Hedera – Ivy leaf (Hederae helicis folium)
|Latin name of the genus:||Hedera|
|Latin name of herbal substance:||Hederae helicis folium|
|Botanical name of plant:||Hedera helix l.|
|English common name of herbal substance:||Ivy leaf|
Latin name of the genus: Hedera
Latin name of herbal substance: Hederae helicis folium
Botanical name of plant: Hedera helix L.
English common name of herbal substance: Ivy leaf
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- Primary pharmacodynamics
- Secondary Pharmacodynamics
- Overall conclusion on pharmacology
- 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- Overall conclusion on pharmacokinetics
- 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- Overall conclusion on toxicological data
- 3.4. Overall conclusions on non-clinical data
- 4. Clinical Data
- 4.1. Clinical Pharmacology
- substance(s)/preparation(s) including data on relevant constituents
- 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.2. Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2. Clinical studies (case studies and clinical trials)
- 4.2.3. Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 6. Overall conclusions
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Hederae folium (Ivy leaf) (European Pharmacopoeia)
Whole or cut, dried leaves of Hedera helix L., collected in spring.
Content: minimum 3.0% of hederacoside C (C59H96O26; Mr 1221) (dried herbal substance).
The species Hedera helix L., Araliaceae, is known under the synonyms: Hedera caucasigena POJARK;
H. chrysocarpa WALSH; Hedera helix ssp. caucasica KLEOP.; Hedera helix var. chrysocarpa TEN.; Hedera taurica CARR.; Hedera helix var. taurica TOBLER (HagerROM, 2006). The species Hedera helix
L., which is a source of the drug, is subdivided into three botanical varieties, Hedera helix var. baltica, Hedera helix var. helix and Hedera helix var. hibernica. (HagerROM, 2006).
In the European countries Hedera helix is designated as follow: German: Efeubätter, Rankenefeu, Mauerefeu, Totenranke, Epig; English: English Ivy, Common Ivy, Woodbind, Bindwood; French: Lierre à cautère, Lierre commun, Lierre des poètes, Lierre grimpant; Italian: Edera, Ellera; Spanish: Hiedra; Danish: Efeu, Vedbend; Dutch: Klimop; Norwegian: Bergflette, Eføi; Polish: Bluszcz; Russian: Pluszcz;
Swedish: Murgröna; Czech: Břečtan obecný; Hungarian: Borostyán (HagerROM, 2006).
According to Wichtl (2004) the most important constituents of the plant are:
−Small amounts of monodesmosides such as
−The main saponin is the hederasaponin C (hederacoside C) with other hederasaponins (B, D, E, F, G, H and I) present as well. Hederasaponin A, described in an earlier publication could no longer be found in subsequent studies. The content ratios of the hederasaponins (C : B : D : E : F : G : H : I) are about 1000 : 70 : 45 : 10 : 40 : 15 : 6 : 5
−Flavonoids such as quercetin and kaempferol including their
−Caffeic acid derivates and other phenolics such as caffeic acid and
−Coumarin glycoside scopolin and the polyacetylenes falcarinone, falcarinol and 11, 12- dihydrofalcarinol
−Phytosterols as stigmasterol, sitosterol, cholesterol, campesterol,
−The volatile oil (in the fresh leaves
−Free amino acids
−The occurrence of the alkaloid emetine could not be confirmed in recent studies (Czygan, 1990). From four varieties grown in Egypt the alkaloid emetine was isolated (Mahran et al., 1975). Convincing studies are missing (HagerROM, 2006).
See chapter 1.2.
•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.
Ivy extracts are also used in combination with other herbal substances/herbal preparations. This monograph refers exclusively to monopreparations.
1.2. Information about products on the market in the Member States
Table 1. Specified products on the market in the European Member State
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
A literature search was performed on 21 April 2008 using the DIMDI database information system. The searched databases were
In the list of references, the references supporting the assessment report are listed first and secondly references used but not introduced into the assessment report. An additional search in the same databases was performed on 26 January 2009 for the period from April 2008 to January 2009.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Madaus (1938) notes, that ivy leaf is mentioned since Dioskurides and Hippokrates. The phytotherapeutical books of the 16th would describe very different indications as jaundice, lithiasis dysenterie, emenaegogum etc. The oral use of ivy (1/2 teaspoon as infusion as daily dose) at rachitis, lithiasis, bile- and liver dysfunction is recommended.
Steinmetz (1961) resumes that although the plant is decidedly poisonous (in large doses death can occur by respiratory paralysis!), the leaves and berries have some good uses in therapy – provided they are administered in safe doses – as a stimulating medicine for chronic catarrh, bronchitis, and especially whooping cough, for which Leclerc said the leaves deserve a place of honour as a “specific”. The use of ivy in whooping cough was the object of clinical tests by Leuret (of Bordeaux), who demonstrated its action. In small doses and taken internally, the leaf is a very active
According to the monograph Hedera helix of the Kommission D (1986), ivy is also used in homeopathic preparations. The homeopathic preparations are indicated in diseases of the respiratory tract, gastrointestinal tract, rheumatic diseases and hyperthyroidism. Due to the lack of clinical studies, those indications are not considered in this assessment report.
Literature on current traditional use of Hedera helix leaves (not for marketed preparations)
Chichiricco (1980) collected information about traditional phytotherapy in the Subequana valley Abruzzo, Central Italy. He noted the boiled leaves of Hedera helix L., applied to the part of the body afflicted, fight ringworm, scabies and worm. The cataplasm of the leaves would rapidly heal furuncles.
Brussel (2004) focused in his study on plants used for medicinal purposes in the Mt. Pelion area of Greece. He reported the traditional use of a libation made by letting crushed ivy leaves set in a container of red wine for two weeks. It was used to treat depression and was said to have stimulant,
narcotic and hallucinogenic properties that were dependent on the amount that was drunk.
Kültür (2007) collected information on traditional medicinal plants of the region of Kirklareli Province in Turkey. A decoction of the leaves of Hedera helix L. was used for diabetes and “blood depurative”. The dosage reported was one teacup two times daily for
De Smet et al. (1993), Hausen et al. (1987), Hausen (1988) and Facino (1990) reported ivy leaves were also incorporated into topical cosmetic preparations, e.g., for the treatment of cellulites and shampoos. No marketed topical preparations exist currently in the member states.
The current use of ivy is described in many recent phytotherapeutic textbooks and has been introduced into Pharmacopoeias or accepted collections in the European countries:
•Hederae folium (Ivy leaf). European Pharmacopoeia 01/2008:2148 corrected 6.0
•Hederae helicis folium, Efeublätter, German Kommission E Monograph (1988) Indication: “Catarrh of the respiratory passages and for symptomatic treatment of chronic inflammatory bronchial illnesses.”
•Hedera helix L. in Medicaments à base plantes (1998): “Traditional used topically as a soothing and antipruriginous application for dermatological ailments and as a protective treatment for cracks, grazes, chapped skin and insect bites”, therapeutic indication 86 “traditionally used as an adjuvant to slimming diets”. Hedera helix stem wood therapeutic indication nr. 111 “Traditionally used in the symptomatic treatment of cough”, therapeutic indication nr. 113: “traditionally used during benign acute bronchial conditions.”
•Hederae helicis folium in HagerROM (2006): “Catarrh of the respiratory passages and for symptomatic treatment of chronic inflammatory bronchial illnesses.”
•Hederae helicis folium in ESCOP Monographs (2003): “Coughs, particularly when associated with hypersecretion of viscous mucus; as adjuvant treatment of inflammatory bronchial diseases.”
•Hederae folium in Wichtl (2004): “Extracts of ivy leaf have expectorant and spasmolytic actions. They are used primarily as expectorants and antispasmodics for catarrh of the respiratory passages and for symptomatic treatment of chronic inflammatory bronchial illnesses.”
•IVY. In Williamson (2003): “Cathartic, febrifuge, diaphoretic, anthelmintic. It is widely used in preparations for bronchitis and catarrh, as an expectorant. Ivy extracts are often used in cosmetic preparations to treat cellulite, with some success.”
•Ivy. In: Sweetmann (2007) “Ivy leaf is used for catarrh and chronic inflammation of the respiratory tract. It has also been applied externally.”
•Ivy Leaf. In British Pharmacopoeia (2008)
•Lierre grimpant. Valnet (1983): internal use: pertussis, chronical bronchitis, tracheitis, laryngitis, rheumatism, lithiasis, hypertension, external use: cellulites, rheumatism, oedemas, erythema/burn
There are no convincing data demonstrating the traditional oral use of ivy leaf as
Conclusion: There is neither traditional nor well established use for the herbal tea preparation of ivy leaf. Most preparations from ivy leaf contain
2.2. Information on traditional/current indications and specified substances/preparations
For the following ivy leaf preparations a period of at least 30 years of medical use, as requested by Directive 2004/24/EC for qualification as a traditional herbal medicinal product, is fulfilled and additionally a marketing authorisation has been granted (see Table 1). This assessment report is discussing which preparations are suitable for
7.liquid extract (1:1), extraction solvent: ethanol 70% (V/V)
For one ivy leaf preparation a period of at least 30 years of medicinal use is not fulfilled:
The analytical comparison of the latter ivy leaf dry extract
The specified products on the market in the European Member States are used orally. The route of administration depends on the pharmaceutical form (coated tablets, capsules, effervescent tablets, drops or oral solution). The preparations are taken with a glass of water. The indications with regard to the respiratory tract are the following:
a)“Catarrh of the respiratory passages”
“Relief of cough associated with catarrhs of the respiratory tract” “acute catarrhs of the airways with cough”
“traditionally used in the symptomatic treatment of coughs”
They can be summarized in “Medicinal product used in common cold associated with cough”.
b)“Traditionally used during benign acute bronchial conditions” “symptomatic treatment of chronic inflammations in the bronchia.” “Symptomatic treatment of chronic inflammatory bronchial disorders” “acute inflammations of the respiratory tract accompanied by coughing”
They can be summarised in “Symptomatic treatment of acute and chronic inflammatory bronchial disorders”.
