Echinacea – Purple Coneflower Herb (Echinaceae purpureae herba)
|Latin name of the genus:||Echinacea|
|Latin name of herbal substance:||Echinaceae purpureae herba|
|Botanical name of plant:||Echinacea purpurea (l.) moench|
|English common name of herbal substance:||Purple coneflower herb|
Latin name of the genus: Echinacea
Latin name of herbal substance: Echinaceae purpureae herba
Botanical name of plant: Echinacea purpurea (L.) Moench
English common name of herbal substance: Purple Coneflower Herb
This Assessment report (and corresponding monograph) is a priori limited to Echinacea purpurea (L.) Moench., herba recens and preparations thereof. Therefore the medicinal products containing the roots of the same plant (or the combination of roots and herb) and other plant species are out of the scope of this document. Nevertheless some data on the research on products with roots and other Echinacea species are given for information.
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Echinacea purpurea (L.) Moench., herba recens
The monograph in the European Pharmacopoeia (reference 01/2008:1823) defines only the dry herbal substance “Purple coneflower herb” as: Dried, whole or cut flowering aerial parts of Echinacea purpurea (L.) Moench.
Content: minimum 0.1 per cent for the sum of caftaric acid (C13H12O9; Mr 312.2) and cichoric acid (C22H18O12; Mr 474.3) (dried drug).
The US Pharmacopeia contains the monograph “Echinacea purpurea Aerial Parts”, which defines the drug as: “consists of the aerial parts of Echinacea purpurea (L.) Moench (Fam. Asteraceae). It is harvested during the flowering stage. It contains not less than 1.0 percent of chichoric acid, and not less than 0.01 percent of dodecatetraenoic acid isobutylamides (C16H25NO) on the dry basis” (Giancaspro 2004).
Fresh herbal drug is described in the monograph Echinacea purpurea in the German homoeopathic pharmacopoeia (2011).
•Caffeic acid derivatives: Cichoric acid
•Alkamides with the isomeric
•Polysaccharides (PS) such as PS I, a
Echinacea purpurea herb is 2 to 7 % (Glavač et al. 2012).
•Melanins (Pasco et al. 2005, Pugh et al. 2005),
•Lipopolysaccharides and lipoproteins (Tamta et al. 2008, Pugh et al. 2013).
Several very different groups of constituents are suggested to be effective principles of Echinacea purpurea: caffeic acid derivatives, alkamides, polysaccharides (ESCOP 2003), melanins (Pasco et al. 2005, Pugh et al. 2005), lipopolysaccharides and lipoproteins (Tamta et al. 2008, Pugh et al. 2013).
Echinacea purpurea (L.) Moench., herba recens, succus, succus siccum
The juice is expressed from the fresh herbal drug as soon as possible. The expressed juice is preserved by pasteurisation or stabilised with a suitable quantity of ethanol.
European Pharmacopoeia monographs are being drafted for Echinacea purpurea herb juice (Pharmeuropa 2014).
•Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
1.2. Search and assessment methodology
The two major electronic databases PubMed and Toxline were searched in 2006 with the search term “Echinacea purpurea”. For revision of the monograph the same databases were searched in May 2013.
PubMed: 940 references obtained in 2013.
Toxline: 385 references obtained in 2013.
The abstracts of the references found were screened manually and all articles deemed relevant were accessed and included in the assessment report.
2. Data on medicinal use
2.1. Information about products on the market in the EU/EEA Member States
Information on medicinal products marketed in the EU/EEA
Table 1: Overview of data obtained from marketed medicinal products
This overview is not exhaustive. It is provided for information only and reflects the situation at the time when it was established.
Information on relevant combination medicinal products marketed in the EU/EEA
There are authorised medicinal products containing a combination of purple coneflower herb tincture (as dry extract) from Echinacea purpurea, herba recens, extraction solvent: ethanol 65% V/V (1:12) and purple coneflower root tincture (as dry extract) from Echinacea purpurea, radix recens (purple coneflower root) (extraction solvent: ethanol 65% V/V (1:11), 95:5, in the form of tablets, chewable tablets and oral drops, solution on the market.
Indications: treatment and prevention of common cold symptoms such as coughing, lacrimation, sore throat, headache and muscle pain. To improve resistance to the common cold, flu accompanied by fever and recurrent infections.
There is also an authorised medicinal product containing tincture from Echinacea purpurea, herba recens (purple coneflower herb), (extraction solvent: ethanol 65% V/V, DER 1:12); tincture from Echinacea purpurea, radix recens (purple coneflower root) (extraction solvent: ethanol 65% V/V, DER 1:11) and tincture from Salvia officinalis folium recens (sage leaf) (extraction solvent: ethanol 68% V/V, DER 1:17) in the form of oromucosal spray on the market.
Indication: symptomatic treatment of inflammation in the mouth and pharynx.
Echinacea purpurea herb is on the market only in a combination product containing 910 mg of Echinaceae purpureae herb. et rad. congelat. extr. spir. fl. (1:3) (extraction solvent: ethanol 48% V/V). Indication: traditional herbal medicinal product for temporary relief and prevention of common cold; treatment of small superficial wounds.
Echinacea purpurea herb preparations are only available in combination products which also contain Echinacea purpurea root preparations. All of the products are registered as traditional medicinal products for relief of common cold and
There is a registered traditional medicinal product containing a combination of dried ethanolic extracts of fresh flowering aerial parts of Echinacea purpurea (corresponding with
Indications: insufficient immunity, influenza and cold.
There are medicinal products on the market containing Echinacea purpurea herb preparations in combination with various herbal drugs/herbal drug preparations for treatment of common cold and other mild upper respiratory tract infections with accompanying cough:
Plantago lanceolata, folium or Plantago lanceolata, folium, Grindelia robusta, herba, Rosa canina, fructus, Thymus vulgaris, herba or Aronia spp., fructus Arctium spp., radix, Matricaria recutita, flos Urtica dioica and/or Urtica urens herba or Allium sativum, bulbus.
There are authorised medicinal products containing combination of purple coneflower herb dry extract from Echinacea purpurea, herba recens, extraction solvent: ethanol 65% V/V (DER 1:12) and purple coneflower root dry extract from Echinacea purpurea, radix recens extraction solvent: ethanol 65% V/V (DER 1:11), 95:5, in the form of tablets, chewable tablets and oral drops, solution on the market. Indications: prevention and treatment of common cold.
There is also a registered traditional medicinal product containing a combination of a tincture from Echinacea purpurea, herba recens (purple coneflower herb), (extraction solvent: ethanol 65% V/V (1:12); a tincture from Echinacea purpurea, radix recens (purple coneflower root) (extraction solvent: ethanol 65% V/V (1:11) and a tincture from Salvia officinalis folium recens (sage leaf) (extraction solvent: ethanol 68% V/V (1:17) in the form of oromucosal spray on the market.
Indication: traditional herbal medicinal product used to relieve symptoms of oral cavity and throat inflammations.
There are medicinal products containing combination of purple coneflower dry extract from Echinacea purpurea, herba recens, extraction solvent: ethanol 65% V/V and purple coneflower root dry extract from Echinacea purpurea, radix recens, extraction solvent: ethanol 65% V/V, 95:5, in the form of tablets, chewable tablets and oral drops, solution on the market. Indications: traditional herbal medicinal product used to relieve the symptoms of the common cold and influenza type infections. There is also a registered traditional medicinal product containing a combination of a tincture from Echinacea purpurea, herba recens (purple coneflower herb), (extraction solvent: ethanol 65% V/V
Information on other products marketed in the EU/EEA (where relevant)
Echinacea purpurea herb is included in the list of herbal substances and herbal preparations allowed in food supplements, published on the website of the Italian Ministry of Health, with the following indications: natural body defence. Urinary ways function. First airways function.
2.2. Information on traditional/current indications and specified substances/preparations
Medicinal uses of Echinacea species among American Indians were many and varied. Echinacea angustifolia was universally used as an antidote for snakebite and other venomous bites and stings and poisonous conditions. Echinacea has been used as a remedy for more ailments than any other plant (Foster 1996). Echinacea purpurea was first mentioned in 1787. It was used for treating ulcers on a horses’ back caused by saddles. Subsequently, the plant was largely neglected until the first edition of the Eclectic Dispensatory in 1852. The European history of the introduction and use of Echinacea purpurea in many ways parallels its history in the U.S. By 1895 Echinacea products for homeopathic physicians had become available in Germany. Over the next 30 years the demand increased, while shortages were prevalent in Europe. Subsequently, in the late 1930s, commercial cultivation of Echinacea purpurea began in Germany, introducing Echinacea products to a wide European audience for the first time. The majority of pharmacological and clinical studies conducted since 1939 have involved Echinacea purpurea preparations made from the fresh expressed juice of the flowering plant . The pharmaceutical forms of the products included an ointment, a liquid form for external use, a liquid form for internal use, as well as ampoules for intravenous injection (Rote liste 1961).
Information about the use of the plant from traditional healers ranges from external application for wounds, burns and insect bites to the chewing of roots for toothache and throat infections, and internal application for pain, coughs, stomach cramps and snake bites. The interest of white settlers was also
drawn to this medicinal plant. The first Echinacea preparation, known as Meyers Blood Purifier, arrived on the market around 1880, with rheumatism, neuralgia and rattlesnake bites as indications (Hostetman 2003).
