Pelargonium – Pelargonium root (Pelargonii radix)

Latin name of the genus:Pelargonium
Latin name of herbal substance:Pelargonii radix
Botanical name of plant:Pelargonium sidoides dc; pelargonium reniforme curt.
English common name of herbal substance:Pelargonium root
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Latin name of the genus: Pelargonium
Latin name of herbal substance: Pelargonii radix
Botanical name of plant: Pelargonium sidoides DC; Pelargonium reniforme Curt.
English common name of herbal substance: Pelargonium root

Pelargonium - Pelargonium root - Pelargonium sidoides DC; Pelargonium reniforme Curt.

Table of Contents

1. Introduction

Pelargonium species (Geraniaceae) indigenous to areas of southern Africa are highly valued by traditional healers for their curative properties. Among those traditional herbal medicines were several Pelargonium species. Whereas Pelargonium species represent very popular ornamental plants in Europe, little was known of the medicinal practice with Pelargoniums in folk medicine in areas of southern Africa. Infusion of the roots of Pelargonium sidoides DC and Pelargonium reniforme Curt. have been used to treat coughs, chest problems including tuberculosis and gastrointestinal disorders such as diarrhea and dysentery. In addition, these plant materials were claimed to provide a cure for hepatic disorders and dysmenorrhea. The aerial parts of these Pelargonium species are employed as wound healing agents (Kolodziej, 2000).

The drug was introduced to England and Europe by the British mechanic Charles Henry Stevens in the 19th century for the treatment of tuberculosis. Stevens believed that he recovered from tuberculosis by the administration of a decoction of Pelargonium root prepared by a traditional healer (Helmstädter, 1996).

By comparative botanical as well as chromatographic studies it could be proved that two species i.e.

Pelargonium sidoides or Pelargonium reniforme were used for the same purposes. Species Pelargonium are very similar and have been much confused in the past. The existence of gradual variation between both species contributed to general problems of taxonomic classification, as reflected in the past by numerous revisions of the Linneaen taxonomic system (Kolodziej, 2002; van Wyk, 2008). The use of both species is also accepted by the European Pharmacopoeia monograph describing Pelargonium sidoides DC and/or Pelargonium reniforme Curt. in one monograph without defining specific parameters for differentiation (Ph. Eur. 6.0, 2008).

The two species can be distinguished by the shape of the leaves, the colour of the flowers and the pollen. P. sidoides is characterised by dark red to almost black flowers, cordate-shaped leaves and yellowish pollen, while the zygomorphosous flower heads of P. reniforme are magenta red with two distinctive stripes on the upper two petals, the pollen is whitish-green, and the reniform leaves represent a characteristic feature that is reflected by its botanical name “reniforme”. Differentiation of the roots is more difficult and refers to the colour of the root wood and the thickness of the phellem. In P. sidoides the root wood is dark brown, while in P. reniforme it is markedly lighter or appears yellow. The geographical range of distribution of two species also differs. P. reniforme mainly occurs in coastal regions in the Eastern Cape of southern Africa, while P. sidoides are predominantly found over large parts of the interior of southern Africa, but also occur in coastal mountain ranges up to 2300 m (Bladt and Wagner, 2007; Brendler and van Wyk, 2008).

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

Herbal substance(s)

Pelargonium root (Pelargonii radix is the dried, usually fragmented underground organs of Pelargonium sidoides DC and/or Pelargonium reniforme Curt. Tannin content, expressed as pyrogallol, minimum 2% (Ph. Eur. 6.0, 2008). Standard scientific monograph compilations (Comission E, ESCOP and WHO monographs) do not include sections on Pelargonium sidoides.

Herbal preparation(s)

Liquid extract (DER 1:8-10), extraction solvent ethanol 11% (m/m)

Dry extract prepared from the liquid extract described above: DER 4-25:1, extraction solvent ethanol 11% (m/m)

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.

Not applicable.

Constituents

Coumarins. Are formed from cis-hydroxycinnamic acid by lactonization and have limited distribution in the plant kingdom. They have been found in about 150 species, mainly in the plant families Apiaceae, Rutaceae, Asteracae. The characteristic constituents of Pelargonium species include a remarkable series of simple coumarins as regards the high degree of aromatic functionalisation including hydroxyl and methoxyl groups (Kayser and Kolodziej, 1995). Apart from the widely distributed di-substituted scopoletin, all the coumarins possess tri- and tetra substituted oxygenation patterns on the aromatic nucleus. Amongst these, 5,6,7- or 6,7,8-trihydroxycoumarin and 8-hydroxy- 5,6,7-trimethoxycoumarin represent the metabolites of the above class of secondary products (Table 1.). Such combined oxygenation patterns are very rare in plant kingdom, but apparently typical for the genus Pelargonium (Kolodziej, 2000).

6,7-dihydroxy-derivative

scopoletin

5,6,7-trisubstituted derivatives

umckalin

5,6,7-trimethoxycoumarin

6,7,8-trioxygenated derivatives

6,8-dihydroxy-7-methoxycoumarine

fraxetin

5,6,7,8-tetrasubstituted derivatives

6,8-dihydoxy-5,7-dimethoxycoumarine

artelin

coumarin glycoside

umckalin-7-β-glucoside

coumarin sulfate

5,6-dimethoxycoumarin-7-sulfate

Table 1. Typical coumarin compounds of P. sidoides (Kolodziej, 2007)

Compositional studies of the roots of two species provided a similar picture of a broad metabolic profile, reflecting a close botanical relationship between them. In spite of the similar patterns of coumarins, a distinguishing feature appeared to be the presence of a 5,6-dimethoxy arrangement within the group of 5,6,7-trioxygenated members of P. sidoides (umckalin, 5,6,7-trimethoxycoumarin) and an unsubstituted 6-hydroxyl function in that of P. reniforme (fraxinol, isofraxetin) (Latte et al. 2000; Kolodziej, 2002) (Table 2.). Another discriminating chemical character was the distinct occurrence of coumarin sulfates and coumarin glycosides in P. sidoides (Kolodziej et al. 2002; Kolodziej, 2007). These coumarin derivatives and umckalin are known to be useful marker compounds for P. sidoides, as they appear to be absent in P. reniforme (Brendler and van Wyk, 2008). In addition, there is much divergence in concentration, with generally significantly higher yields of coumarins in P. sidoides. The total coumarin content of the roots of P. sidoides is approximately 0.05% related to dry weight, with umckalin amounting for about 40% of total coumarin content (Latte et al. 2000).

A rapid TLC method, a HPLC-fingerprint analysis and HPLC-quantitative estimation were developed for coumarins containing the roots of Pelargonium species by Bladt and Wagner (1988). Franco and de

Oliveira (2010) presented a new, validated HPLC method for quality control of plant extracts and phytopharmaceuticals containing P. sidoides, using umckalin as chemical marker.

White et al. (2008) drew the attention to the uncontrolled harvest of at least 20 tons of P. reniforme and P. sidoides in the Eastern Cape in 2002. These facts raised the need for development of sustainable harvesting practice and methods for the effective cultivation of this species. The authors investigated by HPLC the variation in the concentration of umckalin within and between plant populations collected from different geographical locations and monitored the effect of various cultivation techniques including the manipulation of soil water content and pH level. The final conclusion was that the greenhouse-cultivated plants showed equivalent umckalin concentrations and circa six-times greater growth rates than plants in wild-harvest experiments.

Table 2. Coumarin patterns of Pelargonium species * Compounds were indentified in EPs® 7630

Other constituents. Structural examination of root metabolites of Pelargonium species led to the characterisation of other various compounds including phenolic acids, flavonoids, flavan-3-ols with associated proanthocyanidins and one phytosterol. With the exception of gallic acid and its methyl ester, the majority of these metabolites have been found in relatively low yields. In contrast, the oligomeric and polymeric proanthocyanidins occur in high concentration, with catechin and gallocatechin entities, as dominating extender units (Gödecke et al. 2005; Kolodziej, 2002). The heterogeneity of metabolites in P. reniforme root extract was further demonstrated by the characterisation of an unprecedented diterpene ester, designated as reniformin (Latte et al. 2007).

According to the European Pharmacopoeia, Pelargonium root has to contain not less than 2% of tannins, expressed as pyrogallol. The identification method of the European Pharmacopoeia is thin layer chromatography of the methanol root extract, but HPLC fingerprint analysis of Pelargonium extract was already achieved (Bladt and Wagner, 1988). Schnitzler et al. (2008) analysed the compounds of aqueous root extract of P. sidoides by LC-MS spectroscopy. Predominant coumarins, simple phenolic structure as well as flavonoid and catechin derivatives were identified as major the constituents in Pelargonium extract (Figure 1.).

Figure 1. HPLC chromatogram of an aqueous P. sidoides extract at 260 nm (Schnitzler et al. 2008) (Assignment: 3- glucogallin, 8- fraxetin-7-O-glucoside, 11- catechin, 12- dihydroxy-coumarin-sulfate, 15- fraxetinsulfate, 16- monohydroxy-dimethoxycoumarin, 19,22- dihydroxy-dimethoxycoumarin, 23- dihydrokaemferol, 25- umckalin).

Special extract of P. sidoides. EPs® 7630 is a special ethanolic (11% (m/m)) extract of P. sidoides roots. The fundamental structural studies on the Pelargonium species were recently extended to this medicinal product. Schötz et al. (2008) give a detailed account of the constituents of EPs® 7630. The extraction method yields a specific range of constituents markedly different from those obtained from extraction with non-polar solvents. Six main groups of compounds can be found in EPs® 7630: purine derivatives (2%), coumarins (2%), peptides (10%), carbohydrates (12%), minerals (12%) and oligomeric prodelphinidines (40%). The identified coumarin pattern is strongly reminiscent to that of P. sidoides (Kolodziej, 2007). A remarkable feature is that predominant amounts of coumarins occur as their sulfated derivatives. In addition, the stability for sulfated coumarins appears to be enhanced in the extract, whereas these compounds decompose rather quickly when they are isolated. A considerable proportion of high molecular weight proanthocyanidins was found in EPs® 7630. A diverse set of epigallo-and gallocatechin based oligomers were isolated from EPs® 7630, which are connected by A and B-type bonds. Additionally, two series of monosubstituted oligomers, sulfates and aminoconjugates were detected by mass spectroscopy (Schötz and Nödler, 2007).

The total mineral content of EPs® 7630 was found to be 10-12%. The cations were detected by ICP- MS: potassium (4%), sodium (1.2%) and magnesium (0.4%). Anions were quantified by ion chromatography giving sulfate (4.5%), phosphate (2%) and chloride (1%) (Schötz et al. 2008).

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

Austria:

Traditional herbal medicinal products

Preparations:

1)Dry extract prepared from the liquid extract described below

2)Liquid extract (1:8-10), extraction solvent: ethanol 11% (m/m)

Pharmaceutical form:

1)Film-coated tablet

2)Oral liquid (1 ml = 21 drops)

Posology:

all for oral use

1) > 12 years: 3 x daily 1 containing 20 mg extract

2)1-5 years: 3 x daily 10 drops

6-12 years: 3 x daily 20 drops > 12 years: 3 x daily 30 drops

10 g (= 9.75 ml) liquid contain 8 g extract

Indication:

1-2) Common cold

Legal status:

1-2) Registered traditional herbal medicinal products

On the market since:

1)2009

2)2007

Belgium:

Traditional herbal medicinal products

Preparations:

1)Pelargonium sidoides roots, liquid extract EtOH 11% (m/m) DER 1:8-10

2)Pelargonium sidoides roots, dried extract EtOH 11% (m/m) DER 1:8-10

Pharmaceutical form:

1)Oral solution: 8 g extract per 10 g solution

2)Tablets: 20 mg extract per tablet

3)Syrup 0.25 g extract per 100 g syrup

Posology:

1)Adults & children > 12 years: 30 drops, 3 times daily Children 6-12 years: 20 drops, 3 times daily

Children 1-5 years: 10 drops, 3 times daily

Drops to be taken preferably morning, noon and evening with some liquid

Average duration of administration is 7 days. Continue the treatment for some days when symptoms are decreasing.

Maximal duration: 3 weeks

2) TABLETS

Adults & children > 12 years: 1 tablet 3 times daily (morning, noon, evening) Children 6-12 years: 1 tablet, 2 times daily (morning, evening)

Tablets to be taken with some liquid; do not chew

3) SYRUP

Adults & children > 12 years: 7.5 ml, 3 times daily Children 6-12 years: 5 ml, 3 times daily

Children 1-5 years: 2.5 ml, 3 times daily

Average duration of administration is 7 days. Continue the treatment for some days when symptoms are decreasing.

