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«Assessment report on Angelica sinensis (Oliv.) Diels, radix Based on Article 10a of Directive 2001/83/EC as amended (well-established use) Based on ...»

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9 July 2013

EMA/HMPC/614586/2012

Committee on Herbal Medicinal Products (HMPC)

Assessment report on Angelica sinensis (Oliv.) Diels,

radix

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 Angelica sinensis (Oliv.) Diels, radix

the plant, including plant part)

Herbal preparation(s) Liquid extract, dried liquid extract Pharmaceutical forms Oral solution, tablets Rapporteur W. Dymowski Assessor(s) 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7051 E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged.

Table of contents Table of contents

1. Introduction

1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof.. 4

1.2. Information about products on the market in the Member States

1.3. Search and assessment methodology

2. Historical data on medicinal use

2.1. Information on period of medicinal use in the Community

2.2. Information on traditional/current indications and specified substances/preparations.. 11

2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications:

3. Non-Clinical Data

3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof

3.1.1. Primary pharmacodynamics

3.1.1.1. Antithrombotic, antiplatelet activity

3.1.1.2. Antispasmodic activities

3.1.1.3. Oestrogenic activity

3.1.2. Secondary pharmacodynamics

3.1.2.1. Cytotoxicity and antiproliferative effects

3.1.2.2. Anxiolytic effect of the essential oil

3.1.2.3. Effects on the cardiovascular system

3.1.2.4. Protective effect of a polysaccharide fraction on the gastric mucosa

3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof

3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof

3.4. Overall conclusions on non-clinical data

4. Clinical Data

4.1. Clinical Pharmacology

4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents

4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents

4.2. Clinical Efficacy

4.2.1. Dose response studies

4.2.2. Clinical studies (case studies and clinical trials)

4.2.3. Clinical studies in special populations (e.g. elderly and children)

4.3. Overall conclusions on clinical pharmacology and efficacy

5. Clinical Safety/Pharmacovigilance

5.1. Overview of toxicological/safety data from clinical trials in humans

5.2. Patient exposure

5.3. Adverse events and serious adverse events and deaths

5.4. Laboratory findings

5.5. Safety in special populations and situations

5.6. Overall conclusions on clinical safety

–  –  –

1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof Herbal substance(s) • According to European Pharmacopoeia, ed. 7.5 (1), the herbal substance contains the smoke-dried, whole or fragmented root, with rootlets removed, of Angelica sinensis (Oliv.) Diels collected in late autumn, containing minimum 0.050 per cent of trans-ferulic acid (C 10 H 10 O 4 ; M r 194.2).

Assessor’s comments:

The traditional processing of this root in China doesn’t contain a washing process, like in the case of other roots used in Europe. There is no information on cleaning of root surface. It is not clear what microbiological flora is present on the surface of the material after smoke-drying. According to data from Korea and Vietnam, for the microbiological decontamination of the Dang gui root, radiation sterilisation is used.

According to the Pharmacopoeia of the People’s Republic of China (1977), Radix Angelicae sinensis (Danggui) was used “To enrich blood, activate blood circulation, regulate menstruation, relieve pain and relax bowels”.

According to the TCM theory, different parts of Angelicae sinensis radix possess different traditional applications. The whole root (Quan Danggui) is used to quicken, nourish and harmonise blood; root head (Danngui Tou) is used to quicken the blood and to stop bleeding; root body without head (Danggui Shen) consisting of the main body of the root without head and tails is used for nourish the blood when blood quickening properties are not desired; root tails (Danggui Wei) consisting of the primary branch roots is considered to elicit the strongest effect for quickening the blood and breaking up blood stasis; finer roots (Danggui Xu) (“beard”) are used to quicken the blood and free the network vessels. In practice, in herbal trade Danggui Tou is actually the two parts of Danggui Tou and Danggui Schen but Danggui Xu is parts of Danggui Tou and Danggui Schen but Danggui Xu is rare on the market.





The species Angelica sinensis (Oliv.) Diels was described in Bot. Jahrb. Syst. 29 (3-4): 500.1900 [4 Dec 1900] on the basis of an earlier description of Angelica polymorpha Maxim. var. sinensis Oliv.

Hooker’s icon. Pl. 20: t. 1999. 1891 [Aug 1891] (IPNI).