The duration of use is regulated by a warning in the predominant cases. Patients are asked to consult a doctor if the symptoms persist longer than
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
1. dry extract
2. dry extract
3. dry extract
5. soft extract
Summary of posology for soft extract (2.2- 2.9:1), extraction solvent: ethanol 50% (V/V):propylene glycol (98:2)
Adults and adolescents > 10 years:
Single dose: 40 mg extract
(corresponding to 100 mg herbal substance) Daily dose: 120 extract
(corresponding to 300 herbal substance)
(corresponding to 200 mg herbal substance)
Single dose: 20 mg extract (corresponding to 50 mg herbal substance) Daily dose: 60 mg extract
(corresponding to 150 mg herbal substance
Single dose and daily dose: 20 mg extract (corresponding to 50 mg herbal substance)
6. dry extract
7. liquid extract (1:1), extraction solvent: ethanol 70% (V/V)
8. dry extract
(corresponding to 250 mg herbal substance) Daily dose:
Single dose: 25 mg dry extract (corresponding to 125 mg herbal substance) Daily dose:
Single dose: 25 mg dry extract (corresponding to 125 mg herbal substance) Daily dose: 50 mg dry extract (corresponding to 250 mg herbal substance)
Summary of posology for dry extract
Adults and adolescents > 15 years: Single dose:
Single dose: 25 mg dry extract (corresponding to 125 mg herbal substance) Daily dose: 50 mg dry extract (corresponding to 250 mg herbal substance)
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Trute et al. (1997): The antispasmodic activity of a dry extract of Hedera helix (6:1, extraction solvent 30% ethanol) standardised on papaverine (papaverine equivalent value, PE, activity of 1 g test substance equivalent to the activity of x mg papaverine) was studied in
In order to determine the phytochemical basis for the antispasmodic activity, a bioassay guided fractionation and subsequent isolation of phenolic compounds (flavonols and caffeoylquinic acids) and saponins (hederacoside C,
Capasso et al. (1991): Apigenin, quercetin and kaempferol at a concentration of 10 µM (single doses) significantly reduced the contraction of
Ortiz de Urbina et al. (1990): Caffeic and protocatechic acids demonstrated a
Becker (2003) and Beyer (2005) reported from
Hegener et al. (2004): A preincubation for 24 h with the saponin compound
Runkel et al. (2005):
Sieben et al. (2009): Internalization of
hederacoside C and hederagenin did not influence either the binding behaviour of 2AR or the intracellular cAMP level.
Haen (1996): In the compressed air model in conscious guinea pigs, an orally administered ethanolic extract from ivy leaf at 50 mg/kg body weight
Vogel (1963): Considered the hypothesis of the vagal effector mechanism for improvement of expectoration to be unrealistic. He considered the surface activity of the saponins could play a role in the local liquefaction of the mucus in the throat. Additionally, it might be possible that not only saponins but also other substances like e.g. volatile oils contribute to the effect.
Mills and Bone (2000): Saponins are more or less irritating to gastrointestinal mucous membranes (whether this is related to their detergent or haemolytic properties is not understood). This irritant property creates an acrid sensation in the throat when a
März and Matthys (1997): Ivy is used as “expectorant”. For the mucus secretory cell the vagal effector mechanism is only one of several trigger mechanism to induce secretion. Stimulation of gastric receptors by emetic agents causes vomiting by vagal reflex acting through the modularly vomiting centres. Subemetic doses of these agents activate a gastropulmonary mucokinetic vagal reflex, which stimulates the bronchial glands to secrete a watery fluid.
A new mode of action was discussed by
Haen (1996): An orally administered ethanolic extract from ivy leaf at 162 mg/kg body weight inhibited
Kim et al. (1999): Some steroidal and triterpenoid saponins were isolated and evaluated for their anti- inflammatory activity using
Süleyman et al. (2003) tested the possible anti inflammatory effects of a crude saponin extract (CSE) (10:1; extraction solvent ethanol 80% (V/V)) and saponin purified extracts (SPE) of Hedera helix in carrageenan- and
phase of inflammation, with 66% effect. The SPE of Hedera helix was more potent than the CSE in its chronic
Gepdiremen et al. (2005): The
Cioaca et al. (1978) tested the antibacterial activity of saponins from Hedera helix against a large number of microorganisms. The microbiological assay of saponins was made with 23 strains representing 22 bacteria and one yeast species (Candida albicans). In a 10 and 5 mg/ml concentration the saponin solution was bactericidal against al the 23 tested strains. The minimal inhibitory concentration for the
(0.312 mg/ml), Salmonella para A (0.312 mg/ml), Shigella flexneri (0.625 mg/ml), Bacillus anthracis
(0.625 mg/ml), Streptococcus mutans (1.250 mg/ml).
Ieven et al. (1979): An ethanolic extract of ivy leaf completely inhibited the growth of Staphylococcus aureus and Pseudomonas aeroginosa and partially inhibited the growth of E. coli.
Rao et al. (1974) reported about the
Wolters (1966): The antifungal activity of 30 saponin containing plant extracts (methanol 10%, no further information) was tested in 4 different strains. Hedera helix extract had a fungistatic activity on all the tested strains: Piricuralia oryzae, Trichothecium roseum, Claviceps purpurea and Polyporus vesiculosus.
Favel et al. (1992): The antifungal activity of triterpenoid saponins was evaluated
C. tropicalis, C. pseudotropicalis, C. glabrata) were inhibited at 50 µg/ml or less. The MICs for the dermatophytes were within the range
Favel et al. (1994): The antifungal activity of triterpenoid saponins, with hederagenin or oleanolic acid as aglycon, was investigated
Balansard et al. (1980): In
Hostettmann (1980) compared the molluscicidal effects of different ivy extracts and found a crude leaf extract was less active than a crude methanolic extract of the berries. He isolated four saponins from the berries, all of which showed a strong molluscicidal action against the
Hostettmann et al. (1982) tested a series of 24 different saponins isolated from various medicinal plants against Biomphalaria glabrata, one of the snail vectors of schistosomiasis (bilharziasis). In general, monodesmosidic triterpenoid saponins exhibited a strong molluscicidal activity whereas bidesmosidic saponins as well as the aglycones were fully inactive.
Julien et al. (1985): The
Tedlaouti et al. (1991): Moderate
Delmas et al. (2000): The
Ridoux et al. (2001): The
Hensel et al. (2007) and Goetz (2007): Thirty commonly used medicinal plants were screened by a selective and specific
Especially roots from Angelica archangelica, fruits of Cassia angustifolia, C. senna, Coriandrum sativum, leaves from Hedera helix, flowers from Lavandula spec. and from Sambucus nigra contained high amounts (1 to 11μg/g) of mixtures of the different amides 1 to 12. For functional investigations on potential activity in cellular physiology, two amides with an aliphatic
used. (8) and (5) stimulated mitochondrial activity as well as the proliferation rate of human liver cells (HepG2) at 10 μg/ml significantly. When monitoring the influence of selected phase I and II metabolizing enzymes, both compounds did not influence CYP3A4 gene expression, but stimulated CYP1A2 gene expression and inhibited GST expression. Also the proliferation of human keratinocytes (NHK) was increased up to 150% by both, the amides 5 and 8. This stimulation was also detectable on the level of gene expression by an
Liu et al. (1993) examined the protective effect of
Liu et al. (1995) determined the protective effects of
According to Shi and Liu (1996), there were the hepatoprotective effects of
Liu et al. (1997) examined whether
de Medeiros et al. (2000): A chromogenic bioassay was utilised to determine the antithrombin activity of methylene chloride and methanol extracts (no information about the DER of the extract) prepared from 50 plants of the Azores. Extracts of the six plants: Hedychium gardneranum, Tropaeolum majus,
Gunnera tinctoria, Hedera helix, Festuca jubata and Laurus azorica demonstrated an activity of 78% or higher in this bioassay system. The activity of the Hedera helix methylene chloride extract (82%) was higher than the activity of methanol extract (30%). It is believed, that hypercoagulability in cancer is related to an increase of “tissue factor” (TF) in the patients. The author concluded that the lower
activity of thrombin caused the lower coagulability, and subsequently the possibility of tumour cells to spread or to adhere to any tissue.
Mba Gachou et al. (1999): The study was designed to evaluate the protective effect of
Gülcin et al. (2004): The antioxidant activities of
Ibrar (2000) and Ibrar et al. (2003): The study showed that both the aqueous extracts (200 g of powdered leaves in 1 l distilled water, soaking seven days at room temperature, filtrated and concentrated) and methanolic extracts (no information about DER) of Hedera helix L. were hypoglycemic, reducing the blood glucose level in normal rabbits. The methanolic and aqueous extracts were administered orally at a dose equivalent to 4 g of powdered leaf per kg body weight in 20 ml of 2% gum traganth solution. In the
Facino et al. (1990): Evaluation of the
The authors concluded that the recovery of the integrity of hyaluronic acid (and of its functional interactions with proteoglycans) might lead to recovery of the biochemical integrity of the basal amorphous substance in which the periadipocyte microvascular system is embedded, with a sealing effect on the capillary walls.
Facino et al. (1995):
Antiadhesive properties on the adhesion of Helicobacter pylori to human stomach tissue
Hensel et al. (2007) and Goetz (2007): The aliphatic aspartic compound
Vogel and Marek (1962): A saponin mixture isolated from ivy leaf and administered intravenously, inhibited
Schottek (1972): A lung oedema was induced in mice by inhalation of a
Overall conclusion on pharmacology
A spasmolytic/bronchodilatating effect has been documented in
The secretolytic activity shown in clinical praxis is not yet clarified in experiments. Probably subemetic doses of saponins activate a gastro pulmonary mucokinetic vagal reflex, which stimulates the bronchial glands to secret a watery fluid. No
literature (Hänsel and Sticher, 2004). Büechi (2002) considered the hypothesis of vagal reflex mechanism as implausible because a daily dose of 0.5 g drug was well tolerated. The author considered that the surface activity of the saponins could play a role in the local liquefaction of the mucus in the throat thus being more important in clinical praxis. In contrast, Wagner and Wiesenauer (1995) stated that the surface activity was unrealistic in oral administration. The concentration of saponins in the lung would be too low to explain such an activity. The surfactant hypothesis of Hegener et al. (2004) and Runkel et al.(2005) was also stated by
A lot of secondary phamacodynamic studies were performed
The hypoglycemic effects were shown with methanolic and aqueous extracts administered orally at a dose equivalent to 4 g of powdered leaf per kg body weight. The dosage corresponds to 280 g ivy leaf in a 70 kg patient. This is approximately the
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Absorption, Distribution, Metabolism, Elimination
Vogel and Marek (1962) found more than
Schmidt (2003): One hour after a single p.o. application of 1 g/kg of an ivy dry extract
Schmidt (2003) could detect
radioactivity of 1.398 µCi/µg. The results of the pilot study showed absorption and uptake in blood and further passing into liver and lungs. To allow a statement on the pharmacokinetics and tissue distribution, the main study was carried out over 336 h. 335 µg/kg
At 24 h: radioactivity in the lung tissue
A table shows the radioactivity in blood over 336 h. At 24 h, the highest radioactivity in blood is approximately 0.32µCi/ml (in the
At 24 h: radioactivity in blood
Jeong and Park (1998): Treatment of mice with
Pharmacokinetic interactions with other medicinal products
Liu et al. (1995): Treatment of mice (10 and 30 µM/kg, s.c. or vehicle once daily for 3 consecutive days) with
CYP3A enzymes were also suppressed as determined by immunoblotting with antibodies against rat P450 enzymes.