Medicinal use of juice and dried juice from Echinacea purpurea (L.) Moench., herb has been documented continuously in last decades in many pharmacognostical texts, handbooks and compendia (Table 2).
Table 2: Documented oral medicinal use of juice and dried juice from Echinacea purpurea (L.) Moench., herba
Table 3: Documented topical medicinal use of juice and dried juice from Echinacea purpurea (L.) Moench., herba
Information on medicinal products in Member States
The information exchange between the competent authorities of the EU Member States in 2007 showed that in Austria, Bulgaria, Germany, Hungary and Poland medicinal products, containing (dried) expressed Echinacea juice have been on the market as herbal medicinal products for adjuvant therapy and prophylaxis of recurrent infections of the upper respiratory tract (common cold) and also of the urogenital tract while in Belgium, Finland, Latvia, Romania, Slovenia, Sweden have been used for treatment of symptoms of the upper respiratory tract infections (common cold) only.
The use of Echinacea for treatment of urogenital infections is not supported by relevant clinical studies. Echinacea was traditionally known as an
On the basis of the survey between the competent authorities of the EU Member States in 2013 medicinal products containing expressed (DER
Austria: supportive treatment and prophylaxis of recurrent infections of the airways
Belgium: symptomatic treatment of infections of the upper respiratory tract after a serious illness has been excluded
Bulgaria: supportive treatment of recurrent infections of respiratory tract
Croatia, Czech Republic, Hungary, Latvia, Lithuania, Slovenia, Sweden:
Denmark: relief of minor symptoms of cold
Netherlands: traditional medicinal product for relief of symptoms of influenza
Poland: adjunctively in recurrent infections of airways; adjunctively in recurrent infections of airways and descendent urinary tract,
Spain: treatment of common cold
United Kingdom: a traditional herbal medicinal product used to relieve the symptoms of the common cold and influenza type infections based on traditional use only.
The indications of medicinal products, containing (dried) expressed Echinacea juice for oral use can be summarised in
In most EU Member states medicines, containing (dried) expressed Echinacea juice are authorised as herbal medicinal products with
In two Member states (NL, UK) these medicines are considered traditional herbal medicinal products.
There is a history of traditional use of ointment prepared from expressed juice of Echinacea purpurea, herba recens
Indication in Germany: herbal medicinal product traditionally used as mild acting adjuvant in wound healing.
Indication in Sweden: traditionally used for treatment of sores of the lips and on other small superficial wounds such as chapping in the corner of the mouth and fingertips.
In Bulgaria ointment from expressed juice of Echinacea purpurea herba, recens (DER
Wording ‘traditional herbal medicinal product for treatment of small superficial wounds’ integrates above mentioned indications.
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
Table 4: posology and duration of oral use recommended by monographs and reviews are
Information on medicinal products in Member States
The duration of use without interruption is limited mainly to 10 days, sometimes to 14 days.
Kommission E (1989), ESCOP (2003) and WHO (1999) monographs recommend
In the assessment report 2008 there was information that 10 to 20 g of expressed juice per 100 g of preparation was used in products on the European market. Even if that could not be verified in 2013 there seems to be a tradition on usage of that range, e.g. in the Rote liste 1961 there is information on ointment with 10% of Echinaceae purpureae herb pressed juice. It is assumed that dried juice corresponding to the expressed juice above could be equally appropriate for traditional medicinal products for cutaneous use.
From the exchange of information between competent authorities in 2013 it can be seen that 16 g of expressed juice per 100 g of preparation is used in medicinal products on the European market.
Dosage: adolescents, adults and elderly: thin layer of ointment is applied
For detailed information on oral and cutaneous use see the Table 2 and 3 in chapter “2.1 Information on period of medicinal use in the European Union” and Table 5 in chapter “4.2.2. Clinical studies (case studies and clinical trials)”.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
The mechanism by which the clinical effect (treatment and short term prevention of common cold) is achieved is not known. Antiviral and immunomodulatory effects were demonstrated in pharmacological studies, but their relevance for the clinical efficacy is not known. Therefore it was not possible to classify pharmacodynamic studies into primary and secondary pharmacodynamic.
Orinda et al. (1973) reported about a virustatic effect of an Echinacea purpurea expressed juice (dry, DER
the fractions was tested. The virustatic activity was distributed to all fractions of the entire TLC. The antiviral principle could not be inactivated by a
Other herbal preparations, crude fractions
Both a decoction and a 30% ethanolic extract of Echinacea purpurea herb (DER not provided) inhibited the intracellular propagation of ECHO9 HILL virus in a monkey kidney cell culture. A 50% virus inhibition was still observed with dilution rates between 1:6 to 1:15 (Skwarek et al. 1996).
Stems, leaves, and flowers of Echinacea purpurea were fractionated by various solvents and the fractions evaluated for antiviral activity (Vimalanathan et al. 2005). All of the aqueous fractions exhibited potent activity against herpes simplex virus and influenza virus. In addition, the ethanol- and ethyl
Using mouse fibroblasts, it was demonstrated that incubation previous to virus infection for at least 4 hours with methanolic and aqueous extracts of Echinacea purpurea root resulted in resistance to Influenza A2, Herpes, and Vesicular stomatitis virus infection for 24 hours (Wacker & Hilbig 1978).
A high molecular weight fraction (Mr >10,000 D) containing polysaccharides and glycoproteins from purple coneflower root exhibited antiviral activity against Herpes simplex virus (HSV) and Influenza virus (Beuscher et al. 1995).
Extracts of 8 taxa of the genus Echinacea were found to have antiviral activity against HSV Type I in vitro when exposed to visible and
potent inhibitors of HSV were Echinacea pallida var. sanguinea crude (70 % ethanol) inflorescence extract (MIC=0.026 mg/ml), cichoric acid (MIC=0.045 mg/ml) and Echinacea purpurea
Caffeic acid derivatives
Cichoric acid from Echinacea purpurea expressed juice was found to reduce a yield of VSV in mouse L-
3.1.2. Antibacterial Effects
3.1.3. Effects on wound healing
The healing of standardised, surgery made skin wounds on guinea pigs was accelerated by a Echinacea ointment (commercial product, plant species and herbal substance is not specified in the article; in the Rote Liste 1984 the concerned product contained Echinaceae purpurea herb pressed juice (DER 2.5:1) (Kinkel et al. 1984). The wound area at day 6 and 9 after surgery was significantly (p<0.05) smaller than those of the untreated control animals. In comparison with the control group, the clinical picture was significantly improved in the group treated with Echinacea ointment already on day 3 (p<0.05).
Other herbal preparations
10 and/or 30 µl of an extract from Echinacea purpurea fresh plants, manufactured with 90% ethanol, (final ethanol concentration 65%), with a dry residue of 10.5 mg/ml, significantly inhibited the concentration of collagen lattices populated with
3.1.4. Immunomodulatory effects
Treatment of leukocyte suspensions with lyophilised expressed juice of Echinacea purpurea (1.0 or 5.0 mg/ml) induced a
Phagocytosis of isolated peritoneal macrophages from mice and macrophages of isolated perfused rat liver was significantly stimulated after i.p. and/or p.o. application of Echinacea purpurea expressed juice (Bauer 1988a, Bauer et al. 1989).
Other herbal preparations, crude fractions
Tamta et al. (2008) determined the contribution of bacterial lipopolysaccharides and
In another study by the same group (Pugh et al. 2013), the total bacterial load of Echinacea purpurea root and herb samples was determined with
The influence of different Echinacea preparations including Echinacea purpurea herb extract (250 µg/ml) on the regulation of human immune gene expression was studied on
Randolph et al. (2003). Gene expression was studied by measuring the amount of respective mRNA with quantitative PCR. Expression of
The carbon clearance test of an extract manufactured from Echinacea purpurea herb with ethanol (not further specified) showed on mice after p.o. application (dosage equals 1.7 mg extract/kg; 3 times daily for two days) an increased carbon elimination by the factor 1.4 in relation to control. The
Echinacea polysaccharides were isolated from aerial parts and roots of Echinacea purpurea. Further purification yielded a
The concentrations of Echinacea polysaccharides required to obtain the in vitro effect on immune cells discussed above were extremely high. In studies using EPS (Stimpel et al. 1984) concentrations of
1 mg/ml were required to enhance macrophage cytotoxicity. In addition, this high concentration of EPS was required to enhance macrophage
Animal studies using i.v. EPS (0.01 mg/ml) demonstrated enhanced phagocytosis (27%) (Wagner et al. 1985). Arabinogalactan injected i.v. into mice exhibited enhanced resistance against systemic infections with Listeria monocytogenes and Candida albicans in both normal (Roesler et al. 1991) and immunocompromised (Steinmüller et al. 1993) animals. Oral administration of a polysaccharide fraction from Echinacea purpurea aerial parts (125, 1000, 3000 mg/kg/day, which is much more than in the recommended human dosage) had no effect on lung macrophage function in normal rats (Goel et al. 2002).
Caffeic acid derivatives
In a granulocyte assay, cichoric acid concentrations between 10 and 100 ng/ml caused strong stimulation of phagocytosis (Bauer et al. 1989).