Maximal duration: 3 weeks

Indication:

1-3) Common cold, exclusively based on traditional use

Legal status:

1-3) Registered traditional herbal medicinal product

On the market since:

1-3) 2009

Czech Republic:

Herbal medicinal product with well-established use

Preparations:

1) Pelargonii sidoides extractum fluidum (1:8–10), extraction solvent ethanol 11% (m/m)

Pharmaceutical form: 1) Solution, oral drops

Posology:

1) 1 g = 20 drops of the medicinal product contains 800 mg of the extract

Adults and adolescents over 12 years: 30 drops 3 times daily

Children 6–12 years: 20 drops 3 times daily

Children 1–5 years: 10 drops 3 times daily

Duration of use: 7–10 days

Indication:

1) Symptomatic treatment of acute bronchitis not requiring antibiotic therapy

Legal status:

1) Authorised herbal medicinal product

Since when is on the market: 1) 2008

Germany:

Herbal medicinal products with well-established use

Preparations:

1-3) Dry extract prepared from the liquid extract described below

4-9) Liquid extract (1:8-10), extraction solvent: ethanol 11% (m/m)

Pharmaceutical form: 1-3) Film-coated tablet 4-9) Oral liquid

Posology:

all for oral use

1-3) > 12 years: 3 x daily 1 containing 20 mg extract 4-9) 1-5 years: 3 x daily 10 drops

6-12 years: 3 x daily 20 drops > 12 years: 3 x daily 30 drops

10 g (= 9.75 ml) liquid contain 8 g extract

Indication:

1-3) For symptomatic treatment of acute bronchitis

4-9) Acute bronchitis

Legal status:

1-9) authorised herbal medicinal products

On the market since: 1-3) 2009

4) at least since 1976

5-9) 2006

Hungary:

Traditional herbal medicinal products

Preparations:

1) 10 g of oral solution containing 8 g of Pelargonium sidoides radix extract (1:8-10) (EPs® 7630) Extraction solvent: 11% ethanol (m/m)

Pharmaceutical form: 1) Oral solution

Posology:

1)Adults and adolescent above 12 years: 3 x 30 drops daily Children between 6-12 years: 3 x 20 drops

Indication:

1) Acute infections of upper airways, such as symptomatic treatment of common cold

Legal status:

1) Registered traditional herbal medicinal product

On the market since: 1) 2009

Italy:

1)Pelargonium sidoides, radix, liquid extract (1-8:10, ethanol 11% (w/w)) (EPs® 7630) 80% oral drops, solution (multiple application)

2)Pelargonium sidoides, root dry extract (1-8:10, ethanol 11% (w/w)) (EPs® 7630) 20 mg film coated tablets (multiple application)

Therapeutic indication for both: THMP for the relief of common cold, exclusively based on longstanding use.

Latvia:

Herbal medicinal product with well-established use

Preparations:

1) Liquid extract from Pelargonium sidoides DC roots (EPs 7630), extraction solvent: ethanol 11% (w/w), DER: 1:8-10. 10 g (9.75ml) of solution contains 8 g of extract

Pharmaceutical form: 1) Oral solution, drops

Posology:

Adults and children from 12 years – 30 drops 3 times per day; children 6-12 years: 20 drops 3 times per day; children 1-5 years: 10 drops 3 times per day.

Indication:

Use in case of acute un chronical infections, especially infections of respiratory tract and ear, throat and nose (bronchitis, sinusitis, tonsilitis, rhinopharingitis).

Legal status:

1) Authorised WEU herbal medicinal product

On the market since: 1) 2000

The Netherlands

Traditional herbal medicinal products

Preparations:

1)Pelargonium sidoides, radix, liquid extract (1:8 – 10) extraction solvent ethanol 11% (m/m)

2)Pelargonium sidoides, radix, dried extract (1:8 – 10) extraction solvent ethanol 11% (m/m)

Pharmaceutical form:

1.Oral liquid

2.Tablets

3.Syrup (2x)

Posology:

Oral drops containing per 10 g, 8 g extracts of Pelargonium sidoides roots

(DER 1:8 – 10, extraction solvent ethanol 11% (m/m) Oral: adults and children from 12 years

30 drops, 3 times daily

Children from 6 to 12 years:

20 drops, 3 times daily

Children from 2 to 5 years:

10 drops, 3 times daily

Children from 1 year:

5 drops, 3 times daily

Tablets containing 20 mg of a dried extracts of Pelargonium sidoides roots (DER 1:8 – 10), extraction solvent ethanol 11% (m/m)

Oral: adults and children from 12 years

1 tablet, 3 times daily

Children from 6 to 12 years:

1 tablet, 2 times daily

Syrup containing 0.25 g dried extracts of Pelargonium sidoides roots (DER 1:8 – 10), extraction solvent ethanol 11% (m/m),

Oral: adults and children from 12 years

7.5 ml syrup, 3 times daily

Children from 6 to 12 years:

5 ml syrup, 3 times daily

Children from 2 to 5 years:

2.5 ml syrup, 3 times daily

Children from 1 year:

1.25 ml syrup, 3 times daily

Syrup for children containing 0.25 g dried extracts of Pelargonium sidoides roots (DER 1:8 – 10), extraction solvent ethanol 11% (m/m)), the finished product contains no alcohol

Children from 6 to 12 years:

5 ml syrup, 3 times daily

Children from 2 to 5 years:

2.5 ml syrup, 3 times daily

Children from 1 years:

1.25 ml syrup, 3 times daily

Indication:

Common cold, the use is exclusively based upon long-standing use.

Legal status:

Authorised traditional herbal medicinal product

On the market since:

1)June 2007

2)June 2009 (3x)

Slovakia:

Herbal medicinal product with well-established use

Preparations:

1) 10 g (= 9.75 ml) of oral solution containing 8 g of Pelargonium sidoides radix extract (1:8-10) (EPs® 7630), extraction solvent: 11% ethanol (m/m)

Pharmaceutical form: 1) Oral solution

Posology:

1)Adults and adolescent above 12 years: 30 drops 3 times daily Children between 6-12 years: 20 drops 3 times daily Children between 1-5 years: 10 drops 3 times daily

Indication:

1) Acute infections of upper airways.

Legal status:

1) Authorised herbal medicinal product

On the market since: 1) 2007

Spain:

Traditional herbal medicinal products

Preparations:

1)10 g (= 9.75 ml) of oral solution contains 8 g extract from the roots of Pelargonium sidoides DC (1:8–10; 11% ethanol (m/m)), 1 ml (approximately 20 drops)

2)20 mg of dry extract prepared by drying the liquid extract described above

Pharmaceutical form:

1)Solution, oral drops

2)Tablets

Posology:

1)Adults and adolescents: 30 drops 3 times daily Children 6-12 years: 20 drops 3 times daily

2)Adults and children over 12 years: 1 tablet 3 times daily

Indication:

1)Traditional herbal medicinal product used to relieve the symptoms of common cold, based on traditional use only.

2)Traditional herbal medicinal product used to relieve the symptoms of common cold, based on traditional use only.

Legal status:

1)Registered traditional herbal medicinal product

2)registered traditional herbal medicinal product

On the market since:

1)2009

2)2009

Sweden:

Traditional herbal medicinal products

Preparations:

1)Root, dry liquid extract, extraction solvent: ethanol 11% (m/m). DER genuine 1:8-10 (liquid extract), DER 4-25:1 (dried liquid extract), DER manufacturing 0.7-4.5:1.

2)Root, liquid extract, extraction solvent: ethanol 11% (m/m). DER genuine 1:8-10

Pharmaceutical form:

1)Film-coated tablet

2)Oral drops, solution

Posology:

1)Adults and adolescents over 12 years: 1 tablet 3 times daily Children between age 6 and 12 years: 1 tablet 2 times daily Not recommended to children under age of 6.

2)Adults and adolescents over 12 years: 30 drops 3 times daily Children between age 6 and 12 years: 20 drops 3 times daily Not recommended to children under age of 6 years.

1 ml is equivalent to 20 drops.

Indication:

1)Traditional herbal medicinal product for symptomatic relief of the common cold

2)Traditional herbal medicinal product for symptomatic relief of the common cold

Legal status:

1)Registered traditional herbal medicinal product

2)Registered traditional herbal medicinal product

On the market since:

1)2009-05-11

2)2009-05-11

United Kingdom

Traditional herbal medicinal products

Preparations:

1)Root, liquid extract, extraction solvent: ethanol 15% (V/V) DER genuine (1:8-10)

2)Root, dry extract, extraction solvent: 14% (V/V), DER genuine (4-7:1)

3)root, dried liquid extract, extraction solvent: ethanol 11 % (w/w), DER genuine (1:8-10)

4)Root, dry extract, extraction solvent: 11% ethanol (w/w), DER genuine (1:8-10)

5)Root, liquid extract, extraction solvent: 11% ethanol (w/w), DER genuine (1:8-10)

Pharmaceutical form:

1)Oral drops, solution

2)Film-coated tablet

3)Syrup

4)Film-coated tablet

5)Oral drops, solution

Posology:

1.Adults, Elderly and children over 12 years: 30 drops three times per day Children from 6 to 12 years: 20 drops three times per day

The use in children under 6 years of age is not recommended

2.Adults, elderly and adolescents above 12 years of age: Take 1 tablet three times daily The use in children under 12 years of age is not recommended

3.Adults, elderly and adolescents above 12 years of age: Take 1 tablet three times daily The use in children under 12 years of age is not recommended

4.Adults and adolescents over 12 years of age: Take 1 tablet three times daily The use in children under 12 years of age is not recommended

5.Adults and adolescents over the age of 12: Take 30 drops three times per day Children aged between 6-12 years: Take 20 drops three times per day.

The use in children under 6 years of age is not recommended

Indication

1-5) Traditional herbal medicinal product used to relieve the symptoms of upper respiratory tract infections including common cold, such as sore throat, cough and blocked or runny nose, based on traditional use only.

Legal status

1-5) Registered traditional herbal medicinal product On the market since:

1)27/10/2011

2)02/06/2011

3)02/06/2011

4)01/09/2011

5)10/02/2011

Regulatory status overview

MA: Marketing Authorisation TRAD: Traditional Use Registration

Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’

This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.

1.3. Search and assessment methodology

Databases SciFinder, Science Direct, Web of Science and PubMed were searched using the terms [Pelargonium], [EPs® 7630] and [coumarin]. Handbooks and textbooks were also used.

2. Historical data on medicinal use

2.1. Information on period of medicinal use in the Community

Pelargonium sidoides is native to South Africa and is used against several diseases by traditional healers. The Englishmen Charles Henry Stevens discovered the crude herbal drugs when he went to South Africa in 1897 on his doctor’s advice, in order to cure his tuberculosis (TB) in the clear mountain air. He met a Zulu medicine man, who treated him with a boiled root preparation. Three months later he felt well and considered himself as cured. After returning to the UK, he set up a company to prepare and sell his remedy under the name of “Stevens’ Consumption Cure”.

In the early 1900s, Stevens’ Consumption Cure was a very popular remedy against tuberculosis in England. In 1909, the British Medical Association (BMA) published a book with the title “Secret Remedies: What they cost and what they contain”. In that book Stevens was accused of quackery, as the powder showed a microscopic similarity to other tannin drugs, such as rhatany root. He took action for libel against BMA, but the jury decided in favour of BMA and he was ordered to pay 2000 pounds of legal cost.

After the First World War, Stevens continued to promote his Pelargonium-containing preparation. In 1920, the French-Swiss physician A. Sechehaye started to treat TB patients with Stevens’ Cure. During 9 years, he documented the treatment of around 800 patients and reported successful cases to the Medical Society of Geneva. He also investigated the antibacterial action of the remedy in laboratory surroundings. Sechehaye came to the conclusion that in many TB cases, with the exception of acute,

malignant and complicated cases the drug could be seen to be efficacious. In 1933, the physician Bojanowski reported about five cases of successful treatment of tuberculosis with Pelargonium preparations in Germany (Helmstädter, 1996; Taylor et al. 2005; Bladt and Wagner, 2007; Brendler and van Wyk, 2008).

Primarily, Stevens’ Cure was a powder of crude drug suspended in water, but in the early years in England the remedy was sold as liquid, containing alcohol, glycerine and a drug decoction. In Switzerland, a fluid extract was probably the predominant dosage form, while in Germany the drug was sold as powder, extract or tincture (Helmstädter, 1996).

Despite the repeated attempts, the remedy was unidentified until 1977, when Bladt, at the University of Munich, used ethnobotanical, comparative botanical and chromatographic techniques to show that the roots originated from the Geraniaceae species Pelargonium sidoides and/or P. reniforme (Bladt and Wagner, 1977). At this point, the drug received renewed interest and pharmacological research was initiated.

Marketing of the remedy as a treatment for bronchitis and symptoms of common cold already started in the 1970’s. Pelargonium received a full market authorisation by the German drug regulatory agency in 2005. Until this time, a tincture 1+10 from P. sidoides/reniforme was used, from 2005 the ingredients changed to a solution of P. sidoides (Brendler and van Wyk, 2008).

The monograph of Pelargonium sidoides/reniforme root (Pelargonii radix) was introduced into the European Pharmacopoeia in 2008.

Outside Europe, various liquid and solid preparations are available as herbal supplements especially in North America and Mexico.

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

The information about therapeutic indications of preparations from Pelargonium radix is available from clinical trials and manufacturers. The efficacy of Pelargonium extract was examined in patients with acute bronchitis, acute sinusitis, common cold and tonsillopharynhitis. The producers suggest the internal use of Pelargonium extract in case of acute infection of upper airways, common cold and symptomatic treatment of acute bronchitis not requiring antibiotic therapy.

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

According to the market overview, one extract (DER 1:8-10), extraction solvent: ethanol 11% (m/m) of Pelargonii radix has been on the market for more than 30 years with the indication acute bronchitis (see product no. 4 in the German market overview, section 1.2). However, this indication needs medical diagnosis and supervision. Based on other traditional herbal medicinal products with the same composition in other member states, the following indication was accepted: symptomatic treatment of common cold. In accordance with the Directive 2004/24/EC, the native dry extract equivalent to the above mentioned liquid extract (dry extract, DER 4-25:1, extraction solvent ethanol 11% (m/m)) is also included in the traditional use monograph.

