Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
1.3. Search and assessment methodology....................................................................
8
2. Historical data on medicinal use ........................................................................................ 8
2.1. Information on period of medicinal use in the Community ........................................
8
preparations and indications.......................................................................................
8
3. Non-Clinical Data ............................................................................................................... 9
preparation(s) and relevant constituents thereof ...........................................................
9
preparation(s) and relevant constituents thereof ...........................................................
9
preparation(s) and constituents thereof .......................................................................
9
3.4. Overall conclusions on non-clinical data............................................................... 1
0
4. Clinical Data ..................................................................................................................... 10
4.1. Clinical Pharmacology ....................................................................................... 1
0
including data on relevant constituents ...................................................................... 1
0
including data on relevant constituents ...................................................................... 1
0
4.2. Clinical Efficacy ................................................................................................ 1
0
4.2.1. Dose response studies.................................................................................... 1
0
4.2.2. Clinical studies (case studies and clinical trials).................................................. 1
0
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 1
5
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 1
9
5. Clinical Safety/Pharmacovigilance................................................................................... 19
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 1
9
5.2. Patient exposure .............................................................................................. 1
9
5.3. Adverse events and serious adverse events and deaths ......................................... 1
9
5.4. Laboratory findings .......................................................................................... 1
9
5.5. Safety in special populations and situations ......................................................... 1
9
5.6. Overall conclusions on clinical safety ................................................................... 2
0
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page 2/20
1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
not applicable.
Herbal preparation(s)
not applicable.
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.
The herbal preparations with marketing authorisations consist of fixed combinations of dry extracts
(prepared with ethanol/water, methanol/water or water), soft extracts (prepared with ethanol/water,
methanol/water or water) or liquid extracts (prepared with a mixture of ammonia solution 10% m/m :
glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109) or ethanol/water) of thyme and Primula
root.
All of these products are marketed in Germany, some of them are authorised also in Austria, Czech
Republic and Slovakia.
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page 3/20
1.2.
Information about products on the market in the Member States
Austria
Combination of 160 mg dry extract from thyme (DER 6-10:1), extraction solvent ethanol 70% v/v and 60 mg dry extract from Primula root (DER 6-7:1),
extraction solvent ethanol 47.4% v/v. Date of authorisation: 2000. This combination is in Germany on the market at least since 1976 and therefore
considered in the monograph.
Czech Republic
Combination of 160 mg dry extract from thyme (DER 6-10:1), extraction solvent ethanol 70% v/v and 60 mg dry extract from Primula root (DER 6-7:1),
extraction solvent ethanol 47.4% v/v. Date of authorisation: 2001. This combination is in Germany on the market at least since 1976 and therefore
considered in the monograph.
Germany
Code in AR and
monograph
Composition
On the market
Posology
A
1 capsule contains:
75 mg dry extract from thyme (DER 6-10:1), extraction solvent ethanol 70% v/v
and
37.5 mg dry extract from Primula root (DER 3.5-4.5:1), extraction solvent water
at least since 1976 6-12 y: 2 x daily 1
≥ 12 y: 3 x daily 1
B
100 g (=98.23 ml) liquid contain:
75 g liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution
10% m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109)
and
3 g soft extract from Primula root (DER 3-7:1), extraction solvent methanol : water :
ammonia solution 26% (50:49.5:0.5)
at least since 1976 ≥ 12 y: 3 x daily
35 drops (=1.5 g)
1
Data are collected using the template entitled ‘Document for information exchange for the preparation of the assessment report for the development of Community monographs
and for inclusion of herbal substance(s), preparation(s) or combinations thereof in the list’ (EMEA/HMPC/137093/2006)
Code in AR and
monograph
Composition
On the market
Posology
C
100 g (=77.5 ml) liquid contain:
12 g liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution
10% m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109)
and
1.8 g soft extract from Primula root (DER 1-2:1), extraction solvent ethanol 55% v/v
at least since 1976 1-3 y: 3 x daily 3 ml
3-6 y: 3 x daily 5 ml
6-12 y: 3-4 x daily 5 ml
≥ 12 y: 4 x daily 7.5 ml
D