Jeong (1998): The administration of
Overall conclusion on pharmacokinetics
In the available literature, it is assumed that hederasaponins are poorly absorbed following oral administration. This assumption is supported by experiments by Vogel and Marek (1962), cited in De Smet et al. (1993). Mills and Bone (2000) note, that after oral intake, the major part of saponins is not absorbed or is only slowly and partially absorbed as the aglycones.
Schmidt (2003) could detect, in an
The results have to be considered in the assessment of the hypothetic mode of action and in the assessment of toxicology and use in pregnancy. From the results, it can be concluded, that
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Single dose toxicity
Lanza et al. (1980): Oral administration of a dry extract of ivy leaf (ethanol 66% (V/V), no DER information) to rats
On the other hand, oral administration of dry extracts of ivy berries (ethanol 66% (V/V), no DER information) to rats at doses
Vogel and Marek (1962) found
Vogel and Marek (1962) found
Repeat dose toxicity
ESCOP (2003): Daily oral administration of an ivy leaf dry extract to rats at 1.5 g/kg body weight for 100 days caused no toxic effects. Haematological and biochemical parameters, histological findings and kidney and liver weights were normal compared to those of control animals.
Haemolytic effects were detected after oral administration of a hydroethanolic dry extract from ivy leaf to rats at 4 g/kg body weight, for 90 days.
Elias et al. (1990):
14 nmol/ml) were found to exert an antimutagenic effect against the clastogenicity of doxorubicin (1.5 times
Villani et al. (2001) studied the antimutagenic potential of
Data on carcinogenicity studies with ivy leaf extracts or its components are not available.
Reproductive and Developmental Toxicity
Daston et al. (1994) tested the hypothesis that
30 µM/kg and 50% of control at 300 µM/kg. Both 30 and 300 µM/kg increased resorption incidence, and 300 µM/kg also decreased foetal weight and increased the incidence of abnormal foetuses. Abnormalities include encephalocele, undescedent testis, umbilical hernia, hydronephrosis/hydrourether, along of several others of unique incidence. There was also evidence of delayed skeletal ossification in the 300 µmol/kg group. Adding Zn to the serum restored normal embyotoxic development.
Duffy et al. (1997) conducted a study to determine whether repeated administration of low dosages of
Vogel (1963) tested
Ivy has often been reported to cause allergic contact dermatitis. Boll and Hansen (1987) analysed leaves and stems of 10 species. The allergenic polyacetylene falcarinol was present in Fatshedera lizei,
Hedera helix, Hedera helix subsp. canariensis and Tupindanthus calyptrata (T. calyptratus). Bruhn et al. (1987) isolated falcarinol and didehydrofalcarinol from Hedera helix, subspecies helix and subspecies canariensis and identified its structures by mass spectrometry and NMR.
The principal allergens were isolated also by Hausen et al. (1987) using sensitized guinea pigs and were identified as falcarinol and dehydrofalcarinol. Multiple examinations of the extract at different seasons showed a remarkable variation in the concentrations of falcarinol and dehydrofalcarinol as well as their ratio, depending on climate, soil and other regional conditions.
Vogel and Marek (1962), Vogel (1963): Studied the haemolytic effect
Hiller (1966): If saponins get into the bloodstream they are toxic. Toxic signs were found primary in kidneys and liver. At oral administration, no toxic activity is to expect because they are not resorbed by an intact intestinal tract. Infections of the throat, stomach or intestinal tract may elevate the risk of
Wulff (1968): The haemolytic index of hedera saponin C and B is given as 1:1000 and of
Mills and Bone (2000): Saponins are capable of destroying red blood cells by dissolving their membranes (a process known as haemolysis) and releasing free haemoglobin into the bloodstream. The toxic dose of an injected saponin occurs when sufficient haemoglobin is released to cause renal failure. After an oral intake, much of the saponin is not absorbed or is slowly and partially absorbed as the aglycone. The kidneys are thereby spared the sudden influx of haemoglobin.
Danloy et al. (1994): Analysed the effects of
Its cytotoxicity decreased in the presence of serum in the culture medium, indicating that
Bun et al. (2008):
Ibrar et al. (2001): The methanolic leaf extract of Hedera helix (500 g powdered leaves in 1250 ml methanol, vacuum evaporation to semi solid extract) was investigated for cytotoxic potential using brine shrimp bioassay. Results showed that the methanolic leaf extract possessed cytotoxicity (LC50=802.73 µg). The saponin fraction has no cytotoxicity (LC50 greater than 1000 µg). The fraction left after separation of saponin (“residue”) was cytotoxic (LC50=700.54 µg). Further fractionation and subsequent brine shrimp bioassays of the fractions obtained showed that the fraction F4 contained the cytotoxic principle (LC50=161.84 µg). According to infrared, ultraviolet spectroscopic analysis and chemical tests, the F4 fraction was a phenolic compound. The authors concluded that although methanolic extract of Hedera helix leaf was cytotoxic, the saponin isolated was not. This fact is also
confirmed by the findings of
Olariu (2007): The inoculation of cellular B16F10 line melanoma suspension was made subcutaneous on singenic C57B1/6 line mice. Bioactive compounds isolated from Salvia officinalis and Hedera helix were applied s.c. beginning with the second and the third passage, 24 h from melanoma induction. The melanoma occurrence was delayed with
Overall conclusion on toxicological data
Single/repeat dose toxicity, genotoxicity, carcinogenicity and reproductive and developmental toxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance or other particular studies have not been performed according to the state of the art and current guidelines. Only few data have been published based on the results from studies with other intention or summarising secondary literature. The cited studies give only limited information on the acute and chronic toxicity since the DER of the extracts is unclear and the route of administration was mostly i.p. and not oral.
According to Lanza et al. (1980), the oral administration of a single dose of a dry extract of ivy leaf (ethanol 66% (V/V), no DER information) to rats
hederacoside C, and of hederasaponin C and
4.5 mg/kg i.v. for hederin and hederasaponin C>50 mg/kg i.v. in rats after 7 days observation period was reported by Wulff (1968).
Haemolytic effects were detected after oral administration of a hydroethanolic dry extract from ivy leaf to rats at 4 g/kg body weight for 90 days; (Bucher, 1969; an internal report, cited in ESCOP, 2003). Repeated oral administration of an ivy leaf dry extract (no more information) to rats at daily 1.5 g/kg body weight for 100 days caused no toxic effects (ESCOP, 2003).
No genotoxicity studies have been conducted with ivy leaf extracts.
Embryotoxic effects of the monidesmoside
The following points support the view that available data have no clinical relevance:
•Subcutaneous administration cannot be compared with oral administration in
•The mode of action, as increasing the maternal hepatic metallothionein levels,
•In literature (ESCOP, 2003;
•Consumption of different saponins in human alimentation
•The study of
The following arguments support that use during pregnancy and lactation is not recommended:
•A greater resorption in case of infectious diseases as gastritis is hypothetically possible.
•The s.c. administered
•No screening studies about increasing of human maternal hepatic metallothionein levels of oral ivy extracts exist.
•The question, where developmental toxicity occurs only at the maternally toxic dosages is open.
•The saponins are very different in some pharmacological effects (ivy saponins have a great haemolytic effect).
•Different use in tradition: some saponins are used in the human alimentation others are considered to be toxic (beans are eaten, ivy is not eaten and not prepared as tea).
•The observed embryotoxic effect is considered to be an important effect. In the 30 µmol/kg treatment group, all of the litters contained pups that exhibited at least one abnormality.
From the results of the
The results regarding local cutaneous sensitisation with accompanying contact dermatitis, which were reported for fresh parts of Hedera helix only, are of no relevance for the oral route of administration of preparations containing the dried ivy leaf extract.
ivy leaf to rats at 4 g/kg body weight for 90 days. The effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
For human safety laboratory data see chapter 5.4. No relevant changes occur in human laboratory parameters after administration of therapeutically recommended dosages. Concerning the pharmacokinetic results of the in vivo study
Some monodesmosides, especially
3.4. Overall conclusions on
Extracts of ivy leaves are used therapeutically in commercially available preparations in Europe for the treatment at common cold associated with cough and symptomatic treatment of acute and chronic inflammatory bronchial disorders.
The spasmolytic/bronchodilatating effect could be documented in in vitro experiments and in vivo studies in the compressed air model in conscious guinea pigs. The mechanism of the secretolytic activity observed in clinical praxis has not been established experimentally yet. Probably
In summary, the pharmacological data of different in vitro and in vivo experiments, conducted with ivy leaves extract or saponins, support the use of ivy preparations in the context of inflammatory bronchial diseases and cough and colds.
Single/repeat dose toxicity, genotoxicity, carcinogenicity and reproductive and developmental toxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance or other special studies do not exist according to the state of the art and the relevant guidelines. Some aspects have been addressed by the following studies:
Lanza et al. (1980): The oral administration of a single dose of dry extract of ivy leaf (ethanol 66% (V/V), no DER information) to rats
The haemolytic effects were detected after oral administration of a hydroethanolic dry extract from ivy leaf to rats at 4 g/kg body weight for 90 days (ESCOP, 2003). Repeated oral administration of an ivy leaf dry extract (no more information) to rats at daily 1.5 g/kg body weight for 100 days caused no toxic effects.