The clinical studies and the product information provide guidance for the dosage of Pelargonium preparations. In the majority of clinical trials adult patients took 30 drops of liquid preparation three times daily. The duration of application was usually 7 days.

The clinical studies including children suggested 3 x 5 drops of liquid preparation for children under 2 years of age, 3 x 10 drops for children between 2-6 years of age and 3 x 20 drops for children

between 6-12 years of age. In other clinical trials children between 1-6 years of age were instructed to take 3 x 10 drops of liquid preparation (Table 3-7). According to package leaflets, 3 x 30 drops of solution or 3 x 1 tablets (containing 20 mg dry extract/tablet) are prescribed for adults and 3 x

20 drops or 2 x 1 tablets for children between 6-12 years of age. The most recent posology of the reference product with the confirmed 30 years of application is as follows:

1-5 y: 3 x daily 10 drops

6-12 years: 3 x daily 20 drops > 12 years: 3 x daily 30 drops

Although there exist clinical studies involving children under the age of 6 years, there is no stratification for age when assessing the safety (exact number of adverse events in this age group is not known) of the treatment. Hence, the confirmation of safety under 6 years was considered insufficient to allow the application in this age group in the monograph.

10 g of the preparation contains 8 g Pelargonii radix extract (DER: 1:8-10), extraction solvent: ethanol 11% (m/m).

Taking into account the density of the finished product (1.018 – 1.038, mean 1.028 g/ml), the density of the liquid extract (0.975 – 1.000, mean 0.9875 g/ml) and the drop count (20-21 drops/ml finished product):

30 drops finished product = 1.4286-1.5 ml = 1.4686-1.542 g = 1.1749-1.2336 g native extract= 1.1897-1.2492 ml native extract.

20 drops finished product = 0.9524-1 ml = 0.9790-1.028 g = 0.7832-0.8224 g native extract= 0.7932-0.8328 ml native extract.

Based on this, and taking into account safety aspects as well, the posology of Pelargonii radix containing products is as follows:

Adolescents, adults and elderly:

1.19-1.25 ml liquid extract, 3 times daily.

20 mg dry extract, 3 times daily

Children between 6-12 years:

0.79-0.83 ml liquid extract, 3 times daily.

20 mg dry extract, 2 times daily

3. Non-Clinical Data

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

Antibacterial activity

Kayser and Kolodziej (1997) investigated the antibacterial activity of extracts and isolated compounds (scopoletin, umckalin, 5,6,7-trimethoxycoumarin, 6,8-dihydroxy-5-7-dimethoxycoumarin, (+)- catechin, gallic acid and its methyl ester) of P. sidoides and P. reniforme against 8 microorganisms, including Gram-positive (Staphylococcus aureus, Streptococcus pneumoniae and beta-hemolytic Streptococcus 1451) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Proteus

mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae) using an agar dilution method. These pathogens are primarily responsible for numerous respiratory tract infections. The crude Pelargonium extracts were found to be moderately active against the tested bacteria. Apart from (+)-catechin, all the tested compounds exhibited moderate antibacterial activity with MICs ranging from 220-

2000 μg/ml. (Penicillin G and erythromycin were used as reference agents). The MIC value of penicillin G was 5-166 μg/ml and the MIC value of erythromycin was 2-125 μg/ml (under the same experimental conditions). The most potent candidates with MICs of 200-500 μg/ml were umckalin and 6,8- dihydroxy-5,7-dimethoxycoumarin, which are present in considerable amounts in the aqueous phase of Pelargonium species. However, the antibacterial activity of these compounds is significantly weaker compared to antibiotics. The aqueous fraction showed the highest activity from the tested extracts.

Acetone and methanol extracts of P. sidoides were investigated for antimicrobial activity against 10 bacterial (B. cereus, S. epidermidis, S. aureus, M. kristinae, S. pyogenes, E. coli, S. pooni, S.

marcescens, P. aeruginosa, K. pneumoniae) and 5 fungal species (A. flavus, A. niger, F. oxysporium, M. hiemalis, P. notatum) by Lewu et al. (2006a). With the exception of Staphylococcus epidermidis, extracts obtained from both solvents demonstrated significant activity against all the Gram-positive bacteria tested in this study. The MIC ranged from 1 to 5 mg/ml except the acetone extract against Klebsiella pneumoniae where the value was 10 mg/ml. Three Gram-negative bacteria, Escherichia coli, Serratia marescens and Pseudomonas aeruginosa were not inhibited by any of the extracts at the highest concentration (10 mg/ml) tested. The extracts also showed appreciable inhibitory activity against all the fungal species tested.

A comparative study of antibacterial activity of the shoots and the roots of P. sidoides was performed by Lewu et al. (2006b). There was no significant difference between the MIC values of extracts from both parts. Furthermore, the similar bioactivity of plant materials collected from different populations was found. With the exception of Staphylococcus epidermidus and Micrococcus kristinae the extracts from both the roots and the leaves showed activity against all the Gram-positive bacteria tested with MIC ranging from 1 to 7.5 mg/ml. Gram-negative bacteria were not or only slightly inhibited.

Similar moderate antibacterial activities were evident for EPs® 7630 (MIC values: Klebisella pneumoniae 13.8 mg/ml, Escherichia coli >13.8 mg/ml, Pseudomonas aeruginosa >13.8 mg/ml,

Proteus mirabilis 3.3 mg/ml). This extract was also effective against multiresistant strains of S. aureus with MICs of 3.3 mg/ml (Kolodziej et al. 2003).

Nevertheless, the demonstrated direct antibacterial activity cannot adequately explain the documented clinical efficacy of Pelargonium-containing herbal medicines in the treatment of respiratory tract infections. The anti-infectious capabilities may also be due to indirect effects, e.g. interaction between pathogens and epithelial cells (Kolodziej et al. 2003; Kolodziej and Kiderlen, 2007).

A synergistic indirect antibacterial effect of EPs® 7630 in group A-streptococci (GAS) was established through inhibition of bacterial adhesion to human epithelial cells (HEp-2) as well as induction of bacterial adhesion to buccal epithelial cells (BEC) (Brendler and van Wyk, 2008).

Conrad et al. (2007a, b) investigated the impact of a therapeutically relevant concentration of 1-

30 μg/ml EPs® 7630 on the activity of human peripherial blood phagocytes (PBP) and on host-bacteria interaction in vitro. A flow cytometric assay, microbiological assay and penicillin/gentamicin-protection assay were used to determine phagocytosis, oxidative burst and adhesion of GAS on human HEp-2 and BEC, intracellular killing and GAS invasion of HEp-2 cells. The number of phagocytosing PBP and intracellular killing were increased by EPs® 7630 in a concentration dependent manner. EPs® 7630 reduced GAS adhesion to HEp-2 cells significantly, but increased GAS adhesion to BEC. The authors concluded that EPs® 7630 can protect the upper respiratory tract from bacterial colonisation by reducing bacterial adhesion to epithelial cells. On the other hand, the attachment of bacteria to BEC is enhanced, so that pathogens are released during coughing and eventually inactivated by being

swallowed (Conrad and Frank, 2008). Further investigations by Dorfmüller et al. (2005) and Brendler and van Wyk (2008) complemented these findings.

Wittschier et al. (2007) used Helicobacter pylori, as a model microorganism to investigate the effect of EPs® 7630 on microbial adhesion by fluorescent technique. The extract showed antiadhesive activity in a dose-dependent manner in the range 0.01-10 mg/ml, but a direct cytotoxic effect against H. pylori could not be established. Beil and Kilian (2007) also showed that EPs® 7630 interferes with H. pylori growth and adhesion to gastric epithelial cells.

Antimycobacterial properties

The traditional use of Pelargonium extract against tuberculosis prompted to investigate the antimycobacterial effect of Pelargonium species.

The extract of P. sidoides showed inhibitory activity against Mycobacterium tuberculosis in a radiorespiromertric bioassay at a sample concentration of 12.5 μg/ml, while that of P. reniforme was inactive. None of the isolated simple phenolic compounds and coumarins exhibited any antimycobacterial activity under these conditions. In the microdilution Alamar Blue assay, the extract of P. sidoides was moderately active against M. tuberculosis with a MIC of 100 μg/ml in comparison with the clinically used drug rifampicin (MIC of 0.06 μg/ml) (Kolodziej et al. 2003).

The antimycobacterial activity of hexane extracts of roots of P. sidoides and P. reniforme was investigated by Seidel and Taylor (2004) against rapidly growing mycobacterium – M. aurum, M. smegmatis. Several mono- and diunsaturated fatty acids were found as active compounds by bioassay- guided fractionation. Oleic acid and linoleic acid were the most active with MICs of 2 mg/l; isoniazid used as standard had a MIC of 0.06-1 mg/l.

Mativandlela et al. (2006) investigated various extracts and isolated compounds from the roots of Pelargonium species with regard to their antibacterial especially their antimycobacterial activities. Limited activity (MICs of ~5000 mg/l, compared to MIC of 0.2 mg/l of rifampicin) against Mycobacterium tuberculosis could be shown for acetone, chloroform and ethanol extracts of P. reniforme. None of the isolated compounds showed any activity against M. tuberculosis.

The aqueous acetone extracts of both root material and aerial parts as well as fractions of P. sidoides showed negligible antimycobacterial activities against nonpathogenic Mycobacterium aurum and M. smegmatis in a microdilution assay, with MICs of >1024 μg/ml. Inhibition of growth was measured by MTT assays, using ethambutol as a positive control (MIC 2 μg/ml) (Kolodziej and Kiderlen, 2007).

The butanol root extract of P. sidoides was found have inhibitory activity against M. tuberculosis at a concentration of 2500 μg/ml. The isolated compounds (flavonoids and coumarins) did not show activity against M. tuberculosis (Patience et al. 2007).

The aqueous extract of the root of P. reniforme stimulated the macrophage killing of the intracellular pathogen M. tuberculosis. Kim et al. (2009) identified gallic acid and methyl gallate as the most bioactive components of the highly effective water fraction by bioassay-guided fractionation.

Immunomodulatory properties

To assess the immunostimulating activity of P. sidoides and its constituents, functional bioassays including an in vitro model for infection with Leishmania parasites, a fibroblast-virus protection assays (IFN activity), a fibroblast-lysis assay (TNF activity), a biochemical assay for nitric oxides, as well as gene expression analyses were employed.

Kayser et al. (2001) performed an experiment to assess the immune modulatory properties of extract and constituents of P. sidoides in various bioassays. An in vitro model for visceral leishmaniasis was selected in which murine macrophages are infected with the intracellular protozoon Leishmania donovani (control: pentostam). None of the tested samples (methanol, petrol ether, ethyl-acetate and n-butanol extract of P. sidoides root and pure compounds: gallic acid, gallic acid methyl ester, (+)- catechin, 6-hydroxy-7-methyoxycoumarin, umckalin, 5,6,7-trimethyoxycoumarin and 6,8-dihydroxy- 5,7-dimethyoxycoumarin) revealed significant activity against extracellular, promastigote Leishmania donovani. However, apart from the coumarin samples, all the Pelargonium extracts (EC50 <0.1-3.3 microg/ml), gallic acid (EC50 4.4 microg/ml) and its methyl ester (EC50 12.5 microg/ml) significantly reduced the intracellular survival of L. donovani amastigotes within murine macrophages. The samples exhibited no or negligible host cell cytotoxicity. These findings indicated that the samples acted indirectly against Leishmania parasites, possibly activating macrophage functions. Macrophage activation was confirmed by detection of tumour necrosis factor (TNF-α) and inorganic nitric oxides (iNO) in supernatants of sample-treated cell cultures (control: LPS). Gallic acid and its methyl ester were identified as prominent immunomodulatory principles for P. sidoides by bioassay-guided fractionation.

Thäle et al. (2008) concluded that EPs® 7630 significantly increased release of NO, production of intra- and extracellular IL-1, IL-12, and TNF-α, thereby reducing the survival rate of intracellular parasites.

The bone marrow-derived macrophages experimentally infected with intracellular bacteria Listeria monocytogenes were incubated with EPs® 7630 (1-30 μg/ml). Compared with non-infected cells, the effects were more pronounced.

Kolodziej et al. (2003) observed that EPs® 7630 possessed TNF-inducing potency and interferon-like activity in supernatants of sample-activated bone marrow-derived macrophages in several functional assays. In addition, EPs® 7630 stimulated the synthesis of IFN-β in human MG-63 osteosarcoma cells. Stimulation of RAW 264.7 cells with gallic acid, as characteristic compounds of EPs® 7630 resulted in gene expression of iNOS and TNF-α transcripts.

Koch et al. (2002) also confirmed that EPs® 7630 increased the IFN-β prodution in MG-63 cells preincubated with the preparation. Enhancement of cytotoxicity mediated by natural killer cells was also found.

Confirmatory evidence of non-specific immunmodulatory activity of EPs® 7630 as provided by functional assays was available from gene expression analyses. EPs® 7630 and simple phenols, flavan- 3-ols, proanthocyanidins and hydrolysable tannins were studied for gene expressions (iNOS, IL-1, IL- 10, IL-12, IL-18, TNF-α, IFN-α/γ) by RT-PCR. All tested samples were capable of enhancing the iNOS and cytokine mRNA levels in infected cells when compared with those in non-infected conditions (Kolodziej et al. 2005).