100 g granules contain:
3.36 g dry extract from thyme (DER 4.5-7:1), extraction solvent methanol 25% v/v
and
0.64 g dry extract from Primula root (DER 4-6:1), extraction solvent water
at least since 1976 ≥ 12 y: 3 x daily 8 ml
(=3.28 g) granules
prepared as tea
E
10 ml liquid contain:
6.9090 g liquid extract from thyme (DER 1:2-3), extraction solvent ethanol 20% v/v
and
2.2504 g liquid extract from Primula root (DER 1:2-3), extraction solvent ethanol 15%
v/v
at least since 1976 ≥ 12 y: 3-5 x daily
36 drops (=1.8 ml)
F
100 g (=113.5 ml) contain:
2.25 g soft extract from thyme (DER 5-7:1), extraction solvent methanol 25% v/v
and
0.325 g soft extract from Primula root (DER 6-10:1), extraction solvent water
at least since 1976 1-6 y: 2 x daily 5 ml
7-12 y: 2-3 x daily 5 ml
≥ 12 y: 3-4 x daily 5 ml
G
100 g (=92.081 ml) liquid contain
40 g liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution
10% m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109)
and
20 g tincture from Primula root (Ratio herbal substance to extraction solvent 1:5),
extraction solvent ethanol 50% v/v
at least since 1976 6-12 y: 3-5 x daily
25 drops
≥ 12 y: 5 x daily 30
drops
H
100 g (=75.36 ml) liquid contain
5 g liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution 10%
m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109)
at least since 1976 6-12 m: 6 x daily 1 ml
1-4 y: 6 x daily 2.5 ml
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
Page 5/20
EMA/HMPC/130038/2010
Code in AR and
monograph
Composition
On the market
Posology
and
2.5 g liquid extract from Primula root (DER 1:2-2.5), extraction solvent ethanol 70%
m/m
≥ 5 y: 4 x daily 7.5 ml
I
1 film-coated tablet contains:
160 mg dry extract from thyme (DER 6-10:1), extraction solvent ethanol 70% v/v
and
60 mg dry extract from Primula root (DER 6-7:1), extraction solvent ethanol 47.4%
v/v
According to Ernst
et al.
(1997) the dry thyme extract contains essential oil.
at least since 1976 ≥ 12 y: 3 x daily 1
not considered
in monograph
10 g (=10.3 ml) liquid contain:
6 g liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution 10%
m/m: glycerol 85% m/m: ethanol 90% v/v : water (1:20:70:109)
and
4 g tincture from from Primula root (1:5), extraction solvent ethanol 70% v/v
since 2007 ≥ 12 y: 5 x daily
75 drops (ca. 2.3 ml)
Poland
A combination of Extractum compositum spissum (3:1; aq.) ex: Thymi herba et Primulae radix with the isolated compound Thymol is on the market since
2000. Due to the combination with an isolated compound and the short marketing period this combination is not considered in the monograph.
Slovakia
A combination product was authorised in 2005. Due to the short marketing period this combination is not considered in the monograph.
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
Page 6/20
EMA/HMPC/130038/2010
Regulatory status overview
Member State Regulatory Status
Comments
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify: no product
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify: no product
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify: no product
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify: no product
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: no product
Italy
MA
TRAD
Other TRAD
Other Specify: no product
Latvia
MA
TRAD
Other TRAD
Other Specify:
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify:
no product
Poland
MA
TRAD
Other TRAD
Other Specify: no product
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify: no product
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify: no product
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
no product
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.
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page 7/20
1.3.
Search and assessment methodology
Databases assessed (date, search terms) and other sources used:
Search terms: Thymus vulgaris, thyme, Primula, primrose, combination
Databases: Pubmed, Medline and Toxnet.
Libraries: University Vienna, centre of pharmacy; Medical University Vienna, central library.
2.
Historical data on medicinal use
The historical use of thyme and primrose has been discussed in the assessment reports on Thymi
herba and Primulae radix (Doc. Ref. EMEA/HMPC/234113/2006 and EMEA/HMPC/143370/2006,
respectively).
2.1.
Information on period of medicinal use in the Community
The fixed combination of thyme and primrose is a European tradition. All combinations of herbal
preparations included in the monograph are in medicinal use in the Community at least since 1976.
Therefore the criteria of at least 10 years for well-established use and of at least 30 years for
traditional use are fulfilled.
2.2.
Information on traditional/current indications and specified
substances/preparations
The traditional as well as the current indication of thyme, Primula and combinations thereof is the use
as expectorant in cough associated with cold.
Indications
Both thyme and Primula root are traditionally used as expectorants in cough associated with cold. This
indication is also recommended for traditional herbal medicinal products containing a fixed combination
of these two herbs.
In the clinical trials the inclusion criterion was ‘acute bronchitis’. The treatment of acute bronchitis
needs medical supervision and is therefore not suitable for traditional herbal medicinal products.
Duration of use
No restriction on the duration of use has been reported for fixed combinations of Thymi herba and
Primerose root.
Results from clinical trials indicate an onset of the treatment effect on days 3 to 5. The use of
combinations of thyme and Primula shall be restricted to 7 days as it was agreed for the Community
monographs for the single active ingredients.
