Ivy leaf dry extract EA 575 for the treatment of acute and chronic cough in pediatric patients: review and expert survey

Figures & data

Table 1. Summary of controlled clinical trials of EA 575 in pediatric patients.

Reference	Design	EA 575 dosage form(s)	Comparator	EA 575 dose^a	Treatment duration	Disease area	Number of children (age range)	Concomitant medication usage	Setting	Efficacy/tolerability outcomes
Gulyas et al. (1997)^19	Randomized, double-blind, crossover	Syrup, drops	Different dosage forms	Syrup: 630 mg/day Drops: 252 mg/day	10 days	COPD	27 (10–16 years)	Not specified	Germany, inpatients	Spirometry: improvements in FEV1, FVC, VC, and PEF with syrup and drops Body plethysmography: clinically relevant improvements in RAW, ITGV, and sRAW with syrup and drops
Mansfeld et al. (1997)^1^,^20	Randomized, open-label, crossover	Suppositories, drops	Different dosage forms	Suppositories: 1,000 mg/day Drops: 218 mg/day	3 days with each dosage form	Bronchial asthma	26 (5–11 years)	Not specified	Switzerland, inpatients	Patient/parent-rated assessment of cough symptoms: no clinically relevant changes or differences between groups in the intensity/frequency of cough and shortness of breath Spirometry: clinically relevant improvements in FEV1 and FVC with suppositories and drops Body plethysmography: clinically relevant decreases in RAW with suppositories and drops Patient/parent- and clinician-rated global assessment of tolerability: “very good” in 25 children in both groups
Mansfeld et al. (1998)^21	Randomized, double-blind, crossover	Drops	Placebo	210 mg/day	3 days with drops and 3 days with placebo	Bronchial asthma	28 (4–12 years)	Not specified	Switzerland	Patient/parent-rated assessment of cough symptoms: no differences between EA 575 and placebo in frequency of dose-metered aerosol use, in intensity of shortness of breath, and in description of cough Spirometry: clinically relevant, numerically greater improvements in FEV1, FVC, and VC with EA 575 vs placebo Body plethysmography: significant improvements in RAW and ITGV with EA 575 vs placebo Patient/parent- and clinician-rated global assessment of tolerability: “very good” in all children in both groups
Gulyas (1999)^1^,^22	Controlled, pilot	Syrup	Acetylcysteine	630 mg/day	14–20 days	Chronic obstructive bronchitis	20 (9–15 years)	Not specified	Germany, inpatients	Spirometry: similar improvements in VC with EA 575 and acetylcysteine; greater improvements in FEV1 and PEF with EA 575 vs acetylcysteine Body plethysmography: greater improvement in RAW with EA 575 vs acetylcysteine
Unkauf and Friederich (2000)^1^,^23	Randomized, open-label	Syrup	Valverde (ivy leaf dry extract DER 3–6:1, 60% ethanol)^b	Age <4 years: 350–490 mg/day Age 4–10 years: 525–735 mg/day Age 10–12 years: 700–980 mg/day	10 days	Bronchitis	52 (≤12 years)	Not specified	Germany	Clinician-rated assessment of cough symptoms: no relevant between-group differences in bronchitis, expectoration, or cough Clinician-rated assessment of bronchitis-related impairment: bronchitis severity decreased, with non-inferiority of EA 575 vs DER 3–6:1 Clinician-rated disease severity: similar decreases in bronchitis severity with EA 575 and DER 3–6:1 AEs: no AEs were reported
Maidannik et al. (2003)^1^,^24	Open-label, interventional	Syrup	Ambroxol	Age 1–6 years: 1 tsp t.i.d. Age 7–14 years: 2 tsp t.i.d.	Acute disease: 7–10 days Chronic disease: 10–14 days	Acute and chronic respiratory diseases	72 (7 months–15 years)	Not specified	Ukraine, inpatients	Clinician-rated assessment of cough symptoms: frequency of shortness of breath resolved in both treatment groups, and productive cough decreased with EA 575 and ambroxol with no significant between-group differences Patient/parent- and clinician-rated assessment of efficacy: “excellent” or “good” by 86.8% of patients/parents and 90.1% of clinicians Spirometry: abnormal respiratory velocity parameters in 7.2% with EA 575 and 68.6% with ambroxol
Bolbot et al. (2004)^1^,^25	Open-label, interventional	Syrup	Acetylcysteine	Age 2–6 years: 630 mg/day Age 7–10 years: 1,260 mg/day	7–10 days	Acute bronchitis	50 (2–10 years)	26 children (antibiotics, antihistamines, etc.)	Ukraine	Clinician-rated assessment of cough symptoms: cough frequency, sputum viscosity, shortness of breath, and respiratory pain normalized in a similar timeframe with EA 575 acetylcysteine Spirometry: FEV1, FVC, PEF, MEF25, MEF50, MEF75, and AWSV25–75 showed significantly greater improvements with EA 575 vs acetylcysteine after treatment Clinician-rated global assessments of efficacy and tolerability: “very good” or “good” efficacy in 96% with EA 575 and in 79.2% with acetylcysteine; “very good” or “good” tolerability in 100% with EA 575 and in 76% with acetylcysteine
Brattström et al. (2006)^1	Open-label	Syrup	Ivy leaf dry extract (DER 3–6:1)	Age <4 years: 5 ml b.i.d. Age 4–10 years: 7.5 ml b.i.d. Age >10 years: 10 ml b.i.d.	10 days	Acute bronchitis	52	Not specified	Not specified	Assessment of bronchitis symptoms: therapeutically equivalent improvement with EA 575 and DER 3–6.1
Cwientzek et al. (2011)^1^,^26^,^27	Randomized, double-blind	Drops^b	Hedelix (ivy leaf soft extract DER 2.2–2.9:1, 50% ethanol/propylene glycol)	Age 2–4 years: 12 drops t.i.d. Age 4–10 years: 16 drops t.i.d.	7 days	Acute bronchitis	201 (2–10 years)^c	8 children received an inadmissible medication (most antibiotics)	Czech Republic	BSS and BSS subscales: similar improvements in both groups, confirming non-inferiority of EA 575 vs DER 2.2–2.9:1 Patient- and clinician-rated global assessments of efficacy and tolerability: high and comparable between the groups AEs: 2.7% reported an AE; most AEs were gastrointestinal, and all were non-serious
Zeil et al. (2014)^28	Randomized, double-blind, crossover	Syrup	Placebo	5 ml b.i.d.	28–30 days with syrup and 28–30 days with placebo	Bronchial asthma	30 (6–12 years)	All received 400 μg/day budesonide equivalent	Germany	Spirometry: no significant differences in relative change in FEV1 and MEF75–25 before bronchodilation with EA 575 vs placebo Body plethysmography (RAW), FeNO, EBC pH, PAQLQ: no changes with EA 575 or placebo ACQ: decreased with placebo (p < 0.05) but not with EA 575