Cichoric acid in concentration
The upregulation of
A purified alkamide fraction administered orally to rats was found to enhance the phagocytic activity and phagocytic index of lung alveolar macrophages. In addition, alveolar macrophages collected from
Melanin as a tentative active constituent of Echinacea purpurea was shown to have immunostimulant activity (Pasco et al. 2005, Pugh et al. 2005). Ingestion of melanin by mice for four days ex vivo increased the production of
The dry residue of an ethanolic extract of Echinacea purpurea root showed a maximum phagocytosis stimulation of 33% in the granulocyte smear test at the concentrations of
Effects of Echinacea purpurea (plant part not further specified)
CD16+ cells was decreased as well as the mean fluorescence intensity was
Echinacea herb and root powders (plant species not specified) were also found to significantly enhance the viability and/or proliferation of human peripheral blood mononuclear cells in vitro (Rininger et al. 2000).
The dry residue of an ethanolic extract of Echinacea purpurea root was resolved in ethanol 90% (DER 1:10) and given to mice (p.o.; dosage equals 17 mg root/kg; 3 times daily for two days). In the carbon clearance test, the administration lead to a
The study of Currier & Miller (2000) was designed to assess the numbers/production of NK cells in the spleen and bone marrow of aging, normal mice, after dietary administration of 0.45 mg/day (dose/body weight being adjusted from assorted anecdotal and experimental studies in humans and a variety of rodents) of Echinacea purpurea root extract (14 days), or, after injection of thyroxin, a stimulant of NK cell function (10 days). The immunostimulating effect was studied on natural killer (NK) cells since these cells are active in spontaneous,
Alkamides from the roots of Echinacea purpurea were examined for
Other herbal preparations, species
Echinacea pallida var. angustifolia, Echinacea pallida var. pallida) inhibited the
3.1.6. Antioxidative effects
Dried pressed juice from Echinacea purpurea whole plants significantly (p <0.05) elevated superoxide dismutase activity when given to a mice in a dose of 360 mg/kg every other day for 3 weeks (Mishima et al. 2004).
Other herbal preparations, plant species, constituents
The radical scavenging activity of methanolic extracts from the roots of different Echinacea species and isolated phenolic compounds was evaluated in vitro with a spectrophotometric method based on the reduction of an alcoholic
Caffeic acid derivates
Caffeic acid derivates protected collagen from free
3.1.7. Antifungal effects
Isobutylamides and polyacetylenes from Echinacea purpurea have phototoxic antimicrobial activity against fungi, including clinically relevant pathogenic fungi. A hexane extract of Echinacea purpurea herb inhibited the growth of yeast strains of Saccharomyces cerevisiae, Candida shehata, Candida kefyr, Candida albicans, Candida steatulytica and Candida tropicalis under near UV irradiation (phototoxicity) and to a lower extent without irradiation in the conventional antifungal activity (Binns et al. 2000).
3.1.8. Safety Pharmacology
No studies are available.
3.1.9. Pharmacodynamic Interactions
No studies are available.
Theoretically it can be expected, that Echinacea preparations could interact with immunomodulatory therapy (immunostimulatory and immunoinhibitory). However, no clinical cases of drug interactions have been reported (Izzo & Ernst 2001, Izzo & Ernst 2009).
There are many
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Pharmacokinetics of caffeic acid and related hydroxycinnamates (Bourne &
Studies of transport of alkamides trough a cultured monolayer of colonic cells (Jager et al. 2002) were performed on human adenocarcinoma colonic cell line
Close monitoring of the transport during 6 hours revealed a nearly complete transport to the basolateral side after 4 hours and no significant metabolism was observable. Transport experiments performed at 4 °C showed only a slight decrease in transport, which is a strong hint that dodeca- 2E,4E,8Z,10E/Z
supported the assumption that the alkamides could be easily transported from the intestinum and hence may contribute to the in vivo effects of Echinacea preparations.
Permeability of alkylamides and caffeic acid conjugates through
Absolute and relative bioavailabilities of
Matthias et al. (2005b) have investigated the metabolism of the alkylamides by human liver microsomes. No significant degradation of alkylamides was evident in cytosolic fractions. Time- and
3.2.1. Pharmacokinetic interactions
The interaction potential of Echinacea purpurea (the article states, that the herbal preparation was an extract, but the commercial preparation used was declared as juice in other literature (DER
2009). Digoxin (30 nmol) was used as a substrate and verapamil as a control inhibitor. Ethanol, 0.8%, needed for herbal extraction and compatibility with the commercial products, inhibited the net digoxin flux by 18%. Echinacea purpurea influenced to a higher degree the
In in vitro test Echinacea purpurea demonstrated mild inhibition of CYP3A4 activity with 7- benzyloxy-
Ethanolic extracts from fresh Echinacea purpurea roots were examined with regard to their ability to inhibit cytochrome P450 (2E1) mediated oxidation of
Mrozikiewicz et al. (2010) have investigated potential influence of standardised Echinacea purpurea herb extract (DER not reported, not reported if the plant was fresh or dry, extraction solvent 60% ethanol) containing 3.7% polyphenolic compounds, on the mRNA expression level of major CYP450 enzymes using animal model. The level of mRNA expression in liver was analysed by
The in vitro CYP3A4 inhibition profiles of Echinacea purpurea (the article states that the herbal preparation was an extract but the preparation in the concerned product was declared as juice in other literature), was evaluated by three different substrates:
Modarai et al. (2010) found, that inhibition of CYP3A4 is more than 50 fold lower with Echinacea purpurea herb juice (no further details available; IC50=1.8 g/l), compared to Echinacea purpurea herba tincture (no further details available; IC50=0.022 g/l) or to Echinacea purpurea herba et radix tincture
(65% V/V ethanol extract of fresh Echinacea purpurea herb (DER 1:12) and roots (DER 1:11), 95:5; IC50=0.027 g/l). This was correlated to the content of the alkamides in these products.
Different preparations of Echinacea angustifolia, Echinacea purpurea and Echinacea pallida were investigated for their cytochrome P450 (CYP) interaction potential in rats
Oseltamivir is a prodrug that requires metabolic activation by the carboxylesterase.
Many of the above reports show some (even statistical significant) inhibition of CYP activities by alkamides and extracts from Echinacea purpurea. The clinical relevance of this inhibition remains unclear. It appears that the expressed juice from Echinacea purpurea has much lower effect on CYP activities than Echinacea purpurea herba tincture or Echinacea purpurea herba et radix tincture.
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Echinacea purpurea and in particular the expressed juice is toxicologically well examined. Acute intoxications are not reported and on the basis of the animal experimental data are not expected. After single p.o. or i.v. application of Echinacea purpurea expressed juice in dose of p.o. 15,000 mg/kg or i.v. 5,000 mg/kg on rats and p.o. 30,000 mg/kg or i.v. 10,000 mg/kg on mice the animals showed no abnormalities. Since no deaths were observed, the LD50 could only be determined by approximation method. The sections at the end of the experiments did not result in referring to organ changes (Mengs et al. 1991).
A mixture of polysaccharides from the herb of Echinacea purpurea and two polysaccharides, obtained from a cell culture medium of Echinacea, resulted after i.p. application on mice in
After 4 weeks of oral administration of Echinacea purpurea expressed juice in doses of 800, 2,400 or 8,000 mg/kg daily, male rats (2,400 and 8,000 mg/kg) showed a statistically significant fall in plasma alkaline phosphatase compared to control group of rats, while the females (2,400 and 8,000 mg/kg) showed a rise in prothrombin time compared to control. Since all the values were still within the range of physiological variation for the used strain of rats, and since there was no dose proportionality, no toxicological significance could be ascribed to these findings. All the other laboratory results, together with the body weights, food consumption, ophthalmoscopy, necropsy findings and histology failed to show any evidence of relevant differences between the groups receiving different doses of Echinacea purpurea juice and control (Mengs et al. 1991).
Lyophilised Echinacea purpurea expressed juice in concentrations from 8 to 5,000 µg/plate was examined. In the examined bacterial test systems on Salmonella typhimurium (TA98, TA100, TA1535, TA1537, TA1538) with and without metabolic activation by the
Tsai et al. (2012) studied the mutagenic and antimutagenic effects of ethanol extracts obtained from
So far no
In a cell transformation test, expressed juice from Echinacea purpurea herb did not produce any morphological transformation of embryonic hamster cells (Mengs et al. 1991). In vitro model systems of this kind are gaining increasing credibility for the testing of carcinogenic potential, since there is good correlation between the results of such tests and of chronic
3.3.5. Reproductive and developmental Toxicity
A study on mice showed that the
Washed sperms were incubated with Echinacea purpurea (plant part and type of preparation not declared) or control medium. Parameters were measured on a
3.3.6. Local tolerance
Data on local tolerance of Echinacea purpurea preparations are not available.
There are no specialised immunotoxicity studies available for Echinacea purpurea preparations.
Substantial amount of toxicological investigations were performed, including genotoxicity. They indicate no safety concern for the use of Echinacea preparations at recommended doses and duration. Studies on reproductive toxicity and carcinogenicity are not available, therefore the use during pregnancy and lactation is not recommended.
3.4. Overall conclusions on
Results from relevant experimental studies on Echinacea preparations to support the proposed indications are very limited. Several pharmacological effects are reported, however since the mechanism by which the clinical effects are achieved is not known, the relevance of these findings cannot be assessed. The exact pharmacological mechanisms and active compounds for the effects still remain to be elucidated.