No genotoxicity studies have been conducted with ivy leaf extracts.
Embryotoxic effects of the monidesmoside
Safety during pregnancy and lactation has not been established. In view of the
The results regarding local cutaneous sensitisation with accompanying contact dermatitis, which were reported for fresh parts of Hedera helix only, are no relevant for the oral route of administration of preparations containing the dried ivy leaf extract.
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
184.108.40.206. Primary Pharmacodynamics
No data available.
220.127.116.11. Secondary Pharmacodynamics
No data available.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
Schmidt (2003): In a pilot study, the bioavailability of
A repeated dose of 2 times daily 130 mg of the same extract over a period of 7 days was administered to 4 volunteers (cumulative 1820 mg ivy extract with 72.8 mg
Landgrebe (2002): A daily dose of 130 mg of ivy dry extract
4.2. Clinical Efficacy
Ivy preparations are worldwide marketed for treatment of different diseases of the respiratory tract system (“Catarrh of the respiratory passages”; “symptomatic treatment of chronic inflammatory bronchial illnesses”; “acute inflammations of the respiratory tract accompanied by coughing”). The following list shows the classification of WHO
−J00 Acute nasopharyngitis [common cold]
−J01 Acute sinusitis
−J02 Acute pharyngitis
−J03 Acute tonsilitis
−J03 Acute laryngitis and tracheitis
−J05 Acute obstructive lanryngitis [croup] and epiglotitis
−J06 Acute upper respiratory infections of multiple and unspecified site
−J20 Acute bronchitis (NOS in those under 15 years of age, acute and subacute bronchits (with bronchospasm, fibrinous, membranous, purulent, septic, tracheitis), acute tracheobronchits (excludes: chronic obstructive pulmonary disease with acute exacerbation NOS and lower respiratory infection)
−J21 Acute bronchiolitis (includes with bronchospasm)
−J22 Unspecified acute lower respiratory infection
−J40 Bronchitis, not specified as acute or chronic
−J41 Simple and mucopurulent chronic bronchitis (excludes: chronic bronchitis, NOS, obstructive)
–J41.0 Simple chronic bronchitis
–J41.1 Mucupurulent chronic bronchitis
–J41.8 Mixed simple and mucupurulent chronic bronchitis
−J42 Unspecified chronic bronchitis (chronic bronchitis NOS, tracheitis, tracheobronchitis) excludes: chronic asthmatic bronchitis, chronic bronchitis; bronchitis: simple and mucopurulent; bronchits with airways obstuction; emphysematous bronchitis; obstructive pulmonary disease NOS
−J44 Other chronic obstructive pulmonary disease
−J45 Asthma (excludes: acute severe asthma, chronic asthmatic (obstructive) bronchitis, chronic obstructive asthma, eosinophilic asthma, lung diseases due to external agents, tatus asthmaticus)
−J46 Status asthmaticus
Definitions were searched in current guidelines: WHO GOLD guideline. Global initiative for chronic obstructive lung disease (2006), BTS Guideline: Recommendations for the management of cough in
adults (Morice et al., 2006), DEGAM guideline 11 Husten (cough) (2008) and Leitlinie der Deutschen Atemwegsliga (Vogelmeier et al., 2007).
Viral infection (Common cold):
Acute cough with fever, malaise, purulent sputum, or history of recent infection should be assessed for possible serious acute lung infection.
Acute exacerbation of COPD (chronic obstructive pulmonary disease)
Only mild cases can be treated ambulant. The majority of cases have to be treated in hospital. For the ambulant treatment
DEGAM guideline 11 (2008): Chronic bronchitis is defined clinically by the presence of chronic bronchial secretions, enough to cause expectoration, occurring on most days for a minimum of 3 months of the year for 2 consecutive years. The pathological basis of chronic bronchitis is mucus hypersecretion secondary to hypertrophy of the glandular elements of the bronchial mucosa. Two forms can be distinguished:
a)Simple chronic bronchitis, the “uncomplicated” form is not obstructive
b)Chronic obstructive pulmonary disease COPD (WHO definition)
Chronic obstructive pulmonary disease (COPD) is a lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing. It is not fully reversible. The more familiar terms ‘chronic bronchitis’ and ’emphysema’ (emphysema has a pathological definition, which is a condition where there is permanent destructive enlargement of the airspaces distal to the terminal bronchioles without obvious fibrosis) are no longer used, but are now included within the COPD diagnosis. A COPD diagnosis is confirmed by a spirometry test, which measures how deeply a person can breathe and how fast air can move in and out of the lungs (forced expiratory volume in one second FEV1). Clinical symptoms and signs, such as abnormal shortness of breath and increased forced expiratory time, can be used to help with the diagnosis.
According to the WHO (GOLD guideline, 2006), the regular use of mucolytics in COPD has been evaluated in a number of
Asthma bronchiale (WHO definition)
Asthma is a chronic disease characterised by recurrent attacks of breathlessness and wheezing, which vary in severity and frequency from person to person. Symptoms may occur several times a day or a week in affected individuals; for some people become worse during physical activity or at night. The treatment depends on the asthma classification and is based on
The current DEGAM guideline 11 (2008) gives the following definition for acute cough: A cough lasting less than 3 weeks is termed acute.
According to the BTS guideline (Morice et al., 2006), the grey area between 3 and 8 weeks of cough is difficult to define aetiologically since all chronic cough will have started as an acute cough, but the clear diagnostic groups of chronic cough are diluted by those patients with
The differential diagnosis of acute cough includes the following respiratory tract infections: viral infection (common cold), acute bronchitis, pneumonie, viral influenza, acute exacerbation of COPD, asthma bronchiale. Diseases in other organ systems (heart system, gastrointestinal tract) or exogenic causes (medicaments) can also cause acute cough.
Chronic cough (>3 weeks/>8 weeks)
The DEGAM guideline 11 (2008) gives the following definition for a chronic cough: “A cough lasting longer than 3 weeks is termed chronic”. According the BTS guideline (Morice et al., 2006), a cough lasting longer than 8 weeks is defined as chronic. According to the same guideline, a cut of 2 months for chronic cough has been arbitrarily agreed in both American and European guidelines.
The differential diagnosis of chronic cough includes often diseases as chronic bronchitis, postnasal drip syndrome, bronchial hyperreagibility, COPD, asthma bronchiale and gastrooesophagial reflux.
4.2.1. Dose response studies
No data available.
Dose comparative clinical studies
Gulyas (1997): In a randomized,
The parameters of lung function (FEV1, forced vital capacity, vital capacity, peak flow rate) were measured on the 1st day (before the start of treatment), on the 5th day and on the 10th day (before and 3 h after administration). Body plethysmography was also used before the start of the treatment and on the 10th day, 3 h after the last dose to measure the airway resistance, intrathoracic gas volume and specific airway resistance. As in the first study,
The change in airway resistance (RAW) was the main criterion of the study to compare the two presentations in the chosen dosage. The comparison of the airway resistance with the baseline level showed more significant improvement in the first study (after 3 days), than in the second study (after 10 days). Comparable improvements in spirometric and bodyplethysmographic parameters were observed after both treatments. The author concluded that it was necessary to give two times higher dosage of the
This assumption cannot be generalised because the low dose of
For a detailed analysis of the study see chapter 4.2.2. For dosage discussion see the point “dosage” in chapter 4.3.
Unkauf and Friderich (2000): In a randomized prospective multicenter, reference controlled study, 52 children (mean 7.9 years) with a clinically confirmed bronchitis (no information acute or chronic) were treated either with Valverde® (200 ml juice contain
The primary objective endpoint was the bronchitis severity score as judged by the impairment of the state of the patient by means of a visual analogy scale at inclusion and at the end of the study on day 10. Secondary variables were severity of illness (CGI items II), the ratio of the therapeutic effect to the adverse drug reactions (CGI items III), frequency and kind of cough, colour and quality of the expectoration and auscultation.
The primary endpoint “bronchitis severity” was reduced in both treatment groups in the course of the study from day zero to day ten. From 52 children, 51 were responders (98%) and showed an improvement of the variables by at least 50%. The comparison of both medical treatment groups concerning the primary criterion showed a statistically significant equivalence of both ivy products after five days (p=0.0022) and after ten days (p=0.0031). The comparison of the laboratory values at the start and the end of the therapy did not show any relevant variations.
4.2.2. Clinical studies (case studies and clinical trials)
spirometric data (vital capacity, 1 sec. capacity, and peak flow), the symptoms and the auscultation results.
Improvements in spirometric and auscultation parameters were observed in both groups with no significant differences between the groups. The vital capacity in the group treated with the ivy preparation increased slightly more (from 2.84 l to 3.11 l) than in the ambroxol group (from 2.89 l to 2.92 l). The FEV1 remained unchanged in both groups (1.80 l/s ivy leaf extract and 1.88 l/s ambroxol). The global rating for efficacy was “good” in 58.3% of the cases in the ambroxol group and in 55.1% in the ivy group. The patients’ diaries were analysed descriptive because the diaries were not fully completed. The results indicated a tendency towards greater decrease in frequency of coughing, sputum production and dyspnoea in the ivy leaf extract group.
Table 1: Vital capacity (l)
Patients rated the tolerability as “good” or “very good” in 87.8% (ivy leaf extract) and 87.5% (ambroxol) of cases in the 3th week and 93.4% (ivy leaf extract) and 95.5% (ambroxol) in the 4th week. In the verum group, 7 patients had undesirable effects (not described). Two of them were considered to have a causal relation to the medication. In the ambroxol group, 6 undesirable effects occured and 3 of them were considered to have a causal relation to ambroxol. One drop out case occured in the ambroxol group.
The study of
According to the current definition, obstructive chronic bronchitis is subsumed under COPD. Physiological changes characteristic of the disease include mucus hypersecretion, airflow limitation and air trapping (leading to hyperinflation), gas exchange abnormalities, and cor pulmonale. Due to airway fibrosis and alveolar destruction, the airflow limitation is not fully reversible.