^aDose given as mg herbal substance, where provided; ^bEA 575 was the comparator drug in this study; ^cthe study also included adults (data not shown).

Early (before 1992) non-controlled studies are not presented as the EMA considers their methodology to be inadequate to show the efficacy of currently marketed formulations of EA 575¹.

Abbreviations. ACQ, Asthma Control Questionnaire; ADR, adverse drug reaction; AE, adverse event; AWSV_25–75, average inhalation weight hour space velocity at 25–75% of the vital capacity; b.i.d., two times per day; BSS, Bronchitis Severity Score; COPD, chronic obstructive pulmonary disease; DER, drug extract ratio; EBC pH, exhaled breath condensate pH; EMA, European Medicines Agency; FeNO, fractional exhaled nitric oxide; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; ITGV, intrathoracic gas volume; MEF_25/50/75, maximal expiratory flow at 25/50/75% of the vital capacity; MEF_75–25, maximal expiratory flow at 75–25% of the vital capacity; PAQLQ, Pediatric Asthma Quality of Life Questionnaire; PEF, peak expiratory flow; RAW, airway resistance; sRAW, specific airway resistance; t.i.d., three times per day; tsp, teaspoon; VC, vital capacity.

Table 2. Summary of observational studies of EA 575 in pediatric patients.