Pharmacokinetic data are very limited and are focused especially on alkamides. Results support the assumption that alkamides (in contrast with caffeic acid conjugates) can be easily transported from the intestine and hence may contribute to the in vivo effects of Echinacea preparations. Pharmacokinetic data concerning the cutaneous use do not exist.
Studies on metabolism suggest that alkamides of Echinacea are metabolised by cytochrome P450 and may effects the
Toxicity of Echinacea purpurea herb is low. Available genotoxicity data on lyophilised Echinacea purpurea expressed juice showed no reason for concern about the safety of these herbal preparations. Appropriate preclinical data on reproductive toxicity and carcinogenicity are not available. Due to lack of data the use during pregnancy and lactation is not recommended.
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
Stimulation of phagocytic activity and production of cytokines by oral application of a commercially available Echinacea preparation was studied in humans in vivo (Schwarz et al. 2002). Forty healthy male volunteers (ages
In 2005 Schwarz et al. made further research on possible mechanism of action. They investigated whether or not oral Echinacea purpurea pressed juice (EPP) has any effect on important lymphocyte- subpopulations in a
Echinacea preparation (commercial product, tablets, Echinacea purpurea herb and root and Echinacea angustifolia root, no further details available ) was given to healthy volunteers (n=6) and gene expression in their blood cells was examined). In vivo, many lymphokines were down regulated, but the expression of
Ability of Echinacea purpurea to prevent or to relieve experimental infection with rhinovirus type 39
Similarly, effectiveness of Echinacea for prevention of experimental Rhinovirus colds was not statistically significant in an earlier study (Turner et al. 2000). Infection occurred in 44 and 57% and illness occurred in 36 and 43% of the Echinacea– and
Polysaccharides purified from Echinacea purpurea tissue culture injected i.v. into patients undergoing chemotherapy for gastric cancer showed a lessening of leucopoenia (Melchart et al. 2002).
Activation of macrophages leading to enhanced phagocytosis and production of several cytokines found in vitro, failed to be confirmed in in vivo human studies for Echinacea puprurea herb juice. It was not confirmed that lymphocyte subpopulations were increased by oral application Echinacea purpurea pressed juice, either. It appears that stimulation of certain parts of the lymphocyte system by Echinacea preparations observed in in vitro experiments or following parenteral application of the drug are caused by direct contact of the constituents with the cells of the immune system under investigation, a feature which markedly differs from the situation when Echinacea preparations are given orally. Furthermore, the concentration/dose used in
Administration of Echinacea purpurea herb juice before and after exposure to rhinovirus did not significantly decrease the rate or the severity of infection, but the trend of beneficial effect of Echinacea was shown in nearly all measured parameters.
Further studies are needed to clarify the mechanism(s) which are responsible for the beneficial effect of Echinacea preparations observed in clinical studies.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
In a recent study (Goey et al. 2012) three cancer patients ingested 20 drops of a commercial extract of Echinacea purpurea (65% V/V ethanol extract of freshly harvested Echinacea purpurea herb (DER 1:12) and roots (DER 1:11), 95:5) three times daily for fourteen days. After the last ingestion in the morning of day 15, blood samples for pharmacokinetics of
Absorption of alkamides after oral application of Echinacea purpurea was studied (Dietz et al. 2001). One hour after oral application of 65 ml of Echinacea purpurea (plant part is not declared) concentrated tincture, containing 4.3 mg of
Matthias et al. (2005a) have examined serial plasma samples from 9 healthy volunteers who ingested tablets manufactured from ethanolic liquid extracts of Echinacea angustifolia root and Echinacea purpurea root immediately after a standard high fat breakfast. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkamides were rapidly absorbed and were measurable in plasma 20 min after tablet ingestion and remained detectable for up to 12 h. The maximal concentrations for the sum of alkamides in human plasma were reached within 2.3 h post ingestion and averaged 336 +/- 131 ng eq/ml plasma. No obvious differences were observed in the pharmacokinetics in 2 additional fasted subjects. This single dose study provides evidence that alkamides are orally available and that their pharmacokinetics are in agreement with the one dose three times daily regimen already recommended for Echinacea.
There is a huge (more than 1000 fold) difference between the Cmax in a study of Goey et al. (2012) and study of Matthias et al. (2005a). The reasons for the difference might be in different concentration and different types of alkamides (double bond vs. triple bond) present in Echinacea purpurea and Echinacea angustifolia. The studies also differed in the analytical method for alkamides (one isoform vs. sum of alkamides) and design (multiple doses vs. single dose).
Alkamide content in plasma samples obtained from a randomised, open,
Kommission E (1989), ESCOP (2003) and WHO (1999) monographs state no pharmacodynamic or pharmacokinetic drug interactions of any preparations (juice or extract) of Echinacea purpurea herb or isolated constituents in humans. Theoretically it can be expected, that Echinacea preparations could
interact with immunomodulatory therapy (immunostimulatory and immunoinhibitory). However, no clinical cases of drug interactions have been reported (Izzo & Ernst 2001, Izzo & Ernst 2009).
There is one pharmacokinetic drug interaction study of a standardised Echinacea purpurea fresh whole plant ethanol liquid extract 8:1 (250 mg) softgel capsules, containing standardised amounts of alkamides 0.25 mg/ml, polysaccharides 25.5 mg/ml and cichoric acid 2.5 mg/ml. The influence of this Echinacea purpurea preparation with 500 mg (two 250 mg capsules) 3 times/day for 28 days on the pharmacokinetics of lopinavir (400 mg)/ ritonavir (100 mg) twice/day and on CYP 3A and p- glycoprotein activity by using the probe substrates midazolam (8 mg) and fexofenadine (120 mg) as single doses, respectively, has been investigated. Thirteen volunteers received 14 days Echinacea purpurea in combination with lopinavir/ritonavir or 14 days Echinacea purpurea alone. Neither lopinavir nor ritonavir pharmacokinetics were significantly altered by 14 days of Echinacea purpurea co- administration, most likely due to the presence of the potent CYP3A inhibitor, ritonavir. A modest, but statistically significant decrease in midazolam exposure (−27%; p=0.008) and an increase in midazolam apparent oral clearance (37%; p=0.02) were observed. The
In the last decade some investigations on Echinacea purpurea root and combination on Echinacea purpurea root with herb were also performed.
Clinical trial using 12 healthy volunteers (6 women, 6 men) revealed that the effects of Echinacea purpurea root on CYP activity were minor. Nevertheless, authors conclude that further study into the interaction potential of this botanical is merited (Gurley et al. 2004).
The effect of Echinacea (Echinacea purpurea root) on CYP activity in vivo was assessed by use of the CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and midazolam (hepatic and intestinal CYP3A). Twelve healthy subjects (6 men) completed this
of CYP3A at hepatic and intestinal sites. The type of drug interaction observed between Echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites. Caution should be used when Echinacea is
The study of Gurley et al. (2008) evaluated the effects of an Echinacea extract (combination of Echinacea purpurea: aerial, root and seed parts; Echinacea angustifolia: root parts) on the pharmacokinetics of digoxin, a recognised
Pharmacokinetic and pharmacodynamic interactions of Echinacea (1275 mg four times daily containing a mixture of 600 mg of Echinacea angustifolia roots and 675 mg of Echinacea purpurea root; standardised to contain 5.75 mg of total alkamides per tablet; ) with warfarin in healthy subjects were investigated (Abdul et al. 2010). This was an
The potential of Echinacea purpurea root extract to interact with etravirine, a nonnucleoside reverse transcriptase inhibitor of HIV was investigated (Moltó et al. 2012). Fifteen
(500 mg every 8 h) for 14 days. Etravirine concentrations in plasma were determined by high- performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, 12, and 24 h after a morning dose of etravirine on day 0 and etravirine plus Echinacea purpurea on day 14. Echinacea was well tolerated, and all participants completed the study. The geometric mean ratio (GMR) for etravirine coadministered with Echinacea purpurea relative to etravirine alone was 1.07 (90% CI, 0.81 to 1.42) for the maximum concentration, 1.04 (90% CI, 0.79 to 1.38) for the area under the concentration- time curve, and 1.04 (90% CI, 0.74 to 1.44) for the concentration at the end of the dosing interval. In conclusion, the coadministration of Echinacea purpurea with etravirine was safe and well tolerated in
In a very similar study, Moltó et al. (2011) investigated the potential of Echinacea purpurea root extract, to interact with the boosted protease inhibitor
In a systematic review (Hermann & Richter 2012) it was found, that Echinacea is neither a potent nor a moderate inhibitor or inducer of cytochrome P450 (CYP) enzymes or
None of the above reports refers to interaction of Echinacea purpurea herb alone or on Echinacea purpurea expressed juice preparations. The reports on other Echinacea species and/or other plant parts mostly did not show clinically relevant interactions. Nevertheless, it appears that Echinacea may modulate the catalytic activity of CYP3A at hepatic and intestinal sites and inhibit CYP1A2 and CYP2C9 at high doses. Further pharmacokinetic testing is necessary before conclusive statements can be made about Echinacea puprurea herb juice interactions in concomitant use of Echinacea and CYP3A4, CYP1A2 and/or CYP2C9 substrates.