For the diagnosis and assessment of COPD, spirometry is the gold standard as it is the most reproducible, standardised and objective way of measuring airflow limitation. Spirometry should measure the volume of air forcibly exhaled from the point of maximal inspiration (forced vital capacity, FVC) and the volume of air exhaled during the first second of this manoeuvre (forced expiratory volume in one second, FEV1). The ratio of these two measurements (FEV1/FVC) should be calculated. The presence of a post bronchodilator FEV1/FVC <0.70 and FEV1 <80% predicted confirms the presence of airflow limitation that is not fully reversible. According the WHO GOLD guideline (2006), an increase in FEV1 that is both greater than 200 ml and 12% above the
In this study, the FEV1 remained unchanged in both groups (1.80 l/s ivy leaf extract and 1.88 l/s ambroxol). The vital capacity in the group treated with the ivy preparation increased slightly more (rise from 2.84 l to 3.11 l) than in the ambroxol group (rise from 2.89 l to 2.92 l). Neither ambroxol nor the
ivy preparation reduced the FEV1 in the range of 12%. The results indicate that both preparations are not eligible to act as “bronchodilator” for efficacy in obstructive chronic
The study results show no significant differences between the groups in auscultation parameters and clinical symptoms. Patients with viscous sputum may benefit from both preparations.
Ambroxol was granted the indication “For secretolytic therapy in acute and chronic bronchopulmonary diseases, concomitant with disturbance in formation and transport of viscous sputum”.
The study results are in line with the indication of ambroxol, where only a secretolytic therapy is described. The results indicate that patients with simple chronic bronchitis and patients with obstructive chronic bronchitis may benefit from the ivy preparation for decreases in frequency of coughing, sputum production and dyspnoea, comparable to the secretolytic therapy with ambroxol. The long term use as a secretolytic in chronic bronchitis can not be deduced by the study results. The benefit is shown only for short term use of maximum 4 weeks.
Maidannik et al. (2003): In an open and controlled study (in two clinical hospitals in Kiev and Dnepopetrovsk), 72 children (7
The authors resumed, after 7 days of Prospan® treatment, that the velocity parameters of external respiration were normalised nearly in all children with obstructive diseases, while in the ambroxol treatment group normalisation could not be documented, but the parameters got even worse. No results referring to the ambroxol group were shown.
Comparing the course of auscultatory picture in lungs, a fast decrease of crepitation was only seen in the group of children treated with Prospan® (Prospan®: 94.3% before treatment, 45.8% in 7 days; ambroxol: 87.6% before treatment, 47.3% in 7 days).
The comparison of the decrease in productive cough in both treatment groups showed no statistical significant differences. After 7 days of the treatment, the cough in both groups was healed in more than half of the patients, and within 14 days disappeared in general. The clinical symptom “short breath” increased a little bit at day 3 of the treatment, the result at day 7 is not shown. Normalization of leukocytic count was documented after 7+1.5 days. The course of external respiration in % of the normal (VC, FVC, FEV1, PEF, MEF25, MEF50) was shown only for the ivy preparation group. The authors concluded that after 7 days of Prospan® treatment, the velocity parameters of external respiration were normalised nearly in all children with obstructive diseases, while in the ambroxol group normalisation could not be documented.
This study supports the results of the study conducted by
significant differences. Comparing the course of auscultatory picture in lungs, a fast decrease of crepitation was only seen in the group of children treated with Prospan®. After 7 days of the treatment, the cough in both groups was cured in more than half of the patients, and within 14 days it disappeared in general.
No conclusion on efficacy for the specific indications is possible. The number of patients for each of the multifaced diagnosis is
Bolbot et al. (2004): In an open and controlled study (in two clinical hospitals in Krivoy Rog and Dnepropetrovsk, Ukraine), 50 children
After 5 days of the treatment, the improvements of parameters concerning the function of upper and middle airways (FVC, FEV1, PEF, MEF25, MEF50) were greater in the Prospan® group and statistic different from parameters in the ACC group (p<0.05) and from baseline (p<0.05). In 10 days, 15% of the Prospan® group and 28.6% of the ACC group still had cough and sputum. All patients with cough had liquid sputum (no viscous, no
Table 2: External respiration parameters during the treatment (in % from normal)
At the end of the study all patients with cough had liquid sputum (no viscous, no
The comparison of the change of the spirometric parameter FEV1 (ivy: 67%; ACC: 25%) suggests better efficacy in spasmolytic activity for the ivy preparation than for ACC. An increase of 67% (62%
before treatment to 129% after treatment of 10 days) for the ivy preparation cannot be assessed without a positive control and without placebo. The low number of patients and the concomitant medication of antibiotics (comparable in the groups) affect negatively the level of evidence with regard to efficacy.
The results of the study indicate that the ivy preparation has a benefit for secretolytic therapy in acute bronchitis, concomitant with disturbance in formation and transport of viscous expectoration.
Additional controlled clinical studies with influence on spirometric and bodyplethysmografhic parameters
In the preclinical studies, ivy preparations showed a convincing antispasmodic activity (compared to papaverine). The clinical controlled studies by Gulyas (1997), Mansfeld et al. (1997, 1998) and Gulyas (1999) analysed the influence on spirometric and bodyplethysmographic parameters in clinical use. These studies were only conducted on small sample size (n=maximal 26), for a short time (10 days, 3 days, 3 days and
Gulyas (1997): description of the study see chapter 4.2.1
Table 3: Spirometric parameters: average parameters of lung function FEV1 (l), forced vital capacity FVC (l), vital capacity VC (l) and PEV (l/s).
Table 4: Bodyplethysmographic parameters (ITGW: intrathoracal gas volume; RAW: Airway resistance; SRAW: Specific airway resistance).
Comparable improvements in spirometric and bodyplethysmographic parameters were observed after both treatments. The author concludes thay the
The author analysed the reversibility of the bronchial obstruction comparing the data with salbutamol. Salbutamol as a positive control showed changes of 22.5% at first day. Before medication the FEV1 was 2.0 l in both groups. Ten minutes after inhalative application of 200 µg salbutamol medication, the FEV1 was 2.46 l in the juice group and 2.44 l in the drops group.
The data show that the FEV1 rises in the 5th day, 3 h after medication only to 2.08 l in the juice group and 2.09 l in the drop group. The change of proximally 4% is not considered as clinical relevant. After 10 days, the FEV1 was 2.15 l (proximally 8%) in both treatment groups 3 h after medication. After 10 days the FEV1 in both groups was 2.15 l before treatment and 2.45 l after salbutamol medication.
According the WHO GOLD guideline (2006), an increase in FEV1 that is both greater than 200 ml and 12% above the
For dosage discussion see the point “dosage” in chapter 4.3.
Mansfeld et al. (1997): In a randomized, comparative,
The results are comparable to the results of the (asthma) study by Mansfeld et al. (1998), with the difference that no placebo control was conducted in this study. Without a placebo control, the relevance of the data is limited. In the study of Mansfeld et al. (1998) the differences in FEV1 was not statistically significant in comparison to placebo.
Mansfeld et al. (1998): In a randomized,
A statistically significant reduction of 0.14 kPa/l/sec (23.6%) of the airway resistance was proved in comparison to placebo therapy. The verum therapy had a positive effect on bodyplethysmographic and spirometric parameters that was not statistically significant in comparison to placebo. The assessment of the tolerance by the physician and the patients did not show any relevant differences between verum and placebo and was considered as very good.
Table 5: Bodyplethysmographic parameters
A statistic significant reduction of 0.14 kPa/l/sec (23.6%) of the airway resistance was proved in comparison to the placebo therapy. The positive control for reversbility of bronchial obstruction was conducted with inhalative fenoterol.
The author’s conclusion that the bronchodilalatory effect of the ivy preparation was comparable to fenoterol is not convincing. On the first day, ivy has a difference in FEV1 of 0.12 l
The results showed increases in FEV1 from day 1 to day 3, both in the verum group and the placebo
group (verum 0.36 l
Gulyas (1999): In a controlled pilot study 20 children
Regarding the vital capacity (VC), a clinically relevant improvement was seen in the two treatment groups. After
The authors concluded that the results of this study show a clinically relevant effect of ivy leaves extract and also of acetylcysteine on the bronchial obstruction in children with a chronic obstructive bronchitis with a tendency towards greater efficacy of the herbal preparation. No statistical evaluation was performed.
No information about a positive control for reversibility of bronchialobstuction was given in the study. The FEV1 increased under ivy extract from 1.56 l to 1.90 l after 2 weeks and under acetylcysteine from 1.50 l to 1.72 l. Without a positive control the relevance of data cannot be evaluated.
The results of the study by Gulyas (1997) indicate that the FEV1 change is in the range of 8% that corresponds to proximally 1/3 of the FEV1 after inhalative application of 200 µg salbutamol (in patients with chronic obstructive pulmonary complaints).
In another placebo controlled study in children with bronchial asthma by Mansfeld et al., (1998), a statistically significant reduction of the airway resistance of 0.14 kPa/l/sec (23.6%) was proved in comparison to placebo therapy. The author’s conclusion that the bronchodilalatory effect of the ivy preparation was comparable to fenoterol is not convincing. On the first day ivy caused a difference in FEV1 of 0.12 l
All together, the results indicate a statistically significant improvement of lung function in comparison to placebo, but no significant better bronchodilatory effect as placebo. The results on spirometric and bodyplethysmographic parameters in clinical use indicate a benefit for the use as secretolytic. The bronchospasmolytic activity is approximally 1/3 of salbutamol and fenoterol and is concidered to be to low for clinical relevance in severe obstructive diseases.
Controlled clinical studies with only supportive character for the long tradtional use of ivy preparations in the context of cough
Some early controlled clinical studies by Stöcklin (1959) and Rath (1968) cannot proof efficacy because of their limited methodological quality. Blinding and randomisation are two essential features for minimising bias. These studies are not double blinded. The method of randomisation is not described. Substantial differences between the numbers of patients in test and control groups exist (Rath, 1968). This could suggest that inappropriate methods of randomisation were used. Formal sample size or power calculation were not reported. There is a lack of description of
Stöcklin (1959) evaluated the efficacy of ivy extract in 50 children of
The study has only supportive character for the long traditional use of ivy preparations in the context of cough. The extraction solvent, DER and dosage used in the study are unknown. The majority of treated children included in the study suffered from whooping cough. Actually, ivy preparations are not used in whooping cough, so the study is not of relevance. Only 10 children suffered from spastic bronchitis. The methodology was not accurate to proof efficacy in chronic bronchitis. There was no use of FEV1 and no measurement of symptomatic benefit. No statistical analysis was performed.
