27 August 2014 EMA/HMPC/320433/2012 Corr1 Committee on Herbal Medicinal Products (HMPC) Assessment report on Andrographis paniculata Nees, folium Based on Article 10a of Directive 2001/83/EC as amended (well-established use) 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 Andrographis paniculata Nees, folium the plant, including plant part) Herbal preparation(s) Pharmaceutical form(s) Rapporteur Dr Zsuzsanna Biró-Sándor Assessor(s) Dr Dezső Csupor 1 Minor additional information on plant parts/extracts included on page 10, 18, 20 and 24. 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 ............................... 4 1.3. Search and assessment methodology ..................................................................... 5 2. Historical data on medicinal use ........................................................................................ 5 2.1. Information on period of medicinal use in the Community ......................................... 5 2.2. Information on traditional/current indications and specified substances/preparations .... 6 2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications ......................................................................................... 6 3. Non-Clinical Data ............................................................................................................... 8 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ............................................................. 8 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ........................................................... 20 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof ....................................................................... 23 3.4. Overall conclusions on non-clinical data ................................................................ 25 4. Clinical Data ..................................................................................................................... 25 4.1. Clinical Pharmacology ......................................................................................... 25 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 25 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ........................................................................ 25 4.2. Clinical Efficacy .................................................................................................. 25 4.2.1. Dose response studies...................................................................................... 25 4.2.2. Clinical studies (case studies and clinical trials) ................................................... 25 4.2.3. Clinical studies in special populations (e.g. elderly and children) ............................ 27 4.3. Overall conclusions on clinical pharmacology and efficacy ........................................ 27 5. Clinical Safety/Pharmacovigilance ................................................................................... 27 5.1. Overview of toxicological/safety data from clinical trials in humans ........................... 27 5.2. Patient exposure ................................................................................................ 28 5.3. Adverse events and serious adverse events and deaths .......................................... 28 5.4. Laboratory findings ............................................................................................. 28 5.5. Safety in special populations and situations ........................................................... 28 5.6. Overall conclusions on clinical safety ..................................................................... 28 6. Overall conclusions .......................................................................................................... 28 Annex .................................................................................................................................. 28 Assessment report on Andrographis paniculata Nees, folium EMA/HMPC/320433/2012 Page 2/28 1. Introduction 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof • Herbal substance(s) Andrographidis paniculatae folium consists of the leaves of Andrographis paniculata Nees (Acanthaceae). It is not covered by any pharmacopoeial monograph officially in use in the European Union (EU). Other herbal substances have been described: - Andrographidis herba consisting of the dried aerial parts of Andrographis paniculata (Burm. f.) Nees (Acanthaceae) is described in a WHO monograph (2004) and in the Pharmacopoeia of the People’s Republic of China (PPRC 2005); - the entire dried plant of Andrographis paniculata Nees, referred to as Creyat, Kiryat and Kreat, is described in The British Pharmaceutical Codex (BPC 1934); - the whole herb is listed in the Indian Materia Medica (1976). Major constituents The major constituents are diterpene lactones (free and in glycosidic forms) including andrographolide, deoxyandrographolide, 11,12-didehydro-14-deoxyandrographolide, neoandrographolide, andrographiside, deoxyandrographiside and andropanoside (WHO 2004). Of these diterpene lactones, andrographolide is considered to be the most biologically active constituent. Therefore, most of the quantification of Andrographis paniculata extracts is exclusively based on the content of andrographolide (Naik and Hule 2009). • Herbal preparation(s) Preparations described in the literature: - Extract of leaves of Andrographis paniculata (about 17:1) extraction solvent methanol (Saxena et al. 2010) - Extract of leaves and aerial parts of Andrographis paniculata (10:1) extraction solvent 75% ethanol (Burgos et al. 2009) - Extract of leaves of Andrographis paniculata extraction solvent: the ethanol⁄water (90 ⁄10 v⁄v); 8 - 10% andrographolide content (Tang et al. 2011). Combination products containing Andrographis paniculata extract described in the literature: - One capsule comprises 85 mg of the standardised extract of Andrographis paniculata (plant part not specified) equivalent to 5 mg of andrographolides, as well as 10 mg extract of Eleutherococcus senticosus (plant part not specified) extract equivalent to 120 mg of the crude drug per tablet (Gabrielian et al. 2002, Spasov et al. 2004, Melchior et al. 2000); - A combination product (370 mg tablet) of Andrographis paniculataHerba Nees special extract (50 mg) standardized for content of adrographolide 4 mg, Eleutherococcus senticosus special extract (10 mg) standardized for content of Eleutherosid (E >0.8mg), Schizandra chinensis special extract ( 100 mg) standardized for content of Schisandrins (>0.8 mg), and Glycyrrhiza glabra L. extract (10 mg) standardized for the content of Glycyrrhizin (> 0.6 mg) (Amaryan et al. 2003); Assessment report on Andrographis paniculata Nees, folium EMA/HMPC/320433/2012 Page 3/28 - A liquid extract (about 1 in 2) of the whole plant prepared with boiling water and addition of different further constituents, like 2% of fennel oil, 2% of ajowa oil, and 55 - 60% ethanol and then adjusted to a 5% content of andrographolides (Hagers Handbuch der Pharmazeutischen Praxis 1972, Reynolds Martindale the extra Pharmacopoeia 1982). 1.2. Information about products on the market in the Member States Regulatory status overview Member State Regulatory Status Comments Austria MA TRAD Other TRAD Other Specify: Belgium MA TRAD Other TRAD Other Specify: the plant material is included in food supplements Bulgaria MA TRAD Other TRAD Other Specify: Croatia MA TRAD Other TRAD Other Specify: Cyprus MA TRAD Other TRAD Other Specify: No registered product on the market Czech Republic MA TRAD Other TRAD Other Specify: Denmark MA TRAD Other TRAD Other Specify: No product on the market (only one combination product containing the herba) Estonia MA TRAD Other TRAD Other Specify: No medicinal product on the market Finland MA TRAD Other TRAD Other Specify: France MA TRAD Other TRAD Other Specify: Germany MA TRAD Other TRAD Other Specify: No single-component or multicomponent product on the market with German Standard Marketing Authorisations Greece MA TRAD Other TRAD Other Specify: Hungary MA TRAD Other TRAD Other Specify: No single-component product on the market (only 2 multicomponent registered