24 November 2014 EMA/HMPC/320932/2012 Committee on Herbal Medicinal Products (HMPC) Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum 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 Melaleuca alternifolia (Maiden and Betch) Cheel, the plant, including plant part) M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, leaf and terminal branchlets Herbal preparation(s) Melaleuca alternifolia, aetheroleum Pharmaceutical forms Herbal preparation in liquid and semi-solid dosage forms for cutaneous use or in liquid dosage form for oromucosal use. Rapporteur Marisa Delbò Assessor(s) Marisa Delbò Gioacchino Calapai Peer-reviewer Jacqueline Viguet Poupelloz 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, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ................................................................................................................... 2 1. Introduction ....................................................................................................................... 5 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof .. 5 1.2. Information about products on the market in the Member States ............................... 7 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 .. 14 2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications ....................................................................................... 14 3. Non-Clinical Data ............................................................................................................. 21 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 21 3.1.1. Primary pharmacodynamics .............................................................................. 21 3.1.2. Secondary pharmacodynamics .......................................................................... 26 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 28 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof ....................................................................... 29 3.3.1. Single dose toxicity .......................................................................................... 29 3.3.2. Repeated dose toxicity ..................................................................................... 29 3.3.3. Genotoxicity ................................................................................................... 30 3.3.4. Carcinogenicity ................................................................................................ 31 3.3.5. Reproductive and developmental toxicity ............................................................ 32 3.3.6. Local tolerance ................................................................................................ 32 3.3.7. Other special studies ........................................................................................ 34 3.4. Overall conclusions on non-clinical data ................................................................ 35 4. Clinical Data ..................................................................................................................... 36 4.1. Clinical Pharmacology ......................................................................................... 36 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 36 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 39 4.2. Clinical Efficacy .................................................................................................. 39 4.2.1. Dose response studies...................................................................................... 39 4.2.2. Clinical studies (case studies and clinical trials) ................................................... 39 4.2.2.1. Overview ..................................................................................................... 39 4.2.2.2. Clinical studies conducted with TTO ................................................................. 40 4.2.2.3. Clinical studies conducted with combinations containing TTO .............................. 59 4.3. Clinical studies in special populations (e.g. elderly and children) .............................. 60 4.4. Overall conclusions on clinical pharmacology and efficacy ........................................ 61 5. Clinical Safety/Pharmacovigilance ................................................................................... 62 5.1. Overview of toxicological/safety data from clinical trials in humans ........................... 62 Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum EMA/HMPC/320932/2012 Page 2/71 5.2. Patient exposure ................................................................................................ 66 5.3. Adverse events and serious adverse events and deaths .......................................... 66 5.4. Laboratory findings ............................................................................................. 68 5.5. Safety in special populations and situations ........................................................... 68 5.5.1. Use in children and adolescents ......................................................................... 69 5.5.2. Contraindications ............................................................................................. 69 5.5.3. Special Warnings and precautions for use ........................................................... 69 5.5.4. Drug interactions and other forms of interaction .................................................. 69 5.5.5. Fertility, pregnancy and lactation ....................................................................... 69 5.5.6. Overdose ........................................................................................................ 69 5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability ...... 70 5.5.8. Safety in other special situations ....................................................................... 70 5.6. Overall conclusions on clinical safety ..................................................................... 70 6. Overall conclusions .......................................................................................................... 70 Annex .................................................................................................................................. 71 Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum EMA/HMPC/320932/2012 Page 3/71 Abbreviations ASI Acne Severity Index CoNS Coagulase-Negative Staphylococci EMA European Medicines Agency ESCOP European Scientific Cooperative On Phytotherapy EO/LTTO Eucalyptus Oil and Lemon Tea Tree Oil pediculicide IgA Immunoglobulin A GI Gingival Index MBC Minimum Bactericidal Concentration MDCK Madin–Darby canine kidney (cell line) MIC Minimal Inhibitory Concentration MICs Minimal Inhibitory Concentrations MIC90 Minimal Inhibitory Concentration required inhibiting the growth of 90% of organisms MRSA Methicillin-resistant Staphylococcus aureus MSB Mitis Salivarius-Bacitracin agar MSSA Methicillin- susceptible Staphylococcus aureus OPC Oropharyngeal candidiasis PBI Papillary Bleeding Index RHL Recurrent herpes labialis SCCP Scientific Committee on Consumer Products TTO Tea Tree Oil TTO/LO Tea Tree Oil and Lavender Oil pediculicide VAS Visual Analogue Scale VRE Vancomycin-resistant enterococci VSC Volatile Sulphur Compounds Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum EMA/HMPC/320932/2012 Page 4/71 1. Introduction 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof Herbal substance(s) Melaleuca alternifolia tree is a member of the botanical family Myrtaceae.