Rath (1968): A placebo controlled
The study has only supportive character for the long traditional use of ivy preparations in the context of cough. The extraction solvent, DER and dosage used in the study are unknown. The majority of treated children included in the study suffered from other diseases as the relevant. The number of children suffering from chronic bronchitis is less than 10. The duration of the study was only 3 days and there was no use of FEV1 and no measurement of symptomatic benefit. In 53% of the cases, an additional antibacterial treatment was given. No statistical analysis was performed.
Table 7: Controlled studies with ivy leaf products
The methodology of
Lässig et al. (1996): In a multicenter surveillance study, 113 children (aged
Hecker (1999): In an open comparative study 248 children (176 patients (71%) were younger than 15 years) suffering from chronic obstructive bronchitis were treated with two different ivy leaf preparations. 120 patients were treated with Prospan® cough juice (100 ml contains 0.7 g dry ivy extract
Jahn and Müller (2000), Müller and Bracher (2002): In an open study 372 children aged from 2 months to over 10 years (mean 5.7 years, 186 male, 178 female, 8 no data) suffering from respiratory tract infections (64.8%) or infections of the lower respiratory tract (22.8%) and both lower and upper respiratory tract (11.6%) were treated for
Assessment report on Hedera helix L., folium
the average daily doses ranged from 2.8 to 6.7 ml, corresponding to
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≥ 16 years:
no information: n=4
The irritation of the throat improved in the course of the medical treatment for 89.5% of the patients. At the end of the study no cough was observed in 119 patients (32.0%). In the third of the patients (30.3%), the dry cough was solved and changed into a productive one. The frequency of the expectoration was reduced in the course of the medical treatment from 33.6% in the beginning to 19.6% in the end of therapy.
Spirometric data were available from 187 children at least 4 years old. The lung function improved in the course of the ivy treatment, with an increase of the
273 l/min. As expected, a stronger increase in the
Roth (2000): In an open study, 1024 children (mean 4.4 ±3.8 years old) suffering from acute infections of the upper respiratory system (52.4%), acute bronchitis/bronchiolitis (26.6%) and bronchitis (not further specified, 22.2%) were treated with the same ivy leaf dry extract in two different
The patient groups were the following:
A significant decrease (p<0.01) of the complaints (cough, expectoration and dyspnoea) could be recorded at the end of the treatment. 72.6% of the children were cough free at the end of the study period; cough was improved at further 24.2%. No expectoration or an improvement was documented in 3.2% of the children. The symptom dyspnoea could be removed or improved in 99.2% of the children. The tolerability was considered as ‘very good’ and ‘good’ in 95.9% of the patients by the physicians, and in 90.8% by patients’ judgment. According to the publication, infants till 1 year received the drug as a middle daily dose of 0.1 g, children
Hecker et al. (2002): The changes of clinical symptoms and the tolerability of Prospan® acute effervescent Cough Tablets® (one effervescent tablet contains 65 mg ivy leaf dry extract
During a scheduled observational period of 4 weeks, the patients had to take 1(1/2) or 2 tablets per day (depending on their age), according to the manufacturer’s dosing recommendations, corresponding to 97.5 or 130 mg of dried ivy leaf extract (about
Büechi and Kähler (2003): In a multicenter open drug surveillance study over the period of one week, the efficacy and safety of ivy pastilles (one pastille contains 26 mg ivy leaf extract;
Kraft (2004): A retrospective survey in a great number of children (52,478) between 0 and 12 years from 310 medical practices was conducted to evaluate the tolerability of Prospan® cough juice (100 ml contains 0.7 g dry ivy extract
≥ 10 years: 9% (n=4,723)
In children under 1 year, the average daily dose corresponded to 227 mg of herbal substance. Children from
and up to 10 years 710 mg herbal substance daily. 115 (0.22%) adverse effects were reported. The most frequent adverse effects were: diarrhoea (0.1%), enteritis (0.04%), allergic exanthema/urticaria (0.04%) and vomiting (0.02%). In total, gastrointestinal disturbances occurred in 0.17% of children. The incidence of adverse effects was age dependent. In children under 1 year, adverse effects occured in 0.4% and in children upon 9 years in 0.13%.
The study provides substantial information on tolerance and safety, because it included a large number of patients (42,478 patients) and relatively high dosages were administered.
Fazio et al. (2009): A total of 10,562 patients were recruited by 3,287 doctors participating in an open multicenter postmarketing study in 11 Latin American countries. Nine hundred and five patients were not eligible for analysis because they did not show up for the
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The recommended dosages were:
The study provides substantial information on tolerance and safety because it included a large number of patients, and relatively high dosages were administered. The results show a higher event rate than the retrospective study by Kraft (2004). A point for criticism is the high rate of drop outs. Nine hundred and five patients, 8.6% of 10,562 patients, were not analysed because they did not take part in the
antibiotic group was not comparable to that of the ivy group. Therefore, the efficacy results have only supportive character for simple acute bronchitis. The duration of the study was 7 days, so it is not appropriate to draw any conclusions of efficacy in chronic bronchitis.
ache, drowsi- ness, palpitation, sweating and others
46 (0.5%) patients discontinued therapy due to adverse events
Landgrebe et al. (1999): A discussion about an extract of Hedera helix (ivy) was presented, including the contents of active substances and an examination of pertinent literature on clinical tests of the therapeutic effects as an expectorant in obstructive respiratory system disorders. The authors concluded an
Hofmann et al. (2003): A systematic review of trials documented in the literature with re- analysis of original data was performed to investigate the efficacy of dried ivy leaves in the treatment of chronic airway obstruction in children suffering from bronchial asthma. Five randomized controlled trials investigating the efficacy of ivy leaf extract preparations in chronic bronchitis were included. Three of these trials were conducted in children and met the selection criteria. One trial compared ivy leaf extract cough drops to placebo (n=24), one compared suppositories to drops (n=26) and one tested syrup against drops (n=25). The main outcome measures were
The CDR (Centre for Reviews and Dissemination) (2008) assessed the results of the review, that ivy leaf preparations may lead to improvement of respiratory functions, as promising but based on limited and low quality evidence.
Guo et al. (2006): In a review the authors referred to the effectiveness of different herbal medicines for treating chronic obstructive disease. The authors concluded that currently the evidence from randomised clinical trials was scarce and often methodologically weak. For ivy, only one clinical study meets the criteria stated by EMA for COPD.
4.2.3. Clinical studies in special populations (e.g. elderly and children)
Well established use:
Ivy preparations are used commonly in children. In prospective conducted clinical studies more than 7,000 children were involved. More than 52,000 children were analysed in a retrospective study. The safety studies were conducted with a large number of children including groups of low age, for example:
The tolerability was judged by physicians and patients as “good” and “very good” in ranges of approximately
The following studies were conducted in children:
The used dosages of the relevant extracts are tabulated in table 7 and 8. The daily dosages used in children are in high ranges.
maximally 420 mg (over 12 years).
In accordance with the above listed study results and the literature, for all
No study indicates that dosages higher than 656 mg herbal substance are necessary for efficacy in adults.
It is proposed that the group of
The use in children under 2 years is contraindicated due to possible aggravation of respiratory symptoms. See also chapter 5.5.
For the herbal preparation in the traditional use part usage in children has been documented. The use in children under 4 years is not recommended because medical advice should be sought.
4.3. Overall conclusions on clinical pharmacology and efficacy
The comparative study of
Ambroxol has a well established use licence for the indication “For secretolytic therapy in acute and chronic bronchopulmonary diseases, concomitant with disturbance in formation and transport of viscous sputum”. In the ATC classification system of the WHO, ambroxol is classified as R (respiratory system), R05 (cough and cold preparations), R05C (expectorants, excl. combinations with cough suppressants), R05CB (mucolytics).
The study of
productive cough, often fever, sore throat, secretion of the nose and sometimes bronchial obstruction) does not exactly reflect the therapeutic benefit proven for ivy.
Symptom scores were analysed in many of
In summary, the data from numerous clinical trials and the existing medicinal products fulfil the requirements of a
Based on the clinical data the monograph has a WEU part and a traditional part:
a) The data of the following herbal preparations fulfil the requirements of a
The herbal preparations
After the HMPC discussion, it was decided to add the liquid extract (1:1), extraction solvent: ethanol 70% (V/V) in the WEU part of the monograph. It was considered, that the liquid extract (1:1), extraction solvent ethanol 70% (V/V) is comparable to the dry extract
The HMPC also decided to add the dry extract (DER
The HMPC further decided that for the WEU liquid preparation with the extraction solvent ethanol 70% (V/V) the use in children under 6 years of age cannot be recommended due to the content of ethanol per single dosage.
b) For the preparation soft extract (DER
secretolytic in common cold. The following indication is displayed in the traditional use part of the monograph: “Traditional herbal medicinal product used as an expectorant in cough associated with cold. The product is a traditional herbal medicinal product for use in the specified indication exclusively based upon
Table 9: Posology recommended in the literature
The used dosages of clinical studies are tabulated in table 7 and 8. The daily dosages are in high ranges:
In accordance with the above mentioned study results and the literature for all
From the published data it can be concluded, that the discussion about high dosages started in 1997 with the study of Gulyas (1997). The statement of Gulyas (1997) “the
The study by Gulyas (1997) was conducted in 25 children
children for efficacy. There is no study that indicates that younger children
According to Hecker (1997a, b), the dosage of an ethanolic dry extract which is solved in an
The Kooperation Phytopharmaka (2003) concluded, in a statement referring to the dosage of ivy preparations in children, that Gulyas (1997) was wrong. The Kooperation Phytopharmaka was of the opinion that based on the results of surveillance studies with different ivy preparations, it could be concluded that they were well tolerated in a higher range. For example, the open multicenter surveillance study by Jahn and Müller (2000) using both FEV1 and a measure of symptomatic benefit, included 372 children under 12 years, treated with an
Based on the above mentioned data, it is recommend that the maximum dosage of preparations of ivy dry extract
Adults and children over 12 years: 656 mg herbal substance.