According to the Flora of China (China@efloras.org;) the species Angelica sinensis (Oliver) Diels (Dang gui) is a perennial plant, 0.4 - 1 m of height, with cylindric branched and succulent roots that have many rootlets and are strongly aromatic. The plant is further described as follows (Zehui & Watson, 2005): Stems purplish green, ribbed, branched above. Basal and lower petioles 5 - 20 cm, sheaths purplish green, ovate, membranous-margined; blade ovate, 10 - 30 × 12 - 25 cm, 2 - 3-ternatepinnate, pinnae 3 - 4 pairs, proximal and middle pinnae long-petiolulate; leaflets ovate or ovatelanceolate, 2 - 3.5 × 0.8 - 2.5 cm, 2 - 3-lobed, margin irregularly coarse-cuspidate-serrate, sparse papillate-hairy along nerves and margin. Peduncles 8 - 20 cm, pubescent or subglabrous; bracts absent or 2, linear; rays 10 - 30, unequal, scabrous; bracteoles 2 - 4, linear, 3 - 5 mm; umbellules 13

- 36-flowered; pedicels slender, 1 - 3 cm in fruit. Calyx teeth obsolete, rarely minute, ovate. Petals white, rarely purplish red. Fruit ellipsoid or suborbicular, 4 - 6 × 3 - 4 mm; dorsal ribs filiform, prominent, lateral ribs broadly thin-winged, wings as wide as or wider than the body; vittae 1 in each furrow, 2 or absent on commissure. Flowering from June to July, fruiting from July to September. Plant wild or cultivated in forests, on altitudes 2500-3000 m, in provinces Gansu, Hubei, Shaanxi, Sichuan, Yunnan.

Assessment report on Angelica sinensis (Oliv.) Diels, radix EMA/HMPC/614586/2012 Page 4/24 According to the IPNI database, there is one officially recognised variety: Angelica sinensis (Oliv.) Diels var. wilsonii (H.Wolff) Z.H.Pan & M.F.Watson. Acta Phytotax. Sin. 42(6): 562. 2004 [Nov 2004]. In the Flora of China, (Zehui & Watson, 2005), there is also a second variety: Angelica sinensis var. sinensis (differing in shape of fruits and vittae), however it was not officially published and recognized by international databases.

According to the new phylogenetic taxonomy, the species Angelica sinensis does not seem to belong to the Angelica group sensu stricto, and it belongs to a different clade containing Levisticum officinale with Angelica sinensis and Angelica tianmuensis with Angelica peoniifolia, for practical reasons morphological and carpological classification is used.

Apart from the species Angelica sinensis (Oliv.) Diels, the roots of two other species: Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. (Angelicae dahuricae radix) and Angelica pubescens Maxim. f. biserrata R.H.Shan et C.Q.Yuan (Angelicae pubescentis radix) are used in Traditional Chinese Medicine and described in the European Pharmacopoeia.

Nomenclature

The Pharmacopoeia of the People’s Republic of China (1977) uses for Angelicae sinensis radix the name: ‘Danggui’, the Flora of China (Zehui & Watson, 2005) ‘dang gui’, while in textbooks and literature often ‘Dang Gui’ is used (Chen & Chen 2004). In European and American literature names such as ‘Dong Quai’, ‘Tang Kui’ (Merck) or ‘Tang kuei’ were used.

Constituents

According to the WHO Monograph (2002) the characteristic components are the simple alkyl phthalides (ligustilide, (Z)-ligustilide, (Z)-6,7-epoxyligustilide, angelicide, (Z)-butylidenephthalide, butylphthalide, 2,4-dihydrophthalic anhydride), which are the major components of the essential oil of the roots.

Characteristic components of the oil are terpenes (β-cadinene and cis-β-ocimene).

Also aromatic compounds are present: phenol, o-cresol, p-cresol, guaiacol, 2,3-dimethylphenol, pethylphenol, m-ethylphenol, 4-ethylresorcinol, isoeugenol, carvacrol, 2,4dihydroxyacetophenonecadinene (Hagers 1998),

–  –  –

Assessor’s comments:

There are no quantitative data on the content of safrole and isosafrol.

