1.1.5 Support in smoking cessation............................................................................. 22 II.2.1.1.6 Treatment of alcoholism..................................................................................... 22 II.2.1.1.7 Antibacterial activity .......................................................................................... 23 II.2.1.1.8 Antiinflammatory activity .................................................................................. 23 II.2.1.1.9 Wound healing ................................................................................................... 24 II.2.1.1.10 Photodynamic therapy...................................................................................... 24 II.2.1.1.11 Other effects ..................................................................................................... 24 II.2.1.2 Assessor’s overall conclusions on pharmacology..................................................... 25 II.2.2 Pharmacokinetics .......................................................................................................... 25 II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof .................................................................................................. 25 II.2.2.2 Assessor’s overall conclusions on pharmacokinetics................................................ 26 II.2.3 Toxicology ..................................................................................................................... 26 II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof................................................................................................................. 26 II.2.3.1.1 Single-dose toxicity............................................................................................ 27 II.2.3.1.2 Repeated-dose toxicity ....................................................................................... 27 II.2.3.1.3 Mutagenicity....................................................................................................... 27 II.2.3.1.4 Carcinogenicity .................................................................................................. 27 II.2.3.1.5 Phototoxicity ...................................................................................................... 27 II.2.3.1.6 Reproductive Toxicity........................................................................................ 29 II.2.3.2 Assessor’s overall conclusions on toxicology ........................................................... 31 II.3 CLINICAL DATA ......................................................................................................................31 II.3.1 Clinical Pharmacology.................................................................................................. 31 II.3.1.1 Pharmacodynamics ................................................................................................... 31 II.3.1.1.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity. ................... 31 EMEA 2009 Page 2/77 II.3.1.1.2 Assessor’s overall conclusions on Pharmacodynamics...................................... 31 II.3.1.2 Pharmacokinetics ...................................................................................................... 31 II.3.1.2.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity. ................... 31 II.3.1.2.2 Assessor’s overall conclusions on pharmacokinetics......................................... 33 II.3.2 Clinical Efficacy............................................................................................................ 33 II.3.2.1 Dose response studies................................................................................................ 33 II.3.2.2 Clinical studies (case studies and clinical trials)...................................................... 33 II.3.2.2.1 Studies on the treatment of depression............................................................... 33 II.3.2.2.2 Somatoform disorders ........................................................................................ 58 II.3.2.2.3 Schizophrenia ..................................................................................................... 59 II.3.2.2.4 Nootropic effects ................................................................................................ 59 II.3.2.2.5 Subacute atopic dermatitis.................................................................................. 59 II.3.2.2.6 Premenstrual syndrome ...................................................................................... 59 II.3.2.2.7 Menopausal symptoms ....................................................................................... 60 II.3.2.3 Clinical studies in special populations (e.g. elderly and children) ........................... 60 II.3.2.4 Assessor’s overall conclusions on clinical efficacy................................................... 61 II.3.3 Clinical Safety/Pharmacovigilance............................................................................... 62 II.3.3.1 Patient exposure........................................................................................................ 62 II.3.3.2 Adverse events ........................................................................................................... 62 II.3.3.3 Serious adverse events and deaths ............................................................................ 66 II.3.3.4 Laboratory findings..................................................................................................