Trun et al. (2006) carried out gene expression analysis for the iNOS and the cytokines IL-1, IL-12, IL- 18, TNF-α, IFN-α and IFN-γ in non-infected and in Leishmania major-infected RAW 264.7 cells. EPs® 7630 induced strongly the gene expression of iNOS and a series of cytokine mRNAs in infected cells. Similar profiles were obtained for the methanol-insoluble fraction and gallic acid. The methanol-soluble fraction and umckalin did not show any significant gene-inducing capabilities. Other studies also confirmed that there was difference in the gene expression response of infected macrophages when compared to that of non-infected cells (Kolodziej and Kiderlen, 2007).

Koch and Wohn (2007) evaluated the effects of EPs® 7630 on release of antimicrobial peptides from neutrophils using ELISA kits. The cytoplasmatic granules of neutrophil granulocytes contain a variety of antimicrobial proteins – bactericidal/permeability-increasing protein (BPI), human neutophil peptides (HNP) and defensins-, which possess antimicrobial as well as chemotactic, immunomodulating and

wound-healing activity. EPs® 7630 concentration-dependently increased the release of HNP 1-3 and BPI.

Other anti-infective activity- antifungal, antiviral and mucolytic effect

In a microbiological killing assay, human peripheral blood phagocytes were found to significantly reduce the number of surviving Candida albicans organisms, pretreated with EPs® 7630 (3, 10, and 30 μg/ml). Since the extract did not show direct antifungal activity in the test system, the intracellular destruction of the test organism was concluded to be due to enhanced phagocyte killing activity induced by EPs® 7630 (Conrad et al. 2007a).

Schnitzler et al. (2008) examined the antiviral effect of aqueous root extract of P. sidoides in cell culture. Concentration-dependent antiviral activity against herpes simplex virus type 1 (HSV 1) and herpes simplex virus type 2 (HSV 2) could be demonstrated for this extract. Both viruses were significantly inhibited when pre-treated with the plant extract or when the extract was added during the adsorption phase, whereas acyclovir, the commercial antiviral drug demonstrated activity only intracellularly during replication of HSV. The IC50 for P. sidoides extract was determined from dose– response curves at 0.00006% and 0.000005% for HSV-1 and HSV-2, respectively, and a dose- dependent activity of the extract could be demonstrated. Acyclovir showed the maximum antiviral activity when added at a concentration of 22.5 mg/ml during the replication period with inhibition of the viral replication of more than 98% for both herpes viruses. These results indicated that P. sidoides extract affected the virus before penetration into the host cell and reveals a different mode of action when compared to the classical drug acyclovir.

Nöldner and Schötz (2007) studied the inhibition of sickness behavior (anorexia, depressed activity, listlessness and malaise) by EPs® 7630 and its different fractions separated by ultrafiltration in an animal model. In laboratory animals, the sickness behaviour was induced by administration of cytokine-inducer. Oral administration of EPs® 7630 and the high molecular weight fraction (>30 kDa) antagonised the above-mentioned effects in a dose-dependent manner. The animals were treated with LPS at 100, 200 or 400 μg/kg bw and 1, 2 or 3 h later placed in the light compartment of the light- dark-box for 3 min. For main experiments a dose of 400 μg/kg LPS administrated 2 h for

the behavior experiment was used. Control animals received an oral administration of vehicle or the high dose of EPs® 7630 (400 μg/kg bw) and an i.p. injection of saline. Treated animals received EPs® 7630 and an i.p. injection of LPS.

Neugebauer et al. (2005) demonstrated that EPs® 7630 significantly and dose-dependently (1-

100 μ g/ml) increased the ciliary beat frequency in vitro. According to authors, these results suggest the local application of EPs® 7630 close to nasal mucosa, but it could be limited by a moderate astringent effect of tannin compounds of extract.

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

Absorption, metabolism, elimination

There are no available data about pharmacokinetic parameters of Pelargonium extract; the relevant information about constituents is presented.

The pharmacokinetics of coumarin, the basic compound of coumarin group has been studied in a number of species, including humans. These human studies demonstrated that coumarin was completely absorbed from the gastrointestinal tract after oral administration and extensively metabolised by the liver in the first pass, with only between 2 and 6% reaching the systematic

circulation intact. In the majority of human subjects studied, coumarin is extensively metabolized to 7-hydroxycoumarin by hepatic CYP2A6. After administration of coumarin, 68-92% of the dose was 7- hydroxycoumarin in urine as glucuronide and sulfate conjugates. While 7-hydroxylation is the main way of coumarin metabolism in humans, the major pathway in most rodents is by 3,4-epoxidation resulting in the formation of ring opened metabolites including o-HPA, o-HPPA (Figure 2). Several studies examined the toxic effect of coumarin in rats by the formation of these metabolites. A deficiency in the 7-hydroxylation pathway has been observed in some individuals, which appears to be related to a genetic polymorphism in CYP2A6. The limited in vitro and in vivo data available suggest that such deficient individuals will metabolise coumarin by the 3,4-epoxidation and possibly other pathways leading to formation of toxic o-HPAA (Egan et al. 1990) (Lake, 1999).

conjugation and excretion (human)

Figure 2. Some pathways of coumarin metabolism (o-HPA = o-hydroxyphenylacetaldehyde; o-HPAA = o-hydroxyphenylpropionic acid) (Lake, 1999)

According to human data the elimination of coumarin from the systematic circulation is rapid. The in vivo and human studies concluded that there are important quantitative differences between species in the routes of elimination of coumarin metabolites. The majority of studies demonstrated a relatively large amount of biliary excretion in rats. The rapid excretion of coumarin metabolites in the urine of human subjects given coumarin suggested that there is little or no biliary excretion of coumarin metabolites in humans.

The large difference in metabolism and elimination of coumarin between rats and humans suggested that the rat is not an appropriate animal model for the evaluation of the safety of coumarin for humans (Lake, 1999; Loew and Koch, 2008).

Pharmacokinetic interactions

Due to the coumarin content of the roots of P. sidoides an enhancement of the anticoagulant action of coumarin derivative preparations by co-administration of Pelargonium root extract is theoretically possible. Koch and Biber (2007) investigated whether a change in blood coagulation parameters or an interaction with coumarin-type anticoagulants occurred after administration of EPs® 7630 to rats. No effect on (partial) thromboplastin time (PTPT/TPT) or thrombin time (TT) was observed after oral administration of EPs® 7630 (10, 75, 500 mg/kg) for 2 weeks, while treatment with warfarin (0.05 mg/kg) for the same period resulted in significant changes in blood coagulation parameters. If EPs® 7630 (500 mg/kg) and warfarin (0.05 mg/kg) were given concomitantly, the anticoagulant action of

warfarin was not influenced. Similarly, the pharmacokinetics of warfarin was unchanged after pretreatment with EPs® 7630 for 2 weeks.

Moreover, the coumarins so far identified in EPs® 7630 do not possess the structural characteristics needed for anticoagulant activity. The minimal structural requirements for anticoagulant activity in coumarins are an hydroxyl group in position 4 and a non-polar rest in position 3 (Figure 3).

CH3

C O

OH CH2

4

3

O O

warfarin

Figure 3. Minimal structural requirements for anticoagulant characteristic in coumarins

In view of these results, it does not appear very probable that an increased bleeding tendency can arise in patients treated with EPs® 7630 (Loew and Koch, 2008; Brendler and Wyk, 2008).

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

Toxicological data regarding preparations from Pelargonium radix

In a cytotoxicity study with a preparation containing the tincture 1:10 (ethanol 9-11% m/m) of Pelargonium sidoides roots did not produce significant cytotoxic effects on human blood cells and human liver cells in the cell viability test and membrane integrity test within the concentration range tested (30, 100, 300 and 1000 μg/ml). In the human liver cells (HepG2 cells) the extracts produced a slight reduction in cell viability of approximately 20% only at the highest test concentration. Similarly, the extract samples did not produce any cytotoxic effects in the membrane integrity test in both THP-1 and HepG2 cells (Jäggi et al. 2005).

In the brine shrimp lethality bioassay, neither Pelargonium extracts nor its phenolic constituents including benzoic and cinamic acid derivatives, hydrolysable tannins and C-glycosylflavones showed any cytotoxic effects. With LC50 values of >1000 μg/ml and >200 μg/ml for extracts and test compounds, respectively, it was concluded that the cytotoxic potential of ethanolic-aqueous root extract of Pelargonium sidoides and constituents may be negligible, when compared with the LC50 of the reference compounds actinomycin and podophyllotoxin (0.53 μg/ml and 72 μg/ml, respectively)

(Kolodziej, 2002).

Conrad et al. (2007c) published the results of toxicological studies of EPs® 7630: cytotoxicity, acute and 4-week toxicology in rats, 2-week dose verification and 13-week toxicology in dogs, Ames test, chromosome-aberration test, micronucleus test in mouse cells, tumour promotion, local tolerability, immunotoxicity and reproduction toxicology. All the tests showed no negative effects. The full details of the toxicological investigation were not given.

In subacute and chronic toxicological studies in rats and dogs revealed a NOEL>750 mg/kg body weight of EPs® 7630. Applying the recommended dose, the daily intake of 60 mg of extract would be equivalent to 4 and 1 mg/kg body weight (15 kg for a child or 60 kg for an adult, respectively) translating into a safety factor of more than 100 (Loew and Koch, 2008).

Toxicological data regarding constituents of Pelargonium extract

A number of animal studies have examined the mutagenic and carcinogenic potential of coumarin. Overall, the data suggest that coumarin is not a genotoxic agent. However, high doses of coumarin produced liver and lung tumors in some chronic studies. The 3,4-epoxidation pathway of metabolism to yield toxic metabolites explain this phenomenon, not the direct cytotoxic effect (Lake, 1999).

Rajalakshmi et al. (2001) established the safety of gallic acid in mice. In the study, acute administration of gallic acid even at a dose as high as 5 g/kg body weight did not produce any signs of toxicity or mortality. In the subacute 28-day study, gallic acid at a dose of 1000 mg/kg body weight did not significantly alter the haematological parameters. Further, no appreciable change was noted in the various biochemical parameters such as Serum glutamic oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (SGPT), as well as many serum constituents such as plasma protein, cholesterol, urea and bilirubin. The organ weight of the treated animals did not vary significantly from the control, except for a decrease in the spleen weight. Histological examination of the tissues showed no marked treatment-related changes with respect to any of the organs examined, including spleen.

Subchronic toxicity of gallic acid (GA) was investigated in rats by feeding a diet containing 0-5% GA for 13 weeks. Toxicological parameters included clinical signs, body weight, food consumption, hematology, blood biochemistry, organ weights and histopathological assessment were observed. The results of hematological examinations suggested development of anemia, of probably hemolytic origin. However, the severity of the anemia was weak even at 5% gallic acid in diet. The NOAEL was estimated to be 119 mg/kg and 128 mg/kg for male and female rats, respectively (Niho et al. 2001).

Hepatotoxicity

Some investigations have examined the hepatic biochemical and morphological changes produced in the rats by coumarin administration from 1 week to 2 years. The coumarin-induced hepatotoxicity in the rodents can be attributed to the excretion of coumarin metabolites in the bile, thus the enterohepatic circulation enhance the exposure of liver cells to toxic coumarin metabolites, such as o- HPA and o-HPAA (see upper). The different metabolism and excretion in humans can explain the low risk of coumarin-induced hepatotoxicity in humans (Lake, 1999).

Koch (2006) examined the hepatotoxic effect of extracts from the roots of Pelargonium sidoides. Consequently, the studies on rats and dogs (no data on duration) involving the oral administration of up to 3000 mg/kg EPs® 7630 p.o. provided no evidence of liver damaging effects. There were no effect on plasma transaminase, lactate-dehydrogenase and alkaline phosphatase activities and the level of bilirubin. These positive results were backed up by in vitro tests on human hepatocytes and hepatoma cells. The effect on cell viability did not observed after pretreatment with EPs® 7630 (0-50 μg/ml) for 24 hours.

The hepatotoxic risk is present only in specific compounds related to the overall group of coumarins. These substances are structurally different from the 7-hydroxy-coumarins contained in EPs® 7630 which, according to scientific literature, do not have hepatotoxic properties.

3.4. Overall conclusions on non-clinical data

The pharmacological results provide a rationale for the therapeutic application of Pelargonium extract. The moderate antibacterial effect against several Gram positive and Gram negative bacteria, interfering with invasion and adherence of microorganisms to human cells, triggering immune responses and mucolytic properties (via improving ciliar function) a complex mechanism of action of

Pelargonium sidoides preparations. The identity of the pharmacologically active constituents is partly known. However, most of the studies have no controls (at least they are not mentioned) therefore the relevance of these results is not clear. Moreover the concentration of Pelargonium compounds in the body is not known.

Although there is limited knowledge about pharmacokinetic parameters and toxicological data of Pelargonium extract, the results of non-clinical trials raise no safety concern.

Adequate tests on reproductive toxicity, genotoxicity and carcinogenicity have not been published.

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

No relevant data available.

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

No relevant data available.