The use in children under 2 years of age is contraindicated because of the risk of aggravation of respiratory symptoms (See also chapter 5.5.).
One preparation has been marketed in Germany for more than 33 years, where it has been used for the treatment of symptoms of the common cold.
There is a comprehensive bibliographic revision to show the evidence of traditional use.
The safety and plausibility of efficacy of this preparation is based on the
The traditionally used dosages are in “lower” ranges, in comparison with the
Duration of use:
The duration of use in clinical studies varied from 3 days to 4 weeks. In order to assure safe use as a traditional herbal medicinal product in the scope of the registration the duration of use is limited. The following wording is introduced in the monograph: “If the symptoms persist during the use of the medicinal product longer than a week, a doctor or a qualified health care practitioner should be consulted.”
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
Studies referring to allergic reactions
Hausen et al. (1987): The principal allergens were isolated by using sensitized guinea pigs, and were identified as falcarinol and dehydrofalcarinol. In addition, 4 patients with ivy allergy, described by case reports, have been patch tested. Even in low concentrations (0.03%), the main allergen falcarinol elicited strong reactions in all of them. Dehydrofalcarinol elicited equal patch test reactions only when concentrated as high as 1%. The authors demonstrate that falcarinol is the main sensitizer, while dehydrofalcarinol is also an allergen but does not elicit reactions in all patients.
Gafner et al. (1988): In a human maximization test of 5% falcarinol isolated from Hedera helix, 10 of 20 subjects were sensitised. No subjects gave irritant reactions to 5%, 10 became sensitive to 1% and 7 to 0.05%, with 3 of these giving 3+ to 4+ bilious reactions. The authors concluded that the ability of falcarinol to sensitize 10 of 20 subjects at a
Mahillon et al. (2006): A group of 59 patients with allergic rhinitis were submitted to skin prick tests (SPT) using both the leaves of their own indoor plants and commercial extracts of the most frequent airborne allergens. A control group of 15 healthy subjects was tested with the same allergens. While no subject from the control group developed a significant SPT to any of the tested plants, 78% of allergic rhinitis had positive SPT to at least one plant, the most frequent sensitization being Ficus benjamina, yucca, ivy and palm tree. The authors concluded, in allergic rhinitis, that indoor plants should be considered as potential allergens. The allergen avoidance of the concerned plant was considered useful.
So far, data on the allergenic potential of falcarinol focus on cutaneous use. Knowledge on quantities of falcarinol and derivatives in herbal preparations of ivy leaf for oral use is limited.
5.2. Patient exposure
Ivy preparations have been marketed worldwide in many countries in large quantities. More than 10,000 patients have been included in open multicenter prospective surveillance studies with a high dosage range. Approximately 7,000 children were included in prospective clinical studies. A retrospective study was conducted with about 52,000 children.
5.3. Adverse events and serious adverse events and deaths
Wichtl (2004) and Wagner and Reger (1986): The occurrence of the alkaloid emetin could not be confirmed in recent studies. Toxic effects due to the presence of emetine and cephaeline were unlikely, in view of the low concentration isolated (Mayer et al., 1987).
Mühlendahl (1995): In a period of 10 years
Czygan (1990): Vomiting and diarrhoea occurred in 9 cases of 65 children who had eaten ivy berries.
Frohne and Pfänder (2004): In a period of 7 years in a toxicological centre in Berlin, 516 toxicological events had been documented. Only a few adverse events with vomiting and diarrhoea referred to ivy poisoning. The authors recommended fluid intake and symptomatic treatment.
Ivy poisoning in humans
Gaillard et al. (2003) reported one fatal case of asphyxia caused by leaves of common ivy. Macroscopic examination of the corpse during the autopsy disclosed an incredible quantity of leaves of Hedera helix in the mouth and throat of the decedent. In order to rule out the possibility of poisoning by the toxic saponins contained in the plant, they have developed an efficient LC-
Under these conditions, saponins in powdered dried leaves of Hedera helix were measured at a concentration of 21.83 mg/g for hederacoside C, 0.41 mg/g for
The causal relationship to codeine, according the physician’s comment, is probable. Adverse neurotoxical effects of over dosage of narcotics are known. Ibuprofen is metabolised by the liver and an influence on the codeine/morphine metabolism is therefore considerable. An interaction with the ivy preparation is theoretically also possible. Despite of the unknown formulation and dosages in the case reports an interaction with narcotics as codeine and morphine should be considered as a signal (see chapter 4.4 special warnings and precautions for use in the monograph).
There are 63 case reports in the BfArM Database on suspected adverse drug reactions (October 2009). Most of them are related to allergic reactions (urticaria, skin rash, tuberose, dyspnoea) and gastrointestinal reactions (nausea, vomiting and diarrhoea). Beside these reactions, other adverse events occur and are listed below together with the case reports of the literature.
A review of older dermatitis cases (1909 up to 1979) is given by Mitchell (1979). The author concluded, based on present evidence, that it is reasonable to conclude that Hedera helix is an irritant plant, which may also on occasions induce sensitization. Contact dermatitis has also been
reviewed by Hausen et al. (1987) and updated by Lovell (1993). In the majority of cases, a direct contact dermatitis occurs after pruning ivy in the garden. According to Frohne and Pfänder (2004), 60 cases of hyposensitive reactions have been published since 1899.
Hausen et al. (1987) described 32 cases of irritant and allergic contact dermatitis caused by Hedera helix subspecies
Murdoch et al. (2000) and Machado et al. (2002) recommend that patients allergic to falcarinol (present in carrots) should also avoid a number of Araliaceae family plants, such as common ivy, Schefflera actinophylla (umbrella tree) and Schefflera arboricola.
Published case reports
Mitchell (1981): A 33 year old female developed acute vesicular dermatitis of the hands, wrist, forearms and face after pruning garden ivy. A patch test produced a (+) reaction to leaf of Hedera helix.
Boyle (1985): A 31 year old female patient developed an acute weeping eczematous eruption with bulla formation, periorbital oedema and pain. This affected her arms, dorsa of hands, face and neck. The lesions healed under treatment with systemic steroids, antibiotics and wet compresses slowly over 3 weeks. Patch tests to the crushed leaves were positive (++) at 48 and 96 h.
Garcia (1995): A 44 year old non atopic man developed contact dermatitis with erythrema and papules
Johnke and Bjarnason (1994): A case of allergic contact dermatitis to common ivy is presented. The patient a 16 year old female gardener, who developed severe blistering dermatitis of the hands, forearms and face after frequent contact with Hedera helix. The authors wish to draw attention to common ivy as a sensitizer.
Yesudian and Franks (2002): A 50 year old man was admitted in April 1999 with severe eczema on the right upper limb and less florid involvement of the trunk (UK). His wife had simultaneously developed eczema on her trunk. 10 days prior to onset, the patient had scratched his right arm while cutting roses. He subsequently spent time pruning common ivy (H. helix) and his wife helped him to clear the trimmings. Four days later, the patient’s right arm became itchy and exsudative at the site of the scratch. A diagnosis of cellulites was made and penicillin and flucloxacillin were prescribed. The patient felt well and 3 days prior to admission he completed pruning the plant and his wife assisted him again. Over the next 3 days, both husband and wife developed extensive eczema. On examination, an acute eczema with confluent erythematous vesicular and bullous
lesions was noted on the right forearm, with less severe patchy involvement of the trunk. A linear streak of small vesicles was seen on the dorsum of the right hand. His wife showed less florid vesicular erythematous plaques on the forearm and trunk. Allergic phytodermatitis from common ivy was diagnosed.
Özdemir et al. (2003): The authors reported a case of a male hobby gardener with appropriate clinical history (2 days after working in the garden develops an erythrema on hand and neck, and 2 days later an oedema) and positive patch test on Hedera helix. The pathogenic mechanism was a type IV reaction following a sensitization exposure. Contact with common ivy or falcarinol may lead to sensitization and then a delayed hypersensitivity reaction. It was recommended to gardeners and landscape architects with frequent exposure to common ivy and thus a high risk of sensitization to wear appropriate protective clothing.
Hannu (2008): The authors presented the first case of ivy induced occupational asthma. A 40 year old female who had worked in her own flower shop for the past 11 years had symptoms of cough 4 years prior to the current examinations, and one year later dyspnoea. The skin prick test was negative. Peak flow varied between
Thormann et al. (2008) reported a case of contact urticaria to common ivy and rosemary with
Neurotoxicity and psychoactive effects
Turton (1925): A boy aged 3.5 years developed mild delirium after ingestion a considerable quantity of ivy leaves. During the delirious stage clonic convulsions developed. He screamed and cried and could not stay still/upright. He had visionary hallucinations lasting for many hours. An intense scarlatiniform rash most marked on the legs, face and back was present. There was no vomiting. The pupils were widely dilated and the temperature was raised. The pulse was rapid but full and bounding. The symptoms abated after wash out the stomach and in about 3 h he was fairly well. Cited also by De Smet et al., (1993).
Polizzi et al., (2001): A 3 year girl developed episodic stiffness and abnormal posturing with rigidity after ingestion of a mixture of methyl codeine and an extract from Hedera (no information about DER, extraction solvent and dosages). These paroxysmal events persisted for 24 h then promptly disappeared. There was severe painful stimulus sensitive multifocal dystonia, superimposed on voluntary actions and postures each time involving face, eyes, jaw, neck, hands and legs. The patient could neither walk nor stand. The drug was discontinued and the patient was treated with saline solution intravenously. The patient was well thereafter.
Adverse effects and over dosage of narcotics (codeine, dextromethorphane) associated with administration of “cough and cold preparations” (not near explained) in children are reported (Polizzi et al., 2001). Interaction with narcotics as codeine and morphine should be considered as a signal (see chapter 4.4 special warnings and precautions for use in the monograph).
Neurotoxical effects of antihistamine drugs are known and are stronger in children than in adults. Therefore a causal relationship to desloratadin is probable while unlikely to the ivy preparation. Information about the ivy preparation is limited.
Because of limited information, a causal relationship to the ivy preparation cannot be concluded, but also cannot be completely ruled out. Based on this data, at present no labelling is necessary.