4.2. Clinical Efficacy
4.2.1. Dose response studies
There are no
In a study of Brinkeborn et al. (1999) the treatment with
4.2.2. Clinical studies (case studies and clinical trials)
Most of the clinical studies are related to the immunological effect and recurrent infections of the upper respiratory tract.
Table 5: The list of the placebo controlled clinical studies with oral use of expressed juice of Echinacea purpurea herb on the treatment of infections of the upper respiratory tract. These studies were used to assess the indications, posology and safety.
Table 6: The list of other clinical studies with expressed juice or extract of Echinacea purpurea herb or combinations thereof. These studies contributed especially to the assessment of safety.
Controlled randomised trials on medicinal products for oral use containing herbal preparations made of Echinacea purpurea herba recens
Yale & Liu (2004) tested the efficacy of a standardised preparation of Echinacea purpurea in reducing symptom severity and duration of the common cold, in a randomised,
Hoheisel et al. (1997) carried out a randomised
No specific adverse events were reported. The findings demonstrated that early initiation of treatment with the expressed juice of Echinacea purpurea could reduce the development of the disease and significantly shorten the duration of the common cold and reduce the length of the treatment period required.
Schulten et al. (2001) recruited a total of 80 adult male or female patients with first signs of a cold in a randomised
Clinical trials in children are described in 4.3.
Brinkeborn et al. (1999) evaluated the efficacy and safety of different doses and preparations of Echinacea purpurea in the treatment of common cold in a randomised,
2 tablets of different Echinacea purpurea preparations. Group I got a preparation of 95% herba and 5% radix, group II got the same preparation as group I but at 7 times higher concentration, group III got a special Echinacea purpurea radix preparation an group IV got placebo tablets. Duration of treatment was until the patients felt healthy again but not longer than 7 days. Primary endpoint was the relative reduction of the complaint index defined by 12 symptoms during common cold according to the doctor’s record. The preparations of group I and II were significantly more effective than the special root extract or placebo. Treatment with
Barrett et al. (2002) assessed the efficacy of dried, encapsulated,
Goel et al. (2004) studied the efficacy of a well standardised formulation containing alkamides, cichoric acid, and polysaccharides at concentrations of 0.25, 2.5, and 25 mg/ml, respectively, in reducing the severity and duration of symptoms of a naturally acquired common cold. The preparation is prepared from various parts of freshly harvested Echinacea purpurea plants
Throughout the treatment period, the response rate to treatments was greater in the Echinacea group. The average of every individual symptom (runny nose, sore throat, stuffy nose, fatigue, headache, chills) except in cough was significantly lower in Echinacea group compared to placebo. In cough the difference was not significant. No differences in white blood cell differential count were observed between the treatment groups.
Grimm & Müller (1999) randomly assigned 108 patients with a history of more than 3 colds or respiratory infections in the preceding year to receive 4 ml Echinacea purpurea expressed juice (EC3lJO, DER
Turner et al. (2000) assessed the effectiveness of Echinacea for the prevention of experimental rhinovirus colds in a randomised
Sperber et al. (2004) studied the ability of Echinacea purpurea to prevent experimental infection with rhinovirus type 39
Jawad et al. (2012) investigated the safety and efficacy of alcohol extract from freshly harvested Echinacea purpurea (95% herb and 5% root) in the prevention of common cold episodes in a large population over a
for viruses. A total of 293 adverse events occurred with Echinacea and 306 with placebo treatment. 10% of participants in Echinacea and 10% in placebo group experienced adverse events, which were at least possibly related to the study drug. Echinacea reduced the total number of cold episodes (non- significantly), cumulated episode days (significantly), and
Ross (2010) performed an open uncontrolled multicentre study on the efficacy and safety of Echinacea purpurea herb and root (each 750mg tablet contained 1200 mg of tincture mass: 95% herb (DER 1:12) and 5% roots (DER 1:11), extraction solvent 65 % V/V ethanol) in adult athletes (n=80). It was showed that the prophylactic efficacy after 8 weeks of treatment was very good (n=42; 52.5%) or good (n=19; 23.8%). The therapeutic efficacy in case of cold symptoms was very good in 73.5% of cases. The tolerability was high (very good n=68; 85%) (Schoop et al. 2006).
An overview and quantitative
In the review of Melchart et al. 1994, 26 controlled clinical trials were identified, but the methodological quality of most studies was rated low. The authors concluded that clinical trials indicated that Echinacea preparations could be efficacious immunomodulators but the evidence was still insufficient for clear therapeutic recommendations and further methodologically sound, randomised clinical trials should be conducted.
Barrett reviewed 9 treatment trials and 4 prevention trials of sufficient quality. Eight of the treatment trials reported positive results and 3 of the prevention trials reported marginal benefit (Barrett et al. 1999).
Giles et al. reviewed 41 references and concluded that Echinacea appears to be well tolerated with a low frequency of adverse effect, such as mild dyspepsia, headache and dizziness (Giles et al. 2000). Evaluated studies support Echinacea in the treatment of URI, but not to prevent infection.
Bauer reviewed new clinical studies (Bauer 2002). The author summarised that corresponding preparations can diminish the severity and the length of common colds significantly, and that they can also be used efficiently for the treatment of children. Bauer also concluded, that the stimulation of macrophages and induction of cytokines are major parts of the mode of action and the glycoproteins/polysaccharides and alkamides are part of the activity relevant constituents.
Barrett (2003) concluded in his second review that the treatment of acute upper respiratory infections with Echinacea purpurea is tentatively supported by the available literature. Reduction of symptoms with early treatment has been reported in several moderate quality randomised controlled trials. Benefits appear to be a modest, with a 10 to 40% reduction of symptoms as the most widely reported outcome. Benefit as a cold preventative appears marginal, at best, with an estimated 5 to 15% effect size.
The authors of Cochrane Review Linde et al. (2006) concluded: “Echinacea preparations tested in clinical trials differ greatly. There is some evidence that preparations based on the aerial parts of
Echinacea purpurea might be effective for the early treatment of colds in adults but results are not fully consistent. Beneficial effects of other Echinacea preparations, and for preventative purposes might exist but have not been shown in independently replicated, rigorous randomised trials.”
A new Cochrane review was made by
A thorough review and
4.3. Clinical studies in special populations (e.g. elderly and children)
Use in children
Out of the 19 clinical trials reviewed in Tables 1 and 2 and discussed in 4.2.2., 4 were performed in children. The youngest children were included in the two studies by Baetgen (Baetgen 1984, Beatgen 1988) where the minimal age was 1 month. The average age was 3.5 years in one study and 2.8 years and 3.1 years for boys and girls, respectively in the other study.
Taylor et al. (2003) studied the efficacy of Echinacea purpurea (dried expressed juice from the above ground parts of the plant harvested at flowering) in reducing the duration and/or severity of URI symptoms in children. The design of this study was randomised,
2 treatment groups. However, rash occurred during 7.1% of the URIs treated with Echinacea and 2.7% of those treated with placebo (p=0.008). In this study adverse events were found in 45.1% of patients receiving Echinacea (and in 39.5% of patients receiving placebo). The most frequent adverse events were: stomach ache, diarrhoea, drowsiness, headache, ”hyper” behaviour, rash and vomiting. Rash was the only side effect that was significantly more frequent in Echinacea group compared to placebo. The authors of the study concluded that Echinacea purpurea, as dosed in this study, was not effective in treating URI symptoms in patients 2 to 11 years old, and its use was associated with an increased risk of rash.
There were many critics on this study published in scientific literature (Kim et al. 2004, Firenzuoli & Gori 2004, Washam 2004, Le Tourneau 2004, Blumenthal 2004) and one answer of the authors (Taylor et al. 2004). The main critics were that the dosage of Echinacea extract in the product was not stated and the product was not standardised. Additional weakness of the study was that the placebo group used significantly more vitamins and mineral supplements. The patients started to take medication very late. The parents were asked to call coordinator of the study, when at least 2 symptoms of a URI developed, and they started to take medication after the coordinator confirmed that the child met criteria for having a URI. Barrett (2004) published a comment supporting the quality of Taylor’s study.
Weber et al. (2005) made a follow up of the patients from the study of Taylor et al. (2003). The aim of this study was to determine whether Echinacea purpurea (23.4 mg/ml E. purpurea herba dried expressed juice (DER
Götte & Roschke (2001) made an observation in children with recurring infections of the upper respiratory tract to assess the tolerability and efficacy of (alcohol free pressed juice from the aerial parts of Echinacea purpurea). A good to very good tolerability and efficacy was found in children above the age of two years and in young adults. Three hundred
had been affected by at least two infections of the respiratory tract during the past twelve months were included in the observation. The children had to be at least 2 years of age and show recurring signs and symptoms of a respiratory tract infection. At conclusion of the treatment, the tolerability was assessed with the aid of the recorded adverse drug reactions and the global assessment by the physician and the parents of the patients. The considered symptoms were specified on the observation form (sneezing, running nose, blocked nose, sore throat, cough, headache, feeling of illness and chili). Furthermore, the physician and parents evaluated the duration of the respiratory tract infection in historical comparison to the duration of illness without treatment with the juice. A total of 1,322 children and young adults – males and females – were included in the assessment of efficacy. All patients who had taken the juice at least once were included. A total of 5 patients were excluded from the analysis of tolerability, because they had not shown up for the final examination and no data regarding the assessment of tolerability had been recorded for them. The evaluation of efficacy involved 1,192 children and young adults, 579 females and 609 males. In four cases, the data on sex were missing. On average, the juice was administered to the patients over a period of 11 days. The results obtained from this observation of use, with doses adjusted according to age, revealed a good to very good tolerability and efficacy. In more than 95% of cases, the physician and parents globally assessed the tolerability as good or very good. More than 60% of the treating physicians and parents reported that the duration of the respiratory tract infection was shorter in comparison to the duration of disease without treatment with the juice. The efficacy was rated by the physician as well as by the parents as very good or good in more than 80% of the cases. In comparison to treatment without the juice, the physician observed in this respiratory tract infection a shorter duration of disease in more than 60% and the course of disease was rated as less severe in more than 70% of all patients. The parents of the children and young adults made comparable assessments.