Among characteristic non-volatile constituents are phenylpropanoids ((E)-ferulic acid, coniferyl ferulate); benzenoids (valerophenone-o-carboxylic acid and vanillic acid) and coumarins (angelol G, angelicone and umbelliferone), and also 6-methoxy-7-hydroxycoumarin (scopoletin), 6-ethoxycoumarin (Deng 2005).

Furthermore have been found osthole (Hagers 1998, Gruenwald 2004) and furocoumarins: bergapten (5-methoxypsoralen, 5-MOP)(Hagers 1998), imperatorin (Deng 2005, Gruenwald 2004), psoralen, oxypeucedanin (Hagers 1998, Deng 2005, Gruenwald 2004).

–  –  –

Assessor’s comments:

Angelica sinensis radix contains a number of furocoumarins that induce photosensivity. There are no systematic data on the content of furocoumarins in the root. Data on a furocoumarins profile in the Assessment report on Angelica sinensis (Oliv.) Diels, radix EMA/HMPC/614586/2012 Page 6/24 Angelica sinensis radix are also lacking. Bergapten (5-MOP) in the presence of UV light is probably carcinogenic in humans. A quantity of furocoumarins in the roots was not determined but such a determination would allow using the drug according to 1.5 mg acceptable daily intake of these substances. (EMEA/HMPC/317913/2006) The essential oil contains also safrole, described in the EFSA compendium on botanicals containing toxic substances of concern (2009) as a weak carcinogen; as well as in rats and mice and a known genotoxic carcinogen, and isosafrole, a weak hepatocarcinogen in rats and mice. There is no quantitative data on the content of these substances in the herbal substance or in preparations. There are however general estimations of population exposure to genotoxic and possible carcinogenic substances in food and spices, which were currently evaluated in a project coordinated by EFSA (PlantLIBRA PLANT) for food supplements (Van den Berg et al., 2011). These models and estimations do not take into consideration the use of herbal medicinal products.

Polysaccharides: The root contains significant amounts of sugars: galactose, glucose, arabinose, rhamnose and xylose. arabigalactan (WHO), saccharose, hypoxanthine-9-beta-D-ribofuranoside, fructose and polysaccharides: X-C-3-III, X-C-3-IV (composed of galactose, arabinose, rhamnose, glucuronic acid and galacturonic acid) and X-C-3-I (composed of arabinose, galactose, glucose and fructose with a molar ratio of 1:1:4:9) (Deng 2005).

Herbal preparation(s) • Currently there is no information on medicinal products on the European market containing as herbal substance Angelica sinensis, radix.

There are historical data on the use of a product ‘Eumenol’ in Europe between 1899 and 1946.

Eumenol was described in the 3rd edition of the Merck’s Index as a fluid extract of the Chinese root, named (Tang-kui, Man-mu) supposed to be of the Araliaceae. However, genus und species were not yet determined. It was used as emmenagogue in amenorrhoea und dysmenorrhoea, especially when the latter was thought to be of nervous origin. The dose was 3 times daily 1 coffee spoon, i.e.

3 x 2 = 6 g. In 1907, Eumenol was also mentioned in Merck’s Index in the United States. The product was first available in form of an oral liquid. Since 1907, Eumenol was referred to as a new medicinal product, and was known also in Central Europe (for example in Poland in Nowiny Lekarskie, 1907, R. 19, nr 12). However the product was not listed on an official lists of medicinal means available in pharmacies, but still it was imported by many pharmacies and was advertised by the agencies of Merck in the medical press (like in Warsaw Medical Journal, Warszawskie Czasopismo Lekarskie, 1930, R.7, nr 12 and Polish Official Journal of Medical Chambers in 1931 (Dziennik Urzędowy Izb Lekarskich 1931)). In Poland, the product was available in liquid form, in bottles containing 25, 100, 250g and in a form of tablets, in boxes containing 25, 50, 100 units, in following indications: Amenorrhea, Dysmenorrhea, especially in imaginary pregnancy.

Eumenol was authorised in Sweden 1939-1946. It was manufactured by the company Merck in a form of tablets 0.3 g containing dried liquid extract, corresponding 0.6 g of herbal substance, DER (2:1).

Extraction solvent was probably 70% ethanol.

Since 1946 the product has not been distributed and detailed data on the composition, according to contemporary criteria, are lacking.



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