4.2. Clinical Efficacy

4.2.1. Dose response studies

A dose-finding, randomised, placebo controlled, double-blind study was carried out to compare three different doses of EPs® 7630 versus placebo in tablet preparations (10, 20, 30 mg, three times daily). 405 patients suffering from acute bronchitis were included in the study. The outcome measures were changes in bronchitis symptoms score (BSS) at day 7 and changes in individual components of BSS (Table 3). The BSS total score consists of the five symptoms coughing, sputum production, pulmonary rales at auscultation, chest pain while coughing and dyspnoea, which are the most important features associated with acute bronchitis, rated on a scale from 0 (not present) to 4 (very severe) and leading to a maximum total score of 20 points. The decrease of BSS score was significantly higher in patients treated with any doses of EPs® 7630 compared to patients treated with placebo, but there was no significant difference between BSS of patients treated with different doses of EPs® 7630 (Schulz, 2008a; Malek et al., 2007c). All active treatment groups showed a significantly better IMOS (Integrative Medicine Outcome Scale) outcome scale than placebo in the assessment of the investigator (completely recovered 1% vs. 3.9-10.9%, major improvement 9.8% vs. 35.3-68%) and patient (completely recovered 1% vs. 5.9-18.8%, major improvement 14.7% vs. 36.3-68%)(Malek, 2007c).

Table 3. Dose-finding studies with EPs® 7630

Abbreviations: DB=double-blind, PC=placebo-controlled, R=randomised

In this study secondary efficacy variables were (Matthys et al. 2010b): three response criteria: (1) BSS total score less than 3 points on day 7, (2) decrease in BSS total score of at least 7 points from day 0 to day 7, and (3) combination of criteria 1 and 2; treatment outcome assessed by both the patient and the investigator using the Integrative Medicine Outcomes Scale (IMOS; a 5-point verbal rating scale describing the general health status of the patient: 1= ‘complete recovery’, 2= ‘major improvement’, 3= ‘slight-to-moderate improvement’, 4= ‘no change’, 5= ‘deterioration’); onset of effect; intake of paracetamol; change of individual symptoms of the BSS total score; change of general symptoms (hoarseness, headache, limbs pain and fatigue/exhaustion); health status of patients using health- related quality of life questionnaires (SF-12 Health Survey, EQ-5D); duration of activity limitation and inability to work assessed by diary entry (from day 0 to day 7 = maximum inability duration of

8 days); patient’s satisfaction with treatment using the Integrative Medicine Patient Satisfaction Scales (IMPSS; 5-point verbal rating scale: 1= ‘very satisfied’, 2= ‘satisfied’, 3= ‘neutral’, 4= ‘dissatisfied’, 5= ‘very dissatisfied’) (Matthys et al. 2010b).

Between day 0 and day 7, the number of patients unable to work dropped from 92.2, 87.3, 93.1 and 89% to 52, 21.6, 12.9 and 6% of patients in the placebo, EPs® 7630 30, 60- and 90-mg groups, respectively. This reduction was significantly more pronounced in the active treatment groups than with placebo. The median duration of inability to work was 8 days for placebo and 6 days for EPs® 7630 7630, i.e. a reduction by 2 days in all active treatment groups (p<0.0001, in each case, two-sided U- test). The duration of activity limitation between day 0 and day 7 was also shorter in the active treatment groups than with placebo (p<0.0001, in all pair-wise comparisons, two-sided U-test) (Matthys et al. 2010b).

All documented adverse events were of mild to moderate intensity; their frequency was dose- dependent. The most common adverse effects affected the gastrointestinal system (6/102 (5.9%) patients in the placebo group, 5/102 (4.9%) in the 30-mg group, 9/101 (8.9%) in the 60-mg group and 15/101 (14.9%) in the 90-mg group). No serious adverse events were reported (Matthys et al. 2010b).

Treatment with EPs® 7630 7630 led for all three dosages compared to placebo to a statistically significant and clinically relevant improvement of health-related quality of life and patient-reported treatment outcome (Matthys et al. 2010a).

4.2.2. Clinical studies (case studies and clinical trials)

Acute bronchitis

Matthys et al. (2003), Chuchalin et al. (2005), Matthys and Heger (2007a), Romberg (2004d) and Matthys and Funk (2008) carried out randomised, double-blind, placebo-controlled studies to evaluate the efficacy and safety of EPs® 7630 (30 drops three times daily) compared to placebo, in patients with acute bronchitis. The trials were performed according to a similar design. Patients, who met the following criteria, were suitable for the trial: age >18 years, acute bronchitis, duration of complaints

(≤48 hours) and Bronchitis Severity Score (BSS) ≥5 points (except Romberg, 2004d, where patients were aged 18-60 years and suffered from acute bronchitis with productive cough since ≤72 hours, BSS≥8 points). The main exclusion criteria were an indication for antibiotic treatment or treatment with antibiotics during the period of 4-weeks prior to enrolment in the trial, allergic bronchial asthma, tendency to bleed, severe heart, renal or liver disease, immunosuppression, known or supposed hypersensitivity to trial medication. Following enrolment (day 0), control examinations occurred on day 3-5 and day 7 (in case of Romberg, 2004d on day 14 was the final assessment).

The primary outcome criterion was the change of BSS on day 7. BSS scores comprise the most important features of acute bronchitis, namely, cough, sputum, rales/rhonchi, chest pain during

coughing and dyspnoea. Each symptom was assessed by the investigator using a verbal five-point rating scale ranging from zero to four. The secondary outcome criteria were variable; the main ones were disappearance or improvement of individual symptoms (fever, fatigue, pain in limbs, headache and hoarseness), duration of illness, days-off work and satisfaction with treatment. Some studies measured patients’ health status using health-related quality of life questionnaires. Safety outcome criteria were the number, type and severity of adverse events (AEs) and tolerability, based on a verbal and laboratory tests.

Figure 4. Bronchitis-symptoms score (BSS) at different visits for two treatment groups (mean ± 95% confidence interval) (Matthys and Heger, 2007a)

The main results are summarised in Table 4. In each study the decrease of BSS was significantly higher in patients treated with EPs® 7630 compared to patients treated with placebo (Figure 4). The meta-analysis of these treatments also showed a significant decrease of BSS score compared to placebo (Agbabiaka et al. 2008). All individual symptoms recovery and/or improvement rates were higher in the EPs® 7630-treated group compared to placebo group. Remission by day 4 occurred in 69% of the patients under active substance treatment, compared to 33% of patients under placebo (Chuchalin et al. 2005). Treatment with EPs® 7630 shortened the duration of working inability for nearly 2 days. Complete recovery by day 7 was observed by the physician in 45.4% of patients taking active treatment compared to 6.4% of patients on placebo (Matthys and Heger, 2007a). Health-related quality of life improved more in patients treated with EPs® 7630 compared to placebo-treated patients. EPs® 7630 was well-tolerated, mild to moderate advers events were observed in all trials, but there were no significant differences in the number of advers events reported between two treatment groups (Matthys and Heger, 2007a). Some of advers events reported included gastrointestinal disorders, nervous system disorders (nervousness, fatigue, headache and restlessness), ear and labyrinth disorders (Matthys et al. 2003).

Table 4. Placebo-controlled clinical studies with EPs® 7630 – treatment of acute bronchitis

Abbreviations: DB=double-blind, PC=placebo-controlled, R=randomised, MC= multicentre, * studies included in Cochrane Meta-analysis # studies excluded in Cochrane Database (Timmer et al. 2009)

Matthys et al. (2007) designed a multicentre, prospective, open observational study. A total of 2099 patients aged 0-93 years old with productive cough for less than six days without indication for treatment with antibiotics were given EPs® 7630 in age-dependent dosage (the results of treatment of children, see section 4.2.3.). Adults and children >12 years (n=1731) were instructed to take 30 drops of EPs® 7630 three times daily over a period of 14 days. At baseline the mean value of BSS of all patients was 7.1±2.9 points. At the third follow-up the mean value was 1.0±1.9 points (Figure 5, Table 5). According to the response criterion that was defined as the decrease of BSS with at least five points from baseline to the third follow-up, the responder rate was 68%. The remission rate at the last observation for five bronchitis-specific symptoms was above 80% each, except for cough, which showed a remission rate of 59.7% (Figure 5). The investigators documented complete recovery for 1458/2099 patients at the last visit. A total of 28 adverse events occurred, but none of them was serious or significant. 11/28 advers events were classified as “gastrointestinal disorders”.

Figure 5. BSS changes during the study period in all patients and remission rates from baseline to last observation for bronchitis-specific symptoms in all patients (Matthys et al. 2007)

The efficacy of EPs® 7630 was investigated in a prospective, open, multicentre study with 205 patients suffering from acute bronchitis (87.8%) or acute exacerbation of chronic bronchitis. The main outcome measure was the change in the total score of five symptoms (cough, expectoration, wheezing, chest pain during coughing and dyspnoea) typical for bronchitis, which were each rated using a 5-point scale. The mean total score of these symptoms was 6.1±2.8 points at baseline; at the final examination on day 7 this was 2.8±2.6 points (Table 5.). The remission rate of individual symptoms was over 70%. Seventy eight per cent of the patients were satisfied with the treatment at the final visit. Eighteen adverse events were documented; eleven cases were advers events involving the gastrointestinal tract. A serious adverse event was not reported. The disadvantage of this study is that 48.8% of the patients reported the use of other therapy measures (inhalation of chamomile or saline solution, antitussive, mucolytic agent, nasal douches) in addition to taking EPs® 7630 (Matthys and Heger, 2007b).

Table 5. Open clinical studies with EPs® 7630 – treatment of acute bronchitis

Abbreviations: MC= multicentre, P=prospective, OO=open observational, # studies excluded in Cochrane Meta- analysis (Timmer et al. 2009)

Acute sinusitis

A multicentre, prospective, open study investigated the efficacy and change in symptoms in

361 patients (aged 1-94 years) with acute sinusitis and acute exacerbation of chronic sinusitis under administration of EPs® 7630. Adult patients suffering from acute sinusitis received 30 drops every hour up to 12 times on day 1 and 2 and 3 x 30 drops daily on day 3-28. Children under 12 years of age were suggested to take 20 drops every hour up to 12 times on day 1 and 2 and 3 x 20 drops daily on day 3-28. Patients with exacerbation of chronic sinusitis received prophylactic therapy: 2 x 30 drops for adults or 2 x 20 drops for children for another 8 weeks (long term treatment). Following the entrance examination, patients were examined after 7, 14 and 28 days; patients under the long term treatment on day 56 and day 84. A total of 33.5% of patients used co-medication, such as expectorants and antitussive remedies. The primary outcome criteria was the sum of objective and subjective symptoms of the sinusitis score from day 0 to the end of the treatment according to a five- point verbal rating scale. The mean total score of symptoms was 15.2±4.6 points at baseline; at the final examination on day 28 this was 2.4±3.2 points (Table 6.). On the last day of treatment within 4 weeks 80.9% of the patients became symptom-free or experienced a clear improvement in their symptoms. A total of 56 out of 361 patients (15.5%) reported adverse events (mostly gastrointestinal complaints) during the trial. In 17 cases, the causal relationship with the study medication could not be ruled out (Schapowal and Heger, 2007).

Bachert et al. (2009) investigated the efficacy and safety of EPs® in case of rhinosinusitis in a multicentre, randomised, double-blind, placebo-controlled trial. Patients with an age ranging from 18-60 years with radiographically confirmed acute rhinosinusitis and a Sinusitis Severity Score (SSS) of 12 points or greater were eligible. The SSS was calculated as the sum of the 6 symptoms scores (headache, maxillary pain, maxillary pain worsening on bending forward percussion or pressure, nasal obstruction, purulent nasal secretion, purulent nasal discharge visualised in the middle meatus or purulent postnasal discharge) as assessed on a 5 point verbal rating scale ranging from 0-4. Patients were instructed to take 60 drops EPs® 7630 three times daily. Study medication was taken for maximal period of 22 days. The primary outcome measure was defined as the change of the SSS at day 7 of treatment compared to baseline. The main secondary outcome criteria were responses defined as an SSS< 10 points on day 7, a reduction of at least 4 points on day 7, occurrence of complete remission (SSS=0 on day 21) and treatment outcome assessed by the patients and the investigators. The mean decrease in the primary outcome was 5.5 points in the EPs® 7630 and 2.5 points in the placebo group, resulting in a between group difference of 3.3 points (p<0.00001). This result was confirmed by all secondary parameters indicating a more favorable course of disease and a faster recovery in the EPs® 7630 group. A total of 8/103 patients reported at least one adverse event during the trial, 6/51 in the EPs® 7630 group and 2/52 in the placebo group. All adverse events were assessed as non-serious. In four cases (gastrointestinal complaints-3 x, allergic skin reaction-1x) that occurred in the EPs® 7630 group, the causal relationship with the study drug could not be excluded (Bachert et al. 2009).

In a multi-centre, prospective, randomised, placebo-controlled study 272 patients suffering from acute maxillary sinusitis confirmed by radiography were enrolled. Onehundred and thirtysix patients were treated with 3 x 60 drops daily, 136 received placebo for 21 days. Primary outcome criterion was the change of SS (sinusitis-specific symptoms) on day 7. The mean change of SS was -7.0±3.2 in the EPs® 7630 group and 0.0±2.3 points in the placebo group. Beside the significant efficacy, the incidence of adverse events was comparable to placebo in the actively treated group (Romberg, 2004e).