Baetgen (1984) compared the therapy i.m. injection of
A combination of Echinacea and antibiotic is not equally effective. Out of this group of 77 patients only 9% improved within 5 days and 53% within 10 days of treatment. But the combination is superior to treatment with an antibiotic alone. Only 10% of the patients treated with antibiotics alone improved within 5 days and 46% within 10 days. Injections of Echinacea have been tolerated well; temperature rises up to 39°C on the day of treatment were only seen in isolated cases. Erythema and localised pain at the injection site were occasionally reported.
Baetgen (1988) obtained similar results in a comparative evaluation of 1,280 children suffering from bronchitis. In this retrospective evaluation it was demonstrated that 3 or 4 i.m. injections of Echinacea purpurea expressed juice can significantly shorten the duration of the infection in comparison with a group treated with antibiotics alone or with antibiotics plus Echinacea purpurea expressed juice. In Echinacea group 45.7% of patients improved in 5 days, in Echinacea + antibiotics and in antibiotics group the improvement was 25.5% and 16% respectively.
Information on 4 (unpublished) observational studies regarding the safety of the oral application of Echinacea purpurea herb preparations in different dosages for children below the age of 18 was submitted by German authority:
Four hundred fifteen children with a median age of 15 years, thereof 198 children below the age of 12 years, median age 8 years, suffering from acute respiratory tract infection received tablets containing 100 mg dried expressed juice of flowering herb of Echinacea purpurea (DER
to the pharmaceutical form (tablets) the following posology for children (from
Three hundred and
One hundred forty children
Two hundred and seventy children
Use in the elderly
In most clinical studies, the patients up to 65 years old were included (Hoheisel et al. 1997, Brinkeborn et al. 1999, Grimm & Müller 1999, Schulten et al. 2001, Turner et al. 2000, Barrett et al. 2002, Goel et al. 2004, Sperber et al. 2004, Yale et al. 2004).
No restrictions for elderly are known on the use of preparations from Echinacea purpurea.
Use in renal impairment
There are no reports on use of Echinacea in renal impairment.
4.4. Overall conclusions on clinical pharmacology and efficacy
Based on positive results from randomised double blind placebo controlled clinical studies (Hoheisel et al. 1997, Schulten et al. 2001) which demonstrated that early initiation of treatment with the expressed juice of Echinacea purpurea for 10 days can significantly shorten the duration of the common cold and reduce the symptoms and the length of the treatment period required, and supported by other clinical studies, it can be concluded, that there is good clinical evidence on efficacy of expressed juice from Echinacea purpurea, herba recens for treatment of acute upper airways infection (common cold) in adults and adolescents.
Short term prevention
The efficacy of expressed juice from Echinacea purpurea, herba recens for short term prevention of upper respiratory disease can be seen from the study of Hoheisel et al. (1997) where the patients were instructed to take the medicine at the beginning of first signs of disease and where later the development of disease was examined by physicians. In the Echinacea group only 24 patients experienced a “real” cold compared to 36 in the placebo group.
Furthermore, the efficacy of prevention of common cold can be seen from the study of Weber et al. (2005) where short term use of Echinacea purpurea herb dried expressed juice decreased the risk of subsequent URI by 28% (p=0.01, CI
Echinacea purpurea herb was also shown to prevent experimental infection with rhinovirus in clinical pharmacodynamic studies (see chapter 4.1.1).
Published evidence supports Echinacea’s benefit in decreasing the incidence and duration of the common cold.
Preparations of Echinaceae purpurea
Based on literature data and clinical trials the following posology is recommended:
Since the efficacy of Echinacea purpurea herb juice is demonstrated in clinical trials where the medicine was administered for a maximum of 10 days, the duration of use is limited to this period.
The clinical trial by Taylor et al. (2003) failed to demonstrate reducing the duration and/or severity of URI symptoms in children. There are many drawbacks of the study but there is no other
There is no
So, the clinical evidence of efficacy for children, for long term prevention of common cold and for extracts is not sufficient for
There is no clinical study on the efficacy of Echinacea purpurea herb juice ointment or other
Herbal remedies made from Echinacea purpurea in general appear to have a low potential to generate cytochrome P450 (CYP450)
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
In clinical studies preparations with Echinacea purpurea herb were very well tolerated. In most studies no specific side effects were observed or tolerability of placebo and Echinacea was equal.
In a multicentre uncontrolled study, a total of 1,231 patients with relapsing respiratory and urinary infections were treated for 4 to 6 weeks with Echinacea purpurea herb expressed juice. In 5% of patients adverse events were reported (Parnham 1996). The most frequently cited was an unpleasant taste of the study medication in 1.7% of patients, followed by nausea/vomiting (0.5%), recurrent infection (0.4%), sore throat (0.2%), abdominal pain (0.2%), diarrhoea (0.2%), difficulty in swallowing (0.2%), and other single reports (1.5%). The study was
Table 7: Adverse reactions during 8 week use of Echinacea product in a study of Grimm & Müller (1999)
None of the adverse reaction in Echinacea group was significantly different to placebo.
A systematic review, based on clinical studies, case reports and surveillance programmes of national medicines regulatory authorities and WHO (1999), concluded that Echinacea (species and plant part not defined) products have a good safety profile when taken in the short term, while data on
In a study with 407 children no difference in overall rate of adverse events was observed, the only different adverse effect between placebo and verum was rash (rash occurred in 7.1% of the Echinacea group and 2.7% of the placebo group) (Taylor et al. 2003).
There is no clinical trial on the topical use of Echinacea purpurea herb juice preparations in
Adverse effects associated with clinical studies are infrequent, minor and similar to those noted for placebo. Rash was the only significantly different adverse effects between placebo and verum.
5.2. Patient exposure
Echinacea purpurea preparations have been marketed worldwide in large quantities.
More than 5,000 patients have been included in studies listed in Table 5 and Table 6. In many European and
Among a stratified random sample (n=15,985) of the adult members of the Kaiser Permanente Medical Care Program of Northern California it was the most used herb used by 14.7% (Schaffer et al. 2003). It was also the most used herb among Turkish students (n=1871), used by 38.6% (Ayranci et al. 2005). Echinacea is after Salvia and Calendula the third most used herb in Slovenia
5.3. Adverse events, serious adverse events and deaths
On the basis of the results of the investigations reviewed above, the preparations were
In rare cases hypersensitivity reactions e.g. skin reactions may occur (ESCOP 2003, Hänsel et al. 1993, Blumenthal et al. 2000, Mullins 1998). Individuals with allergic tendencies, particularly those with known allergy to other members of the Asteraceae family should be advised to avoid Echinacea (Barnes et al. 2007, Hänsel et al.1993).
In an analysis of the events of
Hypersensitive reactions to Echinacea purpurea herb and its preparations are possible. Known hypersensitivity to Echinacea or to plants of the Asteraceae (Compositae) family should be contraindicated. In case of allergic reaction, Echinacea should not be taken again.
Published case reports of adverse events
Kemp & Franco (2002) published a case report of leucopoenia associated with
Soon & Crawford (2001) reported on a case of a 41 years old man with 4 recurrent episodes of erythema nodosum. According to the authors, it was temporally and perhaps causally associated with the use of Echinacea herbal therapy, but Echinacea species, plant part and herbal preparation is not reported. Each episode was preceded by prodromi of myalgias, arthalgias, fever, headache and malaise, which resolved under prednisolone therapy. Comedication was loratadine as needed, St. John’s wort for 6 month, and intermittent Echinacea (plant species, substance and preparation not reported) for 18 month. Other reasons were excluded. After dechallenge he was free of erythema nodosum despite persistence of intermittent flulike symptoms for over a year. A rechallenge with Echinacea was refused by the patient.
Logan & Ahmed (2003) reported, that a 36 year old woman had taken St. John’s wort, Echinacea and Kava for 2 weeks when she developed a severe general muscle weakness, which resolved under supplementation of NaHCO3 and KCl. Complaints of joint stiffness, fatigue, dry mouth and eyes surfaced 6 weeks later. The serum was negative for double stranded anti DNA, Smith and RNP antibodies. Sjögren’s Syndrome was diagnosed and Plaquenil treatment begun. The abnormalities of renal tubular function resulting in hypokalemia and acidification with muscle weakness are reported because of a Sjögren’s Syndrome. Problems resolved under therapy with prednisone and cyclophosphamide, which underlines the autoimmunogenesis. The authors discussed an association with Echinacea but they also acknowledged that this association may be purely incidental and a temporal association only. Plant species, type of preparation and application or dosage are not reported.