Reference	Design	EA 575 dosage form(s)	EA 575 dose and treatment duration	Disease area	Number of children (age range)	Concomitant medication usage	Setting	Efficacy/tolerability outcomes
Lässig et al. (1996)^1^,^29	Prospective, surveillance	Syrup	At discretion of clinician	Recurrent obstructive respiratory diseases	113 (6–15 years)	73%; mostly inhaled combination cromolyn sodium/sympathomimetic	Germany	Clinician-rated assessment of cough symptoms: significant improvements in frequency of cough and expectoration Spirometry: significant improvements in FEV1, FVC, PEF, MEF25 and MEF50 Clinician-rated assessments of improvement and tolerability: 85.7% of children were “cured” or “significantly improved”; tolerability was “very good” or “good” in 98.2% AEs: no AEs reported
Hecker (1999)^30	Prospective, post-marketing surveillance	Syrup (age 0–9 years) or effervescent tablets (age ≥4 years)	According to manufacturer recommendations	Inflammatory and/or obstructive respiratory diseases	176 (≤15 years)^a	Not specified	Germany	[Adults and children combined] Clinician-rated assessment of cough symptoms: “cured” or improved cough and expectoration in ∼90%, and shortness of breath and respiratory pain in ∼60% Clinician-rated global assessments of efficacy and tolerability: “very good” or “good” efficacy in 86%; “very good” or “good” tolerability in 98% AEs: 1 AE reported (allergic exanthema)
Hecker et al. (2002)^31	Prospective, post-marketing surveillance	Effervescent tablets	At discretion of clinician	Chronic bronchitis	165 (4–12 years)^a	52.0%; an airway- relevant product in 14.8%	Germany	[Adults and children combined] Clinician-rated assessment of cough symptoms: “cured” or improved cough and expectoration in >90%, and shortness of breath and respiratory pain in >80% Clinician-rated global assessment of efficacy: “very good” or “good” in 91% AEs: 6 patients (0.4%); 4 discontinued treatment
Kraft (2004)^32	Retrospective	Syrup	At discretion of clinician	Symptomatic respiratory diseases	52,478 (0–12 years)	Not specified	Germany	ADRs: 0.22% in children (diarrhea, 0.1%; enteritis, 0.04%; allergic exanthema/urticaria, 0.04%; vomiting, 0.02%); incidence was age-dependent (0.4% aged <1 year, 0.13% aged >9 years)
Fazio et al. (2009)^33	Prospective, post-marketing surveillance	Syrup	According to manufacturer recommendations: 2.5–7.5 ml t.i.d. (depending on age) for 7 days	Acute or chronic bronchitis	5,181 (0–14 years)^a	59.1%; 36.2% received antibiotics	Latin America, outpatients	[Adults and children combined, except AEs] Clinician-rated assessment of cough symptoms: improvement/healing of cough, expectoration, dyspnea, and pain in >90% Clinician-rated global assessment of tolerability: “very good” or “good” in 96.6% Discontinuation: 4.0%; 1.9% due to improvement/healing AEs: 112 in children; mostly gastrointestinal
Beden et al. (2011)^34	Prospective, non-interventional	Syrup	At discretion of clinician for 7 days	Acute respiratory tract infection	193^b (2–14 years)	33.7%; 36 received systemic antibiotics	Slovenia	Clinician-rated assessment of cough symptoms: complete or partial improvement in coughing (95.3%) and expectoration (94.7%); most children with difficulty breathing and pain experienced complete improvement Patient-rated assessments of improvement and tolerability: 93.7% had “complete” or “partial” improvement; 97.9% had “very good” or “good” tolerability AEs: 1 AE (hives) was reported; 3 children discontinued treatment
Stauss-Grabo et al. (2011)^35	Prospective, non-interventional, post-marketing surveillance	Tablets	≥2 tablets b.i.d. for ≥7 days	Colds with cough, chronic inflammatory bronchial diseases	36 (11–20 years)^a	Not specified	Germany	[Adults and children combined] Patient- and clinician-rated global assessment of tolerability: “very good” or “good” by 96.4% of patients and by 98.5% of clinicians ADRs: 1 ADR (nausea)
Lang et al. (2015)^36	Prospective, non-interventional, post-marketing surveillance	Syrup, drops, liquid, effervescent tablets, and lozenges	At discretion of clinician for 7 days	Acute bronchitis	1,066 (6–12 years)	27.0% for respiratory conditions, mostly nasal sprays/drops (n = 95) and antibiotics (n = 28) 47 received antibiotics for a co-infection	Germany, outpatients	Patient/parent- and clinician-rated assessment of cough symptoms: patients/parents reported 42.1–58.1% decreases in cough intensity, chest pain, shortness of breath, sleep problems, expectoration, and cough attacks; clinicians reported ∼50% decreases in intensity of cough attacks, expectoration/sputum, dyspnea, and breath sounds BSS: 79.3% improvement Patient/parent- and clinician-rated global assessments of efficacy and tolerability: “very good” or “good” efficacy by 91.2% of patients/parents and 93.2% of clinicians; “very good” or “good” tolerability by 95.4% of patients/parents and 96.7% of clinicians ADRs: 10 (0.9%); 7 gastrointestinal, 2 allergic, 1 other
Kruttschnitt et al. (2020)^37	Prospective, non-interventional, post-marketing surveillance^c	Syrup	At discretion of clinician	Acute bronchitis	30 (6–17 years)^a	18.0% of children and adults received antibiotics; 22.3% received other medication	Switzerland	[Adults and children combined] Patient/parent-rated assessment of cough symptoms: reductions in cough intensity, chest pain, cough-related sleep disturbance, and expectoration BSS: continuous reduction in score Patient- and clinician-rated global assessment of tolerability: EA 575 rated “very good” or “good” by 98.3% of patients/parents and by 99.1% of clinicians AEs: 2 AEs