Common cold

Lizogub et al. (2007) evaluated the efficacy and tolerability of EPs® 7630 compared to placebo in adult patients with common cold. One hundred and three patients with at least two major (nasal discharge,

sore throat) and one minor (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headache, muscle aches and fever) or with one major and three minor cold symptoms present for

24 to 48 hours were randomised to receive either 30 drops of EPs® 7630 or placebo three times daily. The study had a high-dose arm (3 x 60 drops of EPs® 7630 compared to placebo), but the results of high-dose treatment were not reported in the manuscript. The main exclusion criteria were the presence of any other ear, nose, throat and respiratory disease than common cold, positive rapid test for group A beta-hemolytic streptococcus and treatment with other medicines (e.g. antibiotics, decongestants, cough relief medications) that might impair the trial results.

The primary outcome criteria was the sum of symptom intensity differences (SSID) of the cold intensity score (CIS) from day one to five according to a five-point verbal rating scale. The main secondary outcome criteria were changes of individual symptoms of the CIS, changes of further cold- relevant symptoms, ability to work and satisfaction with treatment. From baseline to day five, the mean SSID improved by 14.6 points in EPs® 7630 treated group compared with 7.6 points in the placebo group (p<0.0001) (Table 6.). After 10 days, 63.5% versus 11.8% in the EPs® 7630 versus placebo group were clinically cured (CIS=0). The main duration of inability to work was significantly lower in the EPs® 7630 treated patients (6.9 days) than in the placebo group (8.2 days). The treatment outcome was assessed as better in the EPs® 7630 group than in the placebo group by both the investigator and the patients on day five.

Three of 103 patients experienced adverse events: two of 52 patients (3.8%) in the EPs® 7630 and one of 51 patients (2%) in the placebo group. None of these events were classified as serious. A causal relationship to the study drug could not be excluded in one treated patient (mild epistaxis).

Table 6. Clinical studies with EPs® 7630 – treatment of acute sinusitis and common cold

Abbreviations: DB=double-blind, PC=placebo-controlled, R=randomised, MC= multicentre, O=open,

*studies included in Cochrane Database

#studies excluded in Cochrane Meta-Analysis (Timmer et al. 2009)

A review article presented a multicentre post-marketing surveillance study, which was carried out in 641 patients with respiratory tract infections e.g. tonsillitis, rhinopharyngitis, sinusitis and bronchitis. Outcome criteria were the change in the subjective and objective symptoms during the treatment of EPs® 7630 and an assessment of treatment outcome by both physicians and patients on a 4-point rating scale. After 2 weeks of therapy, a total of 85% of the patients showed complete recovery or major improvement. No adverse reaction was observed (Kolodziej, 2002).

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

Dose-finding study

Kamin et al. (2010a) carried out a double-blind, placebo-controlled dose-finding study for EPs® 7630 performed in children and adolescents (Kamin et al. 2010a; Malek, 2007b). A total of 399 patients (aged 6–18 years) were randomised to receive either 30 mg, 60 mg or 90 mg EPs® 7630 film-coated tablets or placebo daily. Patients suffering from acute bronchitis with symptoms starting <48 h prior to inclusion in the study and with a total score of bronchitis-specific symptoms (BSS) >5 points at screening were included in the study. Individual duration of the study was 7 days. During this time, 3 visits were scheduled (day 0; days 3–5; day 7). The primary efficacy endpoint was the change in the BSS total score from day 0 to day 7 rated by the investigator. The main secondary outcome measurements were treatment response according to three criteria, change of individual symptoms of total score, change of general symptoms and satisfaction with the treatment.

The decrease in the BSS total score between day 0 and day 7 was more pronounced in the active treatment groups compared with that in the placebo group (Table 7). The subsequent pairwise comparisons of each active treatment group with placebo using the ANCOVA model revealed statistically significant differences in the decrease in the BSS total score for the EPs® 7630 60 mg and 90 mg groups (p = 0.0004 and p < 0.0001, respectively).

The treatment response calculated on the basis of the BSS total scores was higher in the active treatment groups than in the placebo group (Figure 6). Statistically, significant differences regarding criterion 1 were determined for the 60 mg and 90 mg EPs® 7630 groups in comparison with placebo. Regarding criteria 2 and 3, a significant difference in the rate of responders compared with placebo was observed for the 90 mg EPs® 7630 group. The mean decrease in the individual symptoms from day 0 to day 7 was markedly more pronounced in the EPs® 7630 (60 mg) and EPs® 7630 (90 mg) groups than in the placebo group. Pairwise comparisons with placebo showed statistically significant advantages of EPs® 7630 in the 60 mg and 90 mg group for the symptoms.

A total of 80 adverse events were observed in 77 of 400 patients (19.3%). The most frequent adverse events were gastrointestinal disorders (11%). With 22.8% (in EPs® 7630 30 mg group), 17.2% (in EPs® 7630 60 mg group) and 19.2% (in EPs® 7630 90 mg group) respectively, the frequency of adverse events in the active treatment groups was similar to that in the placebo group (17.8%). None of the adverse events was classified as serious.

The authors concluded that based on the efficacy and safety results, a daily dose of 60 mg EPs® 7630 could represent the optimal dose with respect to the benefit/risk ratio (Kamin et al. 2010a).

The treatment groups with 60 mg and 90 mg doses of EPs® 7630 showed a significantly higher IMOS outcome scale than placebo in the assessment of the investigator (completely recovered 12.9% vs.

21.2-24.2%, major improvement 31.7% vs. 52.5-57.6%) and patient investigator (completely recovered 14.9% vs. 25.3-28.3%, major improvement 30.7% vs. 48.5-54.5%) (Malek, 2007b).

A subgroup analysis of the Kamin et al. (2010a) study confirmed that the analysis of the total population could also be consistently demonstrated in patients of at least 13 years of age (Tribanek and Buschulte, 2008c).

Figure 6. Treatment response. Frequency of responders for 3 criteria: criterion 1: BSS total score < 3 points at day 7;

criterion 2: decrease in BSS total score of at least 7 points from day 0 to day 7; criterion 3: combination of criteria 1 and 2

Clinical studies

Acute bronchitis

Blochin et al. (1999) examined the efficacy and tolerability of Pelargonium extract in comparison to acetylcystein for children with acute bronchitis in a multicentre, randomized, controlled open trial. Sixty children aged between 6-12 years were randomised into two groups to receive either Pelargonium extract (20 drops every hours up to 12 times on day 1 and 2; 20 drops daily on day 3-7) or acetylcystein granules (2 x 200 mg daily for 7 days). 100 g of Pelargonium solution contained 80 g of ethanolic extract (1+10) from the roots of P. sidoides/reniforme.

The overall scores of bronchitic symptoms of participations were not less than 5 points and onset of complaints was within the last 48 hours. The main exclusion criteria were compulsory indication for antibiotic therapy, asthma bronchiale, heart, kidney, liver diseases, immunosuppression and hypersensitivity to study medication.

Outcome measures were changes in typical symptoms of bronchitis. These symptoms were assessed on the basis of a 5-rating scale. General symptoms, questions around the general state of health and therapeutic tolerability were also evaluated. After 7 days, the overall score of bronchitic symptoms decreased by 7±2 points in the Pelargonium group and 6±3 in acetylcystein group (p=0.285). There were no statistically significant differences between the two groups in relation to reduction of bronchitis-specific symptoms. The full remission of all bronchitic symptoms was 76.7% in the Pelargonium group and 56.7% in the acetylcystein group (p=0.17) (Table 7). Adverse events were not

found. Both the trial physicians and the patients rated the tolerability as very good or good in all cases (Blochin et al. 1999).

In a multicentre, randomised, double-dummy study the efficacy and safety of EPs® 7630 was compared to acetylcysteine in the treatment of children with acute bronchitis. 104 patients were enrolled in the EPs® 7630 group and 109 in the placebo group. All patients were aged between 6 and 12 and had acute bronchitis with BSS ≥5 points. Patients were treated either with 3 x 20 drops EPs® 7630 or 200 mg acetylcysteine granules, 2 times daily, solved in water. The primary outcome

criterion was the change in BSS. After 7 days treatment, the mean change of BSS was -6.7±2.1 in the EPs® 7630 group and -6.6±2.3 in the acetylcysteine group, showing a significant non-inferiority of EPs® 7630 compared to acetylcysteine. The number of patients experiencing adverse events was lower in the EPs® 7630 group (4.8%) as compared to the acetylcysteine group (9.2%). No serious adverse events were reported (Romberg, 2004b).

Haidvogl et al. (Haidvogl and Heger, 2007) (Haidvogl et al. 1996) described an open, uncontrolled study which 742 children (aged between 0-12 years) with acute bronchitis or acute exacerbation of chronic bronchitis were treated with EPs® 7630 (children up to 2 years: 3 x 5 drops, 2-6 years: 3 x 10 drops, over 6 years: 3 x 20 drops), for a mean period of 14 days. The exclusion criteria included antibiotic treatment in the pre-phase, liver disease and blood coagulation disorders. Five bronchitic specific symptoms (BSS) were summed up to give an overall measure of disease severity. Non-specific disease symptoms (loss of appetite, headache, vomiting and fever) were also recorded, together with adverse events. Concomitant medication for a part of patients (48.2%) was antitussive and broncholytic agents. The overall BSS score decreased during the treatment from 6.0±3.0 points at baseline to 2.7±2.5 points after 1 week and to 1.4±2.1 points at the end of the study. According to overall BSS score, complete or partial remission of bronchitis was achieved in 90.2% of children. The non-specific symptoms also improved substantially. During the course of study, 13 adverse events were documented. In 8 cases, a causal relationship to the test medication was not excluded (exanthema, psychomotor unrest with crying fits, dyspnoe and diarrhoea). In a total of 5 of these patients, the test medication was discontinued.

Matthys et al. (2007) examined the efficacy and safety of treatment with EPs® 7630 in patient (aged 0-93 years) with acute bronchitis in an open observational trial. Four hundred and twenty patients were between 3-18 years of age and 78 patients were under 3 years of age. The dosage of EPs® 7630 was adapted to age as follows: >12 years: 3 x 30 drops daily, 6-12 years: 3 x 20 drops/day and <6 years: 3 x 10 drops. In the subgroup of children, the decrease of BSS was 3.3±2.6 points, 1.6±1.9 points and 0.9±1.8 points at the first, second and third follow-up, respectively (Figure 7).

Figure 7. BSS changes during the study period in children and infants. (Matthys et al. 2007)

Thirteen out of 420 adverse events occurred in children and 3 out of 78 in infants. Severe adverse events were documented in the subgroup of children and were coded in the organ class “infections and infestations”, but none was assessed as related to study medication. In one child the relation to medication of a hypersensitivity reaction was assessed as possible.

Two randomised, double-blind, placebo-controlled studies were carried out to evaluate the efficacy of EPs® 7630 compared to placebo in children (1 to 18 years old) with acute bronchitis. Patients (study 1: n=200, study 2 n=220), who met the following criteria, were suitable for the trial: acute bronchitis, duration of complaints (≤48 hours) and Bronchitis Severity Score (BSS) ≥5 points. Children between

1-6 years were given 3 x 10 drops/day, children between 6-12 years were given 3 x 20 drops daily and children over 12 years were given 3 x 30 drops/day. The primary efficacy parameter was the change in the total score of the five bronchitis specific symptoms (BSS) – assessed by the physicians by the use of a five point verbal rating test. The mean decrease of BSS was 3.4 (study 1), 4.4 (study 2) points in the EPs® 7630 and 1.2 (study 1), 2.9 (study 2) points in the placebo group, resulting in a significant difference between treatment and placebo group (p<0.0001). Adverse events were observed in 31/103 in the EPs® 7630 group and 24/97 in the placebo group (study 1). A causal relationship to the study drug could not be excluded in six treated patients (5: gastrointestinal problems and 1: allergic skin reaction). In case of study 2, a total of 2 out of 220 patients reported adverse events during the trial (Schulz, 2008b). The subgroup analyses of Study 1 and Study 2 confirmed the positive effects of

EPs® 7630 in patients below 7, between 7-12 and above 12 years (Tribanek and Buschulte, 2008a; Tribanek and Buschulte, 2008b). In study 2, the EPs® 7630 treatment group showed a significantly better IMOS (Integrative Medicine Outcome Scale) than placebo in the assessment of the investigator and patient. On day 7, in the investigator’s assessment 47.7% of the patients were completely recovered, whilst in the placebo group 11%. In the treated group in 38.7% of the patients major improvement was documented, in the placebo group in 27.5% of the patients. The rate of patients in the EPs® 7630 group reporting the onset of effect between day 1 and 4 was significantly higher in the treated group than in the placebo group (Malek, 2007d).

Kamin et al. (2010b) demonstrated the efficacy of EPs® 7630 in the treatment of patients (1-18 years) with acute bronchitis outside the strict indication for antibiotics. A total of 200 patients were randomised to receive either EPs® 7630 (1-6 years: 3 x 10 drops, 6-12 years: 3 x 20 drops, 12-

18 years: 3 x 30 drops, daily) or placebo for 7 consecutive days. Primary outcome measure was the change in the total score of BSS from day 0 to day 7. Main secondary outcome criteria were treatment outcome, satisfaction with treatment and bed rest. From baseline to day 7, the mean BSS score improved significantly more for EPs® 7630 compared to placebo (3.4±1.8 vs. 1.2±1.8 points, p<0.0001). On day 7, the treatment outcome was significantly better, the satisfaction with treatment was more pronounced and the time of bed rest was shorter as compared to placebo (Kamin et al. 2010b; Malek, 2007a). The EPs® 7630 treatment group showed a significantly better IMOS outcome scale than placebo in the assessment of investigators (completely recovered 21.4% vs.2.1%, major improvement 58.6% vs.17.5%) and patients (completely recovered 23.3% vs. 4.1%, major improvement 58.6% vs.15.5%) (Malek, 2007a).