Schwarz et al. (2000) describes one case of encephalitis disseminata following the injection of Echinacea angustifolia containing homeopathic combination product. This product contains different plant species, different herbal substance and its route of application is different to the products covered in this Assessment report.
Liatsos et al. (2006) reported on a case (32 years old Caucasian male) of severe thrombotic thrombocytopenic purpura 20 days after the use of a
Maskatia & Baker (2010) reported on a case of hypereosinophilia associated with Echinacea (no detailed description of the product) use.
started taking Echinacea supplements several weeks prior around the time his abdominal pain started. He otherwise had an allergy to iodine. Labs revealed a white blood cell count of 24,900/μl with 74% eosinophils, for an absolute eosinophil count of 17,800/μl (normal <350 eosinophils/μl). The rest of the differential included 7% neutrophils, 11% lymphocytes, and 11% monocytes. His hemoglobin was 12.7 g/dl, with a platelet count of 208,000. Serum chemistries were normal except for slightly elevated creatinine, which normalised a few weeks later. Liver function tests and lactate dehydrogenase levels were also normal. Of note, he had a very elevated Immunoglobulin E (IgE) level of 1390 IU/ml (normal <114 IU/m). Bone marrow aspirate showed a mildly hypercellular bone marrow, marked eosinophil hyperplasia with mild atypia, and trilineage hematopoiesis with normal maturation. No evidence of myeloproliferative disease, lymphoma, or infection was noted. Flow cytometry revealed increased eosinophils, but no monoclonal B cell population, aberrant T cell antigen expression, or increased immunophenotypic blasts. Bone marrow cytogenetics were also normal. Tests for adrenal insufficiency and parasitic and connective tissue disorders were also negative, including evaluation for human immunodeficiency virus (HIV), systemic lupus erythematosus, scleroderma, Wegener granulomatosis, celiac disease, Clostridium difficile, Bartonella, Toxocara, Coccidioides, Cryptococcus, and Brucella.
Stool ova and parasite studies and serologic testing for IgG antibodies against Strongyloides antigens were also negative. Since the cause of hypereosinophilia was not readily apparent at first, the patient was treated for hypereosinophilic syndrome, a disorder characterised by persistent eosinophilia with no evident cause, and signs or symptoms of organ involvement by eosinophilic infiltration. Both hydroxyurea and imatinib were tried, but the only effective therapy was prednisone. Any attempt to taper prednisone resulted in increasing eosinophil counts and worsening nausea and diarrhoea. Three years after treatment had started, the patient mentioned that he had stopped taking Echinacea supplements but had continued taking the rest of his medications. Two weeks after Echinacea discontinuation, his eosinophil counts and IgE levels were checked, and they had markedly improved to almost normal levels. Prednisone was quickly tapered off, and, at the patient’s last visit, he continued to have normal eosinophil counts and IgE levels six months after discontinuation of the supplement.
Table 8: Spontaneous reports of suspected adverse drug reaction associated with Echinacea preparations submitted to the UK Committee on Safety on Medicines/Medicines and Healthcare products Regulatory Agency for the period 01/07/1963 to 01/06/2004 (Adverse Drug reactions
INR=international normalised ratio; NOS=not otherwise stated
The World Health Organisation’s Uppsala Monitoring Centre
Jeschke et al. (2009) published the results of a prospective pharmacovigilance study of Asteraceae extracts, including Echinacea. Out of 18,830 patients (58.0% female, 60.3% children), who received 42,378
Analysis of spontaneously reported adverse reactions submitted to the Swedish Medical Products Agency (Jacobsson et al. 2009) in the course of nearly 20 years showed that among a total of 64,493 reports, only 778 reports concerned adverse reactions related to CAM products. 63 reports concerned Echinacea purpurea, among them mostly urticaria (11) and exanthema (13).
Table 9: Pharmacovigilance reports from Member States on hypersensitive reactions and autoimmune diseases (causality has not been evaluated):
Italy 2014 7 case reports with only one product, containing Echinacea, administered:
–acute hepatitis with severe jaundice
–tongue and lower lips oedema, laryngeal constriction/oedema, taste disturbance, difficulty in breathing, tachycardia
–dermatitis eczematosa on the hands and forearm, urticaria
–gastrointestinal disturbances, diarrhoea
–aggravation of anxiety and nervousity in a predisposed person
–dry cough after administration
In the report of Istituto Superiore di Sanità on phytovigilance of natural products there are other 21 cases of adverse reactions for combination of products (containing Echinacea as well).
There is another case reported in the National Pharmacovigilance
The existing pharmacovigilance reports are mostly with undeclared or different plant species (Echinacea angustifolia), undeclared or different plant part (roots), undeclared or different herbal preparations (extract), different type of product (homeopathic or parenteral) or different duration of use (up to several months).
Hypersensitive reactions in the form of rash, urticaria, itching, swelling of the face are possible. Cases of severe hypersensitivity reactions, such as
Hypersensitive reactions (local rash, contact dermatitis, eczema and angioedema of the lips) may occur also after dermal administration of liquid and
Association with autoimmune diseases (encephalitis disseminata, erythema nodosum, immunothrombocytopenia, Sjögren’s syndrome with renal tubular dysfunction) has been reported.
The causality of adverse events in pharmacovigilance cases concerning autoimmune diseases is not known or inconclusive (insufficient data). The cases are complex, a link to development of autoimmune diseases appears unlikely. It must be considered that infectious agents and inflammatory processes present in common cold can themselves promote autoimmune diseases. However, association with autoimmune diseases cannot be excluded.
Since gastrointestinal adverse reactions in clinical trials were equally frequent in placebo and verum group, it can be assumed that gastrointestinal adverse events reported in pharmacovigilance reports are not Echinacea related.
5.4. Laboratory findings
No clinical studies with laboratory examinations were performed. A case of leucopenia was found in apparently healthy woman. Laboratory examination showed that her white cell count was 3,300/µl (normal range 4,000 to 11,000). The details of this case are described above in the chapter 5.3.
(Kemp & Franco 2002).
5.5. Safety in special populations and situations
5.5.1. Use in children and adolescents
Several prospective interventional clinical trials were performed with Echinacea in children (see Chapter 4.2.3). Here additional information on other type of surveys is presented.
Godwin et al. (2013) determined how common it is for parents to give natural health products (NHPs) to their children, which NHPs are being used, why they are being used, and parents’ assessments of the benefits and side effects of NHPs. A total of 202 (53.4%) of the 378 eligible parents who were contacted completed the survey. This represented 333 children. Mean (SD) age of the children was 5.1 (3.3) years. Overall, 28.7% of parents reported using nonvitamin NHPs for their children. A total of 137 children (41.1%) had taken NHPs (including vitamins); 61.1% of the NHPs being used were vitamins. The remainder fell under teas (primarily chamomile and green teas), Echinacea, fish or
children had experienced adverse side effects. Slightly less than half of the parents (45.0%) had informed their physicians that their children were taking NHPs.
There is no clinical trial or evidence of traditional use on the topical use of Echinacea purpurea herb juice preparations in
In spite of evidence of relatively safe use of Echinacea purpurea herb in children between 1 and 12 years of age Echinacea purpurea herb cannot be recommended for
Atopic patients and those with asthma should be cautious since rare allergic reactions have been reported (Barnes et al. 2005, Barnes et al. 2007, Huntley et al. 2005).
In case of hypersensitivity to the active substance or to plants of the Asteraceae (Compositae) family the use is contraindicated. No other concerns requiring contraindication were indicated.
5.5.3. Special Warnings and precautions for use
Based on the presumption that Echinacea purpurea herb has immunomodulatory effects, some authors declared, that its use is contraindicated in progressive systemic diseases such as tuberculosis, diseases of the white blood cells system, collagenoses, multiple sclerosis, AIDS, HIV infections, and other immune diseases (Barnes et al. 2005, Barnes et al. 2007, ESCOP 2003, Hänsel et al. 1993).
At present there is a lack of reliable clinical evidence to support the immunomodulatory effects of Echinacea, but in the view of the seriousness of the conditions listed above it is appropriate to avoid use in these disorders until further information is available (Barnes et al. 2005, Barnes et al. 2007).
In accordance with the ‘Guideline on the Summary of Product Characteristics’ dated September 2009, the statement that Echinacea purpurea herb is not recommended in progressive systemic disorders, autoimmune diseases, immunodeficiencies, immunosupression and diseases of the white blood cell system appears in the section ‘Warnings and precautions for use’ of the monograph on Echinaceae purpureae herba (not as a contraindication).
5.5.4. Drug interactions and other forms of interaction
The first report on possible
laetrile and his other vitamins after cycle 1, a potential interaction between laetrile and etoposide or cisplatin cannot be fully excluded.
Authors of the report concluded that since the exact preparation of Echinacea and corresponding plant extract constituents, was unknown, the interaction remains equivocal. Cautions should be exercised in patients receiving chemotherapy including CYP3A4 substrates (antracyclines, etoposide, vinca alcaloids, taxanes) while taking Echinacea (Bossaer & Odle 2012).