^aThe study also included adults; ^bthis study enrolled 18 children aged <2 years who were excluded from the analyses; ^cthis study also enrolled children who were treated with acetylcysteine; the decision to treat with acetylcysteine or EA 575 was made by the clinician before study enrolment, and only two children received acetylcysteine.

Abbreviations. ADR, adverse drug reaction; AE, adverse event; b.i.d., two times per day; BSS, Bronchitis Severity Score; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; MEF_25/50, maximal expiratory flow at 25/50% of the vital capacity; PEF, peak expiratory flow; t.i.d., three times per day.

Figure 1. Clinician-rated effectiveness of EA 575 on reducing symptoms in pediatric patients with cough (n = 10).

Effectiveness was rated on a 5-point scale: very good, good, moderate, poor, or very poor. No clinicians rated the effectiveness of EA 575 as very poor at reducing symptoms.

Figure 2. Clinician-reported aspects of quality of life that improve with EA 575 (n = 8).

This was an open question.

Gulyas A, Repges R, Dethlefsen U. Consequent therapy of chronic obstructive respiratory tract illnesses in children. Atemw Lungenkrkh. 1997;5:291–294. [Translated title]

 Google Scholar

European Medicines Agency (EMA) Committee on Herbal Medicinal Products (HMPC). Assessment report on Hedera helix L. folium. 2017; EMA/HMPC/325715/2017.

 Google Scholar

Mansfeld HJ, Höhre H, Repges R, et al. Sekretolyse und bronchospasmolyse. TW Pädiatrie. 1997;10(3):155–157.

 Google Scholar

Mansfeld HJ, Höhre H, Repges R, et al. Therapie des Asthma bronchiale mit Efeublätter-Trockenextrakt. Munch Med Wochenschr. 1998;140(3):26–30.

 Google Scholar

Gulyas A. Efeublätter-Extrakt zeigt bei Kindern mit chronisch obstruktiven Atemwegserkrankungen vergleichbare Effekte wie Acetylcystein. 1999; [cited 2023 Feb 1]. Available from: https://phytokompass.de/efeublaetter-extrakt-zeigt-bei-kindern-mit-chronisch-obstruktiven-atemwegserkrankungen-vergleichbare-effekte-wie-acetylcystein/.

 Google Scholar

Unkauf M, Friederich M. Bronchitis bei kindern: klinische studie mit Efeublätter-Trockenextrakt. Der Bayerische Internist. 2000;4:1–4.