Kolodziej (2002) presented three clinical trials, which investigated the efficacy of treatment with Pelargonium extract in children suffering from acute bronchitis, angina catarrhalis and acute tonsillitis. One thousand and forty two children with acute bronchitis (up to 12 years) were treated with Pelargonium extract. This prospective, multicentre observational study concluded that the remission or improvement rate of all individual symptoms (cough, expectoration, difficulty in breathing, wheezing and chest pain) was over 80%.

In a prospective, randomised, controlled trial involving 60 children between 6 and 10 years with angina catarrhalis, the response rate after 4 days of treatment with Pelargonium extract was 76% compared to that of 30% with symptomatic treatment.

In randomised, double-blind, placebo-controlled trial, 78 children with acute tonsillitis were treated with Pelargonium extract or placebo for 6 days. The primary outcome criterion was the response rate defined as total score of tonsillitis specific symptoms <4 points at day 4. The response rates were 90.0% in the treated group and 44.7% in the placebo group (p<0.0001). The mean decrease of total score was 6.8±2.8 points in the Pelargonium group and 3.7±3.3 points in the placebo group (p<0.0001). Tolerability was rated as good or very good by 97.5% of patients treated with

Pelargonium extract.

Haidvogl and Heger (2007) referred an uncontrolled observational study carried out by Dome and Schuster. The efficacy of EPs® 7630 treatment (5-20 x 3 drops daily) of acute bronchitis or acute exacerbation of chronic bronchitis in 259 children with the preparation from Pelargonium roots was examined in 53 paediatric practices. The BSS decreased from 6.0±2.9 points to 2.3±2.8 points within 2 weeks. Remission or improvement rates of the individual symptoms were more than 80%. In 96.5% of the cases, physicians assessed tolerability of the treatment as very good or good. Only a few mild- and short-termed adverse events were recorded (Dome and Schuster, 1996).

Tonsillopharyngitis

In a multicentre, prospective, randomised, double-blind, placebo-controlled trial, the efficacy and safety of EPs® 7630 (3 x 20 drops daily) was examined and compared to placebo in 143 children aged 6-10 years suffering from acute non-streptococci-induced tonsillopharyngitis. The maximum duration of the complaints was 48 hours and the minimum degree of Tonsillopharyngitis Severity Score (TSS) was 8 points. The tonsillitis-specific symptoms (dysphagia, sore throat, salivation, rubor and fever) were rated using 4-point scale. Following the entrance examination patients were examined after 2, 4 and 6 days and the clinical findings recorded. Patients with a fever >38.5°C were allowed to be given paracetamol suppositories as additional medication. The most frequent premature withdrawal in EPs® 7630 group was lack of compliance (2/4), and the lack of efficacy in the placebo group (29/44).

The primary target criterion for assessing of the efficacy of EPs® 7630 was the decrease of TSS from baseline to day 4. The main secondary outcome criteria included change of individual symptoms and further complaints, treatment outcome according to the Integrative Medicine Outcome Scale. The decrease of the TSS to day 4 was 7.1±2.1 points under EPs® 7630 and 2.5±3.6 points under placebo (p<0.001) (Figure 8, Table 7). The remission rates of the individual symptoms dysphagia, fever and salivation on day 4 under EPs® 7630 and placebo were at 60-79% and 47-27%, respectively, followed by sore throat with 32 and 16% and rubor with 6 and 1%. When assessing the therapeutic success, the trial physicians on day 4 observed freedom of complaints or a significant improvement in symptoms in 65/73 (89%) patients under EPs® 7630, as compared to the placebo group where 12/70 (17.1%) patients were free of complaints or showed significantly improved symptoms. Moreover, children in the EPs® 7630 group received paracetamol less frequently and over a significantly shorter time than children in the placebo group (1.6±0.9 g vs. 2.0±1.2 g paracetamol). The authors concluded that treatment with EPs® 7630 reduced not only the severity of symptoms, but also shortened the duration of illness by at least 2 days (bed rest on day 4: 15.1% vs. 62.9%).

Adverse events were observed in 1/73 in the EPs® 7630 group and 14/70 in the placebo group, but all events represented typical symptoms of the acute infection. None of the cases was correlated with the test medication (Heger and Bereznoy, 2002; Bereznoy et al. 2003; Neidig, 2002c).

Tonsillopharyngitis symptoms scale

Placebo

EPs® 7630

Figure 8. Decrease of the Tonsillopharyngitis Severity Score in the course of a 6-day therapy (Heger and Bereznoy, 2002) (Bereznoy et al. 2003)

Acute angina catarrhalis

In a multicentre, prospective, randomised, placebo-controlled study patients aged 6-10 years with acute angina catarrhalis were recruited. 60 patients were treated with EPs® 7630 (3 x 20 drops daily), 64 with placebo. The primary variable for assessing efficacy was the change from baseline of the total score of angina-specific symptoms (five symptoms, including difficulty in swallowing, sore throat, salivation, erythema, fever) on day 4. In the EPs® 7630 group the angina-specific score decreased with 6.7±2.8 compared to the mean decrease of 3.8±4.2 in the placebo group which confirmed the efficacy of the active treatment over placebo. Also, higher efficacy of EPs® 7630 in comparison with placebo was observed taking into account the single angina-specific symptoms. 49 out of 60 patients were symptom-free or experienced a strong improvement of their symptoms after EPs® 7630 therapy. In contrast, this proportion was only 19 out of 64 in the placebo group (Neidig, 2002b).

Table 7. Clinical studies with Pelargonium extract– children

Abbreviations: DB=double-blind, PC=placebo-controlled, R=randomised, MC= multicentre, O= open, C= controlled, UC= uncontrolled, DD=double-dummy

4.3. Overall conclusions on clinical pharmacology and efficacy

This assessment report presents seven clinical studies (including one dose-finding trial) (Schulz, 2008a; Matthys et al. 2003; Chuchalin et al. 2005; Matthys and Heger, 2007a; Matthys et al. 2007); Matthys and Heger, 2007b; Romberg, 2004d), which examined the efficacy and safety of Pelargonium sidoides extract in adult patients with acute bronchitis. Children with acute bronchitis were treated with Pelargonium extract in seven clinical trials (Kamin et al. 2010a; Blochin et al. 1999; Haidvogl and Heger, 2007; Matthys et al. 2007; Schulz, 2008b; Romberg 2004b; Kamin et al. 2010b). All clinical studies concluded the effectiveness of Pelargonium preparation in treating acute bronchitis. Overall nine studies were randomised, double-blind (double-dummy) and placebo-controlled. Although the results of open studies are also promising, the lack of true control group, blinding and randomisation limits the usefulness of these trials.

The majority of trials used uniform posology in adults, but there is heterogeneity in case of children regarding the dosage. Some trials offered to take 20 drops of liquid preparation every hour up to

12 times on first and second day of treatment, but no information was given on the true frequency of administration. In case of some trials the concomitant medication prevents the objective evaluation of effectiveness of Pelargonium extract.

On the other hand, the definition of ‘acute bronchitis’ is still under discussion in the medical society and debatable and the diagnosis is solely based on clinical findings without standardised diagnostic signs and sensitive or specific confirmatory laboratory tests. As a result of the current lack of standardised criteria, all outcomes applied in trials are subjective. The BSS score is not validated, but appears to be associated with a clinical benefit (Kamin et al. 2010a). However, there are validated scores to assess the efficacy in similar conditions (Mwachari et al. 2007). The Cochrane review on Pelargonium sidoides also drew attention that the studies used non-validated symptom scores as a primary endpoint and none of the trials were designed to examine time to complete symptom recovery based on a predefined clinically relevant difference. In spite of the shortcomings, the Cochrane review concluded that the herbal preparation may be effective in relieving symptoms in acute bronchitis in adults and children (Timmer et al. 2009), but more well-designed, placebo controlled trials with endpoints such as time to complete recovery, lost days of work, and use of antibiotics are recommended. In conclusion, this indication cannot be accepted at well-established use level because the studies did not use a reliable and very important endpoint such as the use of antibiotics instead a non-validated score which is not considered a reliable instrument to evaluate the efficacy of Pelargonium.

The evaluation of the effects of the drug in adult patients with acute sinusitis was based on three trials (Schapowal and Heger, 2007; Bachert et al. 2009; Romberg, 2004e). These studies showed significant treatment effects for the alleviation of symptoms. Considering the small sample size and the lack of control in case of one study, more trials using validated instruments are needed in order to allow a firm conclusion to be drawn on the use of Pelargonium extract in the treatment of acute sinusitis.

There was a single study on treatment of the common cold in adults (Lizogub et al. 2007). In the critical evaluation of this study, the reviewers concluded that the preparation from Pelargonium was effective in reducing symptoms associated with common cold, but the presentation of a high-dose arm of the trial would have given more confidence in the findings (Patrick and Hickner, 2008). The replication of these results may support the well-established use of Pelargonium extract in the treatment of common cold.

5. Clinical Safety/Pharmacovigilance

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

The safety of clinical trials was assessed with respect to the adverse events and the results of laboratory test. In placebo-controlled clinical studies there was no significant difference in the severity and frequency of adverse events between active treatment group and placebo group. However, the adverse events were almost always described as mild to moderate. Severe allergic reaction also occurred (see 5.3).

One clinical trial was conducted to assess the safety and tolerability of long-term administration of EPs® 7630 in 2 different dosages over 6 weeks compared to placebo in healthy volunteers (18-

55 years). The study was performed as a prospective, randomised, double-blind, placebo-controlled, monocenter clinical trial in a parallel group design with 24 subjects per treatment group. The trial consisted of a screening with pre-trial examinations prior to enrolment followed by a 6 weeks double- blind treatment period. The subjects were randomly assigned to one of three treatment groups. Group I (24 subjects) received EPs® 7630, 3 x 30 drops, group II (24 subjects) EPs® 7630, 3 x 60 drops, Group IIIa (12 subjects) placebo, 3 x 30 drops, group IIIb (12 subjects) placebo, 3 x 60 drops. The mean duration of treatment was 41.5±2.8 days.

The number of advers events in the EPs® 7630 high dose group (33 advers events in 18 out of 24 subjects (75%)) was slightly higher than in the EPs® 7630 low dose group (31 advers events in 15 out of 24 subjects (62.5%)) and the placebo group (28 advers events in 13 out of 24 subjects (54.2%)). Most of the advers events [29 out of 33 (87.9%) in the EPs® 7630 high dose group, 30 out of 31 (96.8%) in the EPs® 7630 low dose group and 24 out of 28 (85.7%) in the placebo group] were assessed as “not related” to the trial medication. For 9 out of 92 (9.8%) advers events [4 out of 33 (12.3%) in the EPs® 7630 high dose group, 1 out of 31 (3.2%) in the EPs® 7630 low dose group and 4 out of 28 (14.3%) in the placebo group] a causal relationship with the investigational medication could not be excluded. Most of the advers events were of mild or moderate intensity. One patient in the EPs® 7630 high dose group and three subjects in the EPs® 7630 low dose group experienced advers events of severe intensity; all of them were considered as “not related” to the investigational medication. There were no serious adverse events during the course of the study. Mean values of laboratory parameters (haematology, chemistry and coagulation parameters), urinanalyis, vital signs and ECG did not show any relevant change throughout the trial (Zind et al. 2011).

5.2. Patient exposure

The clinical trials referred in assessment report were conducted on over 3500 adult patients and approximately 3,000 children suffering from acute bronchitis. Four hundred sixty four adults with acute sinusitis, 103 patients (>18 years) with common cold and 143 children with tonsillopharyngitis were exposed to Pelargonium sidoides treatment.

5.3. Adverse events and serious adverse events and deaths

There is a large number of studies and the section 4.2 and Table 3-7 contain a detailed presentation of adverse events observed during clinical trials. In these studies on the treatment of respiratory infections with an extract of P. sidoides the adverse events were assessed as being non-serious or minor or transitory. In a review article about the treatment of acute bronchitis with Pelargonium extract, the most frequent adverse events were light gastrointestinal complaints (diarrhoea, epigastric discomfort, nausea or vomiting, dysphagia). These gastrointestinal problems, which were usually

harmless and disappeared spontaneously, could be associated with the tannins contained in Pelargonium preparation (Conrad and Schulz, 2007).

Conrad et al. (2007c) summarised the adverse events for the period from 1990 until 2003. In this period, 109 million defined daily doses (DDD) of EPs® 7630 were marketed. In that time, 73 adverse events occurred spontaneously and 79 were reported in clinical trials, most of these 79 were rated as not being related to EPs® 7630. In 1 million DDD there were 0.67 spontaneous reports which in a treatment cycle of ten days maximum corresponding to 1 report in 100.000 patients. Overall, only seven critical adverse events were reported between 1994 and 2003, and in all cases the causal relationship with EPs® 7630 was uncertain. EPs® 7630 is marketed as medicinal product in the European Union and therefore it is bound to a pharmacovigilance system.