In a pharmacological study it was found that Echinacea purpurea radix inhibits intestinal CYP3A4 and induces hepatic CYP3A4 (Gorski et al. 2004). Modarai et al. (2010) found, that inhibition of CYP3A4 is more than 50 fold lower with Echinacea purpurea herb juice (no further details available;
IC50=1.8 g/l), compared to Echinaceae purpureae herba tincture (no further details available;
IC50=0.022 g/l) or to Echinaceae purpureae herba et radix tincture (65% V/V ethanol extract of fresh Echinacea purpurea herb (DER 1:12) and roots (DER 1:11), 95:5; IC50=0.027 g/l). Nevertheless, due to unknown formulation and dosages of Echinacea preparation in this case interaction with etoposide could be considered as a signal also for Echinacea purpurea herb preparations and their possible interaction with etoposide and other CYP3A4 substrates.
5.5.5. Fertility, pregnancy and lactation
No prospective interventional clinical trials have been performed with Echinacea in pregnant or lactating women.
Pregnancy outcome in women who used Echinacea during pregnancy was studied to evaluate the safety of Echinacea (Gallo et al. 2000). Since at least half of all pregnancies are unplanned, many women inadvertently use Echinacea in their first trimester. A total of 206 women were enrolled and prospectively followed up after contacting the Motherisk Program (in Toronto, Canada) regarding the gestational use of Echinacea. In this study group, 112 women (54%) used the herb in the first trimester, with 17 (8%) exposed in all 3 trimesters; Echinacea tablets /capsules (58%,
In a survey among 400 Norwegian women (Nordeng & Haven 2004) 36% used herbal drugs during pregnancy with an average of 1.7 products per woman. Echinacea was used by 23% of pregnant woman and was by far the mostly used herb. No information about the plant species, plant part or type of preparation or duration of intake/trimester is given in the article.
A review on safety of Echinacea during pregnancy and lactation was published (Perri et al. 2006). The authors searched 7 electronic databases and compiled data according to the grade of evidence found.
A good scientific evidence from a prospective cohort study was found: oral consumption of Echinacea during the first trimester did not increase the risk for major malformations (study performed by Gallo et al. 2000).
Nordeng et al. (2011) investigated the use of herbal drugs by pregnant women in relation to concurrent use of conventional drugs, delivery, and pregnancy outcome. Six hundred women at Stavanger University Hospital Norway were interviewed using a structured questionnaire within five days after delivery. Medical birth charts were reviewed with respect to pregnancy outcome. 39.7% of the women reported the use of herbal drugs during pregnancy, most commonly ginger,
(3,663 g vs. 3,508 g). There was a significant association between the use of
The study of Cuzzolin et al. (2010) explored the use of herbal products among Italian pregnant women and the possible influence of herbal consumption on pregnancy outcome. It was conducted over a 10- month period (2 days a week, from January to October 2009) at the Maternity wards of Padua and Rovereto Hospital. Data were collected through a
Holst et al. (2011) performed a survey at the antenatal clinic at Norfolk and Norwich University Hospital between November 2007 and February 2008 among 578 expectant mothers at least
and Echinacea. No information about the Echinacea species, plant part or type of preparation is given in the article.
No fertility data are available.
Echinacea is among the most commonly used medicinal herbs during the pregnancy with no documented reports on
In a prospective cohort study it was found that oral consumption of Echinacea during the first trimester did not increase the risk for major malformations comparing with
Referring also to the Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling (EMEA/CHMP/203927/2005) which requires at least 300 first trimester exposed prospectively collected pregnancies (a moderate amount) with known pregnancy outcomes (births or fetopathological examinations) to make conclusion about save use and recommendation for use during pregnancy, use of Echinacea in pregnancy cannot be recommended.
In the absence of sufficient data, the use in pregnancy and lactation should not be recommended unless advised by a doctor. The doctor should consider the balance between benefit and potential risk for the patient based on the presented data.
There are no data on dermal use of Echinacea during pregnancy or lactation. Products containing Echinacea should not be applied to the breast of breastfeeding women.
No case of overdose has been reported.
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
No studies on the effects on the ability to drive or operate machinery or impairment of mental ability have been performed.
5.5.8. Safety in other special situations
No safety concerns in other special situations were reported.
5.6. Overall conclusions on clinical safety
Based on clinical trials with Echinacea purpurea herb expressed juice preparations and pharmacovigilance reports it can be concluded, that medicinal products containing this herbal preparation are safe for intended use, taking into account recommended contraindications, warnings and precautions for use. In most clinical studies no side effects were observed or their frequency was equal or lower than in placebo. Only in one study, the frequency of one adverse effect (rash) was higher in Echinacea group (Taylor et al. 2003).
There is a relatively low number of pharmacovigilance reports on adverse effects of Echinacea products, especially comparing to extremely high frequency of use of these products. In some cases, it is not possible to distinguish the side effect of the drug from the complication of a disease (e.g. inflammatory processes can trigger autoimmune disease). On the other hand there is
of adverse effects of herbal medicinal products in many European countries, and the actual frequency of adverse effects might be higher.
Hypersensitive reactions in the form of rash, urticaria, itching, swelling of the face are possible. There are reported cases of severe hypersensitivity reactions, such as
Known hypersensitivity to Echinacea or to plants of the Asteraceae (Compositae) family is to be contraindicated. In case of allergic reaction, Echinacea should not be taken again.
Association with autoimmune diseases (encephalitis disseminata, erythema nodosum, immunothrombocytopenia, Sjögren’s syndrome with renal tubular dysfunction) cannot be excluded.
There is one case of leucopenia after
Echinacea purpurea herb preparations.
Based on the presumption that Echinacea purpurea herb has immunomodulatory effects, its use is not recommended in progressive systemic disorders, autoimmune diseases, immunodeficiencies, immunosuppression and diseases of the white blood cell system.
In spite of evidence of relatively safe use in children between 1 and 12 years of age Echinacea purpurea herb cannot be recommended for
Limited data (several hundreds of exposed pregnancies) indicated no adverse effects of oral use of Echinacea on pregnancy or on the health of the foetus/newborn child. These data are not sufficient since there is no study of adequate scientific quality with sufficient number of first trimester exposed prospectively collected pregnancies and no other relevant epidemiological data are available. In the absence of sufficient data, the use during pregnancy and lactation is not recommended unless advised by a doctor.
There are no data on dermal use of Echinacea during pregnancy or lactation. Products containing Echinacea should not be applied to the breast of breastfeeding women.
No fertility data are available.
6. Overall conclusions
Based on positive results from randomised double blind placebo controlled clinical studies which demonstrated that early initiation of treatment with the expressed juice of Echinacea purpurea for 10 days can prevent, reduce the development of the disease and significantly shorten the duration of
the common cold and reduce the symptoms and the length of the treatment period required, supported by other clinical studies, it can be concluded, that there is good clinical evidence on efficacy of expressed juice from fresh herb of Echinacea purpurea for the short term prevention and treatment of acute upper airways infection (common cold) in adults and adolescents.
Therefore, medicinal products with expressed juice from fresh herb of Echinacea purpurea fulfil the criteria for
According to literature data and clinical trials the following posology is recommended:
The clinical evidence of efficacy for children, for long term prevention of common cold, for cutaneous use and for extracts is not sufficient for
There is evidence of traditional topical use of liquid and
Benefit – Risk – Assessment
The overall body of evidence which includes several clinical trials proves the efficacy of expressed juice from fresh herb of Echinacea purpurea in accordance with EMEA/HMPC/104613/2005.
There is acceptable safety profile: mainly mild allergic reactions (rash, urticarial, angioedema) are reported in literature and pharmacovigilance reports. Cases of serious hypersensitivity reactions have been reported, especially in atopic patients. Atopic patients should consult their doctor before using
The use of the product is contraindicated in cases of hypersensitivity to Echinacea purpurea and to other plants of the Asteraceae (Compositae) family.
The use in children under 12 years of age is not recommended because efficacy has not been sufficiently documented although specific risk in children over 1 year of age is not documented.
Based on the presumption that Echinacea purpurea herb may have immunomodulatory effects, its use is not recommended in progressive systemic disorders, autoimmune diseases, immunodeficiencies, immunosuppression and diseases of the white blood cell system.
Genotoxicity investigations are available for lyophilised Echinacea purpurea expressed juice and ethanol extracts and they showed no genotoxicity.
Well documented interactions of the herbal preparations containing preparations from Echinacea purpurea herb with other medicinal products are not reported in literature.
Limited data (hundreds of exposed pregnancies) indicated no adverse effects of oral use of Echinacea on pregnancy or on the health of the foetus/newborn child. No other relevant epidemiological data are available. In the absence of sufficient data, the use in pregnancy and lactation is not recommended unless advised by a doctor.
No fertility data are available.
Intoxication, due to Echinacea medicinal preparations, is not reported in literature or reference sources.
It can be concluded that the benefit/risk assessment for Echinacea purpurea, herba recens, succus and succus siccus preparations is positive for the
There is the evidence of traditional cutaneous use of liquid and
The risk is at an acceptable level for traditional herbal medicinal products.
No new safety concerns appeared during this revision. We therefore recommend to keep the inclusion in the European Union list.
List of references