 Google Scholar

Maidannik V, Duka E, Kachalova O, et al. Efficacy of prospan application in children’s diseases of respiratory tract. Pediatr Tocol Gyn. 2003;4:1–7.

 Google Scholar

Bolbot Y, Prokhorov E, Mokia S, et al. Comparing the efficacy and safety of high-concentrate (5–7.5:1) ivy leaves extract and acetylcysteine for treatment of children with acute bronchitis. Drugs of Ukraine. 2004;11:1–4. [Translated title]

 Google Scholar

Cwientzek U, Ottillinger B, Arenberger P. Acute bronchitis therapy with ivy leaves extracts in a two-arm study. A double-blind, randomised study vs. an other ivy leaves extract. Phytomedicine. 2011;18(13):1105–1109. doi: 10.1016/j.phymed.2011.06.014.

 PubMed Web of Science ®Google Scholar

EU. Clinical Trials Register (2007-003272-19); [cited 2023 Feb 1]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-003272-19.

 Google Scholar

Zeil S, Schwanebeck U, Vogelberg C. Tolerance and effect of an add-on treatment with a cough medicine containing ivy leaves dry extract on lung function in children with bronchial asthma. Phytomedicine. 2014;21(10):1216–1220. doi: 10.1016/j.phymed.2014.05.006.

 PubMed Web of Science ®Google Scholar

Lässig W, Generlich H, Heydolph F, et al. Wirksamkeit und Verträglichkeit efeuhaltiger Hustenmittel. TW Pädiatrie. 1996;9:489–491.

 Google Scholar

Hecker M. Wirksamkeit und Verträglichkeit von Efeuextrakt bei Patienten mit atemwegserkrankungen. Natura Med. 1999;14(2):28–33.

 Google Scholar

Hecker M, Runkel F, Völp A. Behandlung chronischer Bronchitis mit einem Spezialextrakt aus Efeublättern – multizentrische Anwendungsbeobachtung mit 1350 patienten. Forsch Komplementärmed Klass Naturheilkd. 2002;9:77–84. doi: 10.1159/000057269.

 PubMedGoogle Scholar

Kraft K. Verträglichkeit von Efeublättertrockenextrakt im Kindesalter. Z Phytother. 2004;25:179–181.

 Google Scholar

Fazio S, Pouso J, Dolinsky D, et al. Tolerance, safety and efficacy of Hedera helix extract in inflammatory bronchial diseases under clinical practice conditions: a prospective, open, multicentre postmarketing study in 9657 patients. Phytomedicine. 2009;16(1):17–24. doi: 10.1016/j.phymed.2006.05.003.

 PubMed Web of Science ®Google Scholar

Beden AB, Perko J, Terčelj R, et al. Potek zdravljenja akutne okužbe dihal pri slovenskih otrocih s sirupom, ki vsebuje izvleček listov bršljana. Zdrav Vestn. 2011;80:276–284.

 Google Scholar

Stauss-Grabo M, Atiye S, Warnke A, et al. Observational study on the tolerability and safety of film-coated tablets containing ivy extract (Prospan® cough tablets) in the treatment of colds accompanied by coughing. Phytomedicine. 2011;18(6):433–436. doi: 10.1016/j.phymed.2010.11.009.

 PubMed Web of Science ®Google Scholar

Lang C, Staiger C, Wegener T. Efeu in der pädiatrischen Praxis: Anwendung von EA 575® in der Therapie der akuten Bronchitis bei Schulkindern. Z Phytother. 2015;36(05):192–196. doi: 10.1055/s-0041-105237.

 Google Scholar

Kruttschnitt E, Wegener T, Zahner C, et al. Assessment of the efficacy and safety of ivy leaf (Hedera helix) cough syrup compared with acetylcysteine in adults and children with acute bronchitis. Evid Based Complement Alternat Med. 2020;2020:1910656. doi: 10.1155/2020/1910656.

 PubMed Web of Science ®Google Scholar

Data availability statement

The dataset supporting the conclusions of this article is included within the article and its supplementary files (see Supplementary file 2).