Other adverse drug reactions described in the literature
Hoppe (1981): Ivy has cardiac effects. No near explanations or case reports are given.
According to the monograph Hedera helix of the Kommission D (1986) ivy is also used in homeopathic preparations. The homeopathic is indicated among others in hyperthyroidism. Homeopathic preparations up to D4 can increase a hyperthyroidism (Hedera helix, monograph of the Kommission D (1986).
Ivy poisoning in animals
Brömel and Zettl (1986) reported ivy poisoning in a roe deer after eating ivy after a fall of snow. It was showing signs of nervous disease; therefore the animal was killed and sent to the laboratory. Ivy leaves were present in the rumen.
On the other side, Metcalfe (2005) describes in a
Mills and Bone (2000): Saponins are toxic to fish and other
5.4. Laboratory findings
Unkauf and Friderich (2000): In a randomized prospective multicenter, reference controlled study, 52 children (mean 7.9 years) with a clinically proved bronchitis were treated either with Valverde® (200 ml juice contains
2 x 10 ml daily. The duration of the study was 10 days. The comparison of the laboratory values (haemoglobin, haematocrit, erythrocytes, thrombocytes, LDH, GOT,
5.5. Safety in special populations and situations
Mills and Bone (2000): Saponins readily increase the permeability of the mammalian small intestine
There were two adverse events (Polizzi, 2001; BfArM case nr. 06002941) occurring by administration of narcotics (as antitussives) and ivy preparations. The hepatic glucoronidation pathway is incompletely developed in infants, which places them at particular risk of adverse dose- related effects (ex. from codeine or dextromethorphan). Furthermore, alteration of hepatic enzyme pathways by illness or concurrent drug therapy may further alter metabolism of these drugs and increase the risk of drug toxicity (American Academy of Paediatrics 1997). Adverse effects and over dosage of narcotics (codeine, dextromethorphan) associated with administration of cough and cold preparations in children are reported. Due to the unknown formulation and dosages of the ivy products and less information in the case reports, an interaction of ivy products with narcotics should be considered as signal (see chapter 4.4 special warnings and precautions for use in the monograph).
Safety studies in children
Well established use:
The safety studies were conducted with a large number of children in low age groups as well, for example:
In prospective conducted clinical studies more than 7,000 children were involved. The tolerability was assessed by physicians and patients as “good” and “very good” in ranges of approximately
Fazio (2009): In the study 5,181 (53.73%) children was treated with Prospan® cough juice (100 ml contains 0.7 g dry ivy extract
discontinued therapy due to adverse events, mainly to gastrointestinal disorders. The main adverse
events were: 1.5% gastrointestinal disorders (diarrhoea 0.8%, abdominal and epigastric pain 0.4%, nausea and vomiting 0.3%), 0.1 skin allergy. Other adverse events occurring less than 0.1% were: dry mouth and thirst, anorexia, eructation, stomatitis, anxiety, headache, drowsiness.
Kraft (2004): The retrospective study was conducted with approximately 52,478 patients. The most frequent adverse effects were: diarrhoea (0.1%), enteritis (0.04%), allergic exanthema/urticaria (0.04%) and vomiting (0.02%). In total, gastrointestinal disturbances occurred in 0.17% of the children. The incidence of adverse effects was age dependent. In children under 1 year, adverse effects occurred in 0.4% and in children up to 9 years in 0.13%.
In April 2010, The French Health Agency decided to contraindicate the use of mucolytic agents in children below 2 years of age. This decision was based on a national Pharmacovigilance Survey on mucolytics and agents that fludify bronchial secretions. The investigation revealed a risk of respiratory congestion and rising bronchiolitis in infants due to functional features of their air passages and thoracic cavity (small calibre bronchi, immature bronchial surfaces that limit the lung’s capacity to remove mucus flow). The Italian Medicines Agency took the same measure.
The HMPC decided to accept the use in children from
Soft extract (18.104.22.168:1), extraction solvent ethanol 50% (V/V): propylene glycol (98:2):
The HMPC considered the use in children under 4 years of age as generally not recommended in traditional use, due to considerations concerning clinical safety for this age group where medical advice should be sought.
Considering the traditional use of 30 years in children and the data on posology the following posology is recommended:
Daily dose: 80 mg
Children of 4 years of age
Herbal preparation A:
Single dose: 20 mg
Daily dose: 60 mg
Use in pregnancy and lactation
Mahran et al. (1975) separated emetine alkaloid from an alcoholic extract (90% ethanol) of four varieties of Hedera helix L. growing in Egypt. The author concludes, since ivy possibly contains small amounts of emetine, that it should not be recommended during pregnancy, as emetine may increase uterine contractions. According to Wichtl (2004), the occurrence of the alkaloid emetine could not be confirmed in recent studies.
ESCOP (2003): No human data are available. In accordance with general medical practice, the product should not be used during pregnancy and lactation without medical advice.
Safety during pregnancy and lactation has not been established. In view of the
Overdose, drug abuse
Teat and Ellis (1981): Symptoms of poisoning vary among individuals and may include salivation, nausea, vomiting, diarrhoea, abdominal pain, headache, fever, excessive thirst, rash, and mydriasis. Haemolysis has also been reported which is proportional to the amount ingested. Ataxia, muscular weakness and incoordination may also occur. The author recommends that the treatment English Ivy poisoning should be initiated by inducing emesis with syrup of ipecac. Gastric lavage and the administration of activated charcoal should be considered for large ingestions (e.g. four or more berries or two or more leaves). After the ingested plant has been removed from the stomach, the patient should be given demulcents to provide comfort from the local irritation produced by the ivy.
This is a
ESCOP (2003): Overdosage can provoke nausea, vomiting, diarrhoea and excitation.
Withdrawal and rebound
Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
5.6. Overall conclusions on clinical safety
Ivy fresh plant is known to cause contact dermatitis, which is documented in numerous reports (Mitchell, 1979). Such reactions are attributed to falcarinol and derivatives in relation to skin contact or cutaneous use. With respect to oral administration, neither data from clinical studies nor case reports on adverse events give a clear hint on potential risks. However, the quantities of falcarinol and its derivatives in herbal preparations of ivy leaf are not well documented. Until now, it can not be completely excluded that even low levels could contribute to elicit an allergic response in patients with a
There are suggestions of an association between ivy and rhinitis symptoms (Mahillon, 2006) and a first case of occupational asthma, related to the fresh plant, is documented (Hannu, 2008). Mild
delirium occurred in a 3 year boy after ingestion of a considerable quantity of ivy leaves. During the delirious stage clonic convulsions developed, the boy screamed and cried, and he could not stay still upright. He had visionary hallucinations.
According to Kommission D monograph, (homeopathic) ivy preparations up to D4 can increase a hyperthyroidism. Because no published well documented cases of hyperthyroidism are reported, the effect is not mentioned in the monograph.
The dosage of ivy preparations (preparations intended for
In the chapter “overdosage” the information that overdose of ivy preparations can provoke nausea, vomiting, diarrhoea and excitation should be included. One case of aggressivity occurs. Further neurotoxical reactions observed after consumption of ivy fresh leaves are not reported neither for the medicinal use of normal dosages nor for overdoses of ivy leaf preparations.
Interactions are not expected from the results of non clinical
From the long traditional use of ivy preparations in children no general safety concerns referring the use in therapeutic dosages can be derived. The use in children under 4 years of age is generally not recommended in traditional use, due to general considerations concerning clinical safety for this age group. Furthermore, medical advice should be sought for this patients group. Considering the traditional use of 30 years in children and the results of the two surveillance studies, the use is recommended only for children over 4 years of age. From the prospective clinical studies with approximately 7,000 children and a retrospective study conducted with about 52,000 children, it can be concluded that ivy preparations
Allergic reactions and gastrointestinal reactions may occur. From the study Fazio et al. (2009) which included more than 5,000 children, the frequency of adverse events can be calculated: gastrointestinal reactions in 1.5% (common ≥1/100 to <1/10) and allergic reactions in 0.1% (uncommon ≥1/1000 to ≤1/100). They must be included in the monograph. The saponins can induce nausea and vomiting that can lead to aspiration in infants. The use for children below 2 years of age is contraindicated because of the risk of aggravation of respiratory symptoms. Because of gastrointestinal reactions caution is recommended in patients with gastritis or gastric ulcer.
Safety during pregnancy and lactation has not been established. In view of the
6. Overall conclusions
Based on the data documented in this Assessment Report, the
Ivy preparations have been marketed worldwide in many countries, in large quantities. Symptom scores were analysed in a lot of studies, which were not blinded. There were more than 10,000 patients included in open multicenter prospective surveillance studies with a high dosage range. Most of the studies were conducted in children. Thus, the safety of the herbal medicine is appropriately analysed and known. The recommended dosages for the preparations correspond to the dosages used in praxis and are up to the maximum dosage used in the Gulyas (1997) study.
The data on one preparation do not fulfil the requirements of a
The herbal substance is subject of a European Pharmacopoeia monograph. An unambiguous macroscopic, microscopic chemical identification of the herbal substance is possible. Adulteration/contamination of the herbal substance is not reported. There are acceptable side effects concerning gastrointestinal reactions and allergic reactions with a therapeutic posology of the herbal preparations reported in literature or reference sources. No serious adverse events with a therapeutic posology of the herbal preparations are reported in literature or reference sources with a well documented history.
Genotoxicity investigations are available for some ivy saponines which are constituents of the herbal preparations and the herbal medicinal products. No genotoxic tests are available for the whole plant extracts. Well documented
The use in children under 2 years is contraindicated because of the risk of aggravation of respiratory symptoms. In the
Safety during pregnancy and lactation has not been established. In view of the
Therapeutic alternatives for the indication are available including chemical substances such as ambroxol. Ambroxol is known to have side effects concerning gastrointestinal reactions and allergic reactions. For no other herbal preparation a
Intoxication, due to ivy herbal medicinal preparations, is not reported in literature or reference sources. One case of overdose led to aggressivity and diarrhoea.
It can be concluded that the benefit/risk assessment for ivy preparations is positive for the use as an expectorant in the context of infections of the upper respiratory tract under specific conditions and in therapeutical dosages.