The safety profile of EPs® 7630 has been systematically reviewed based upon 25 clinical trials and post-marketing surveillance studies with 9,218 patients suffering from acute or chronic respiratory tract infections such as bronchitis, tonsillopharyngitis, broncitis or sinusitis and from 31 healthy subjects. EPs® 7630 was well tolerated and no serious adverse drug reactions were reported. Comparing EPs® 7630 and placebo, adverse events were similar with regard to quality and quantity throughout almost all organ systems and symptoms, the only difference being a slightly higher incidence of gastrointestinal disorders (epigastric pain, nausea, diarrhoea) and of hypersensitivity reactions (mostly skin reactions), as well as gingival bleeding and epistaxis associated with EPs® 7630 compared to placebo (Matthys and Köhler, 2010).

The Uppsala Monitoring Centre, in conjunction with the international pharmacovigilance program of the World Health Organisation, received 34 case reports between 2002 and 2006 of allergic reactions to the ethanolic extract of Pelargonium root, all originating from Germany. In ten reports, concomitant use of other drugs was noted, but none of the concomitantly administered medication was recorded as being co-suspect. In 15 of the 34 reports, the description and timing of the event, notably the combination of a skin rash with itching, urticaria, angioedema and/or systematic involvement (e.g. dyspnoe, bronchospasm, diarrhoea, tachycardia or circulatory failure) were suggestive of a Coombs and Gell Type I acute hypersensitivity reaction. Two patients needed treatment for circulatory failure or anaphylactic shock, however, insufficient information was provided to determine if they had experienced an anaphylactic shock. Further details of these two cases are provided as below:

Case report 1, concerning a 20-year-old woman, was reported by a dermatologist. After taking Pelargonium extract for the common cold the patient experienced life-threatening acute urticaria and circulatory failure, requiring emergency medical attention. The reaction subsided within 4 hours of initiation of corticosteroid and antihistamine treatment. The patient had not received any other drugs and a positive skin-pick test confirmed the causal involvement of Pelargonium extract.

Case report 2 was submitted by a pharmacist to the Medicines Committee of the German Pharmaceutical Association. The patient was a 71-year-old man who, within a day after first taking Pelargonium extract, experienced dyspnoea and swelling of the lips and tongue, necessitating hospital treatment (de Boer et al. 2007; Patrick and Hickner, 2008).

Coumarins belong to the typical compounds of Pelargonium extract. They have been under scrutiny regarding the increased risk of bleeding and a possible impact on concomitant treatment with coumarin-type anticoagulants. To date, no case has been recorded in all the clinical trials that definitely proved any increased bleeding tendency that could be attributed to the treatment with Pelargonium extract (Kolodziej, 2008) (see below). One in vivo experiment affirmed this hypothesis. None of the coumarin compounds so far identified in the preparation from Pelargonium roots used in this in vivo experiment meets the criteria of minimal structural requirements for anticoagulant characteristics in coumarins, which would correspond to a hydroxy group in position 4 and a non-polar rest in position 3. Indeed, no anticoagulant effects were observed in this study. In addition, it could be

demonstrated that comedication has no effect on the pharmacokinetics of warfarin (Koch and Biber, 2007).

According to the Cochrane Review, the available data from clinical trials with short-term therapies and results from uncontrolled post-marketing studies did not show an elevated risk of serious adverse events (Timmer et al. 2009).

According to a pharmacovigilance report from Italy, a patient suffering from congenital cardiac malformation, bronchial pneumonia, epilepsy, hypothyroidism, oligophrenia was taking a number of medicines, among them a Pelargonium product, and was diagnosed with acute hepatopathy. Although there was a positive dechallenge, taking into account the comorbidities and polymedication in case of this patient, a cause-effect relationship with Pelargonium could not be established. This case can only be considered as a signal. It is suggested that in case there is a hepatic disorder in the anamnesis, preparations containing no alcohol should be preferred.

A case of primarily assumed liver injury in connection with the use of Pelargonium has been reported by the Drug Commission of the German Medical Association (DCGMA) and it was assumed that other cases of liver disease might be attributable to the treatment. Therefore, reports of spontaneous cases of purported Pelargonium hepatotoxicity were reviewed to assess data quality and causality as originally presented since 2004. The study group consisted finally of 15 patients originating from Germany and included cases of spontaneous reports with liver disease in primarily assumed temporal and causal association with the treatment by P. sidoides. Teschke et al re-evaluated the data of these patiens to assess the causality. The data of all 15 cases were submitted to a causality algorithm that consisted of four steps: assessment of key items related to a temporal association (step 1), criteria of Pelargonium hepatotoxicity and definition of the pattern of liver injury (step 2), application of a liver specific, quantitative, and structured causality assessment method (step 3), and exclusion of alternative diagnoses (step 4). Evaluations considered not only Pelargonium but also synthetic drugs, herbal drugs, and dietary supplements, summarised as comedicated drug(s). The analysis revealed confounding factors such as numerous final diagnoses unrelated to Pelargonium and poor data quality in several cases. In only a minority of the cases were data provided to consider even common other diseases of the liver. For instance, biliary tract imaging data were available in only 3 patients; data to exclude virus infections by hepatitis AC were provided in 4 cases and by CMV and EBV in 1 case, whereas HSV and VZV virus infections remained unconsidered. The assessment showed lack of convincing evidence for a hepatotoxic risk associated with the treatment of Pelargonium when the present spontaneous reports were analysed and Pelargonium use was as recommended. In none of the 15 analysed cases could Pelargonium hepatotoxicity be confirmed as the final diagnosis (Teschke et al. 2012a).

In a subsequent publication (Teschke et al. 2012b), it was examined whether and to what extent treatment by Pelargonium was associated with the risk of liver injury in further 13 spontaneously reported hepatotoxicity cases. The patients originated from Germany (9), Switzerland (2), Italy (1) and Singapore. Their data were submitted to a thorough clinical evaluation that included the use of the original and updated scale of CIOMS (Council for International Organisations of Medical Sciences) to assess causality levels. These scales are liver specific, validated for liver toxicity, structured and quantitative. According to the analysis, none of the 13 spontaneous cases of liver disease generated a positive signal of safety concern, since causality for Pelargonium could not be established on the basis of the applied CIOMS scales in any of the assessed patients. Confounding variables included comedication with synthetic drugs, major comorbidities, low data quality, lack of appropriate consideration of differential diagnoses, and multiple alternative diagnoses. Among these were liver injury due to comedication, acute pancreatitis and cholangitis, acute cholecystitis, hepatic involvement following lung contusion, hepatitis in the course of virus and bacterial infections, ANA positive

autoimmune hepatitis, and other preexisting liver diseases. In the course of the case assessments and under pharmacovigilance aspects, data and interpretation deficits seemed to be evident for the authors. Consequently, the authors ascertained lack of hepatotoxicity by Pelargonium in all 13 analysed spontaneous cases (Teschke et al. 2012b).

Until June 2012, the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM, Germany) received 30 spontaneous reports (26 from Germany, 2 from Switzerland, 1 from Italy and 1 from Singapore) on the hepatic adverse effects (11 hepatitis, 8 icterus, 3 hepatic injury) associated with Pelargonium product application. One patient suffering from hepatitis has had liver transplantation. In 7 hepatitis cases, the association of hepatitis and Pelargonium consumption was evaluated to be possible, in 1 case possible-probable, in 1 case probable. In case of icterus, the association was evaluated to be possible in 6 cases and probable in 2 cases. From the 3 hepatic injury cases 2 were evaluated to be possibly associated with Pelargonium application. In 19/30 cases there was reported co-medication. BfArM concluded that there is at least a possible association between Pelargonium application and hepatotoxicity and therefore a Graduated Plan came into force to minimise risks and a post authorisation safety study was requested for the further assessment of the hepatotoxic risk.

The Summary of Product Characteristics of the products marketed in Germany has to be supplemented with the following (BfArM, 2012):

Special warnings and precautions for use: “Hepatotoxicity and hepatitis cases were reported in association with the application of <product name>. In case of signs of hepatotoxicity occur, the application of <product name> should be stopped immediately and a medical doctor should be consulted.”

Undesirable effects: “Hepatotoxicity and hepatitis cases were reported in association with the application of <product name>. Since these cases were reported spontaneously, the frequency is not known.”

5.4. Laboratory findings

The clinical trial carried out by Matthys et al. (2003) mentioned that the final assessment on day 7 of treatment included laboratory a test (leukocytes, erythrocyte sedimentation test, γ-GT, GOT, GPT, Quick’s test and partial thromboplastin time-PTT). The mean values of all laboratory parameters did not change during the trial, neither for patients under EPs® 7630 nor for patients under placebo.

Chuchalin et al. (2005) examined the tolerability assessed by the results of laboratory tests including leukocytes and erythrocyte sedimentation rate, γ-glutamyl transpeptidase, aspartate aminotransferase, alanine aminotransferase, Quick’s test and PTT. Regarding the coagulation parameters, no differences between the two treatment groups were observed.

Matthys and Heger (2007) observed an increase of erythrocyte sedimentation rate (9.3% of patients in EPs® 7630 group vs. 9.2% of patients in placebo group) and a change of leukocyte count (3.7% of patients in EPs® 7630 group vs. 4.6% of patients in placebo group). These laboratory findings were due to the underlying infectious disease.

Matthys and Funk (2008) examined the liver function, leukocytes and erythrocyte sedimentation rate at baseline and at the end of treatment. No relevant differences were observed.

Bachert et al. (2009) reported that there was no clinically relevant change in any laboratory parameter and no clinically relevant individual deviations occurred in both treatment groups. No detailed information on laboratory test is available.

In a review os clinical trials and post-marketing studies involving 9,218 patients, data on treatment- emergent changes in liver enzymes from placebo-controlled trials gave no indication of an unfavourable influence of EPs® 7630 (Matthys and Köhler, 2010).

In spontaneous hepatotoxicity reports, liver enzyme deviations were documented in some cases. Among the 13 cases assessed in the paper of Teschke et al. 2012b, values of ALT, AST and ALP were available in 8, 6 and 5 cases, respectively. ALT was on average 1041 U/L (101-2500), with AST, the average was 1288 U/L (49-4000) and ALP showed an average value of 140 U/L (63-178). ALT values following Pelargonium cessation were restorted in 6 cases and found decreased, but in none of the overall 13 patients ALT normalisation has been reported (Teschke et al. 2002b).

Among the 15 study patients analysed by Teschke et al. (Teschke et al. 2012a), values of ALT, AST, and ALP were available in 12, 11, and 6 cases, respectively. ALT was on average 1124 U/L with a range of 68 to >3000 U/L; with AST, the average was 827 U/L and the range from 70 to >3000 U/L; and ALP showed an average value of 215 U/L with a range of 144 to 319 U/L. In only 4 patients ALT normalisation was reported. In none of the 15 cases were the liver values presented for the time before Pelargonium use to verify lack of preexisting hepatobiliary diseases. In a single patient, however, increased aminotransferases of ALT 196 U/L and of AST 54 U/L were still observed 6 months following cessation of PS.

5.5. Safety in special populations and situations

One study examined the possible interaction between EPs® 7630 and antibiotics using penicillin V, as test substance. Twenty eight healthy test persons took for seven days 3 x 1 tablets Isocillin® 1.2 Mega alone (n=13) or in co-medication with 3 x 30 drops of EPs® 7630 . The pharmacokinetic parameters of penicillin V on day 0 and day 7 were compared. Main target criteria were area under curve (AUC) and the maximum concentration (Cmax) of penicillin V in the plasma. The trial revealed no significant differences between the treatment with and without co-medication with EPs® 7630 (Conrad and Schulz, 2007) (Arold and Wollny, 2003; Roots et al. 2004).

On the basis of available non-clinical and limited clinical data, it can be ssumed that Pelargonium preparations do not influence either the blood coagulation parameters or the anticoagulant action of medicines (Koch and Biber, 2007; Matthys et al. 2003; Chuchalin et al. 2005).

To date, neither safety studies including women who are pregnant or breastfeeding, nor individuals with hepatic or renal disease, have been performed.

No information is available on overdose, drug abuse and withdrawal. The ethanol content of preparations from Pelargonium roots may influence the ability to drive.

5.6. Overall conclusions on clinical safety

On the basis of available safety data, the preparation of Pelargonii radix seems to be safe in the dosage administered in clinical and post-marketing trials.

6. Overall conclusions

Based on the available clinical data, the efficacy of Pelargonii radix in the symptomatic treatment of acute respiratory diseases is not proven properly. Based on the clinical evidence, the well-established use of Pelargonii radix is not acceptable in any of the investigated conditions.

According to the market overview, one liquid extract (DER 1:8-10), extraction solvent: ethanol 11% (m/m) of Pelargonii radix has been on the market for more than 30 years with the indication acute

bronchitis (see product no. 4 in the German market overview, section 1.2). However, since this indication needs medical diagnosis and supervision, based on other traditional herbal medicinal products with the same composition in other member states, the following indication was accepted: symptomatic treatment of common cold. The dry extract equivalent to the above mentioned liquid extract (dry extract, (DER 4-25:1), extraction solvent ethanol 11% (m/m)) is also included in the traditional use monograph.

There is no relevant information about the safety of P. sidoides during pregnancy and lactation. The administration of preparations from Pelargonium roots in this patient group is not recommended.

Due to insufficient data on toxicity the inclusion of Pelargonii radix in the Community list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products cannot be recommended.

Annex

List of references

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