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page 8/20
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
The phytochemical composition, pharmacology, pharmacokinetics and the toxicology of both thyme
und Primula root and their preparations have been discussed in the assessment reports on
thyme (Doc. Ref. EMEA/HMPC/234113/2006)
thyme essential oil (Doc. Ref EMEA/HMPC/131901/2009)
Primula root (Doc. Ref. EMEA/HMPC/143370/2006).
Main pharmacological effects:
Thyme
Spasmolytic activity:
in vitro
experiments show spasmolytic activity of different types of extracts:
Recent investigations suggest, that thymol, which is considered by the European Pharmacopoeia as
relevant substance for the quality of thyme, does not contribute to the spasmolytic activity (Engelbertz
et al.
2008).
Antimicrobial activity: the essential oil exhibits a strong antibiotic activity.
Primula root
Saponins, which are considered as the most important constituents of Primula root, are suggested to
increase bronchial secretion by irritation of the gastric mucosa. Additionally, saponins exhibit
antifungal, antibacterial and antiviral activities.
Non-clinical data on the combination of thyme and
Primula
root
Nauert
et al.
(2005) investigated the influence of extracts of Primula root, thyme and of their
combination on the LPS-induced release of interleukin-8 in primary human monocytes in
concentrations between 0.001% and 1%. Primula extract inhibited (the LPS-induced release of IL-8)
dose-dependently in the range of the extract concentration between 0.1% and 1%. Thyme extract did
not show an effect. The combination of both extracts had a more pronounced effect compared to the
sum of the single extracts. The authors suppose that this effect might contribute to the mucolytic
effect of the extracts.
Assessor’s comment:
No data are provided on the type of the extracts (DER, extraction solvent).
Therefore the relevance of these findings for the therapeutic use of the combination cannot be
evaluated.
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
No preclinical safety data on genotoxicity, carcinogenicity and reproductive toxicity are published for
the combination.
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page 9/20
3.4.
Overall conclusions on non-clinical data
The non-clinical data make the use of the combination of thyme and Primula root as an expectorant
plausible. The therapeutic effects observed in clinical trials may be explained by the results of
pharmacological testing.
4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No data available.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
Kohlert
et al.
(2002) determined the systemic availability and the pharmacokinetics of thymol after
oral application of a single dose of 160 mg dry extract from thyme (DER 6-10:1), extraction solvent
ethanol 70% v/v and 60 mg dry extract from Primula root (DER 6-7:1), extraction solvent ethanol
47.4% v/v (=Combination WEU C). Thymol sulfate and thymol glucuronide were found in urine and
only thymol sulphate in plasma. The mean terminal elimination half-life was 10.2 hours. Thymol
sulphate was detectable up to 41 hours after administration. No unchanged Thymol could be found in
plasma or urine.
4.2.
Clinical Efficacy
4.2.1.
Dose response studies
No data available
4.2.2.
Clinical studies (case studies and clinical trials)
In most of the clinical trials the bronchitis severity score (BSS) was defined as an important tool for the
evaluation of the efficacy of the study medication. The BSS documents the symptoms cough, sputum,
rales/rhonchi, chest pain during coughing and dyspnoea. Each symptom is assessed by the investigator
using a verbal rating scale: 0=absent; 1=mild; 2=moderate; 3=severe; 4=very severe.
No data on a validation of the score are published.
Herbal preparation G
(Liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution
10% m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109) and tincture from Primula
root (Ratio herbal substance to extraction solvent 1:5), extraction solvent ethanol 50% v/v
Preparation:
100 g (=92.081 ml) liquid contain
40 g liquid extract from thyme and
20 g tincture from Primula root
Efficacy and tolerability of a fixed combination of thyme and Primula root in patients with acute
bronchitis
(Gruenwald
et al.
2005):
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
Double-blind, placebo-controlled, randomised, multicenter, prospective clinical trial including
150 outpatients (≥ 18 years of age).
Inclusion criteria:
acute, not previously treated bronchitis, lasting less than 48 hours; BSS ≥ 5 points.
Exclusion criteria:
obstructive or non-obstructive chronic bronchitis; allergic asthma bronchiale;
simultaneous treatment with or indication for antibiotic treatment; treatment with antibiotics during
the past 4 weeks; concomitant treatment with corticoids, beta-2-mimetics, theophylline, expectorants
or anti-tussives or treatment with these medications during the past 7 days prior to the study; clinical
relevant deviations in laboratory parameters due to severe organ or systemic diseases; patients with
cancer or HIV; pregnancy and lactation; chronic alcohol abuse, medication or drug dependency.
Concomitant medications without influence on the results were allowed (e.g. paracetamol, maximum
3 g per day).
Duration of treatment: 7-9 days.
Posology: 30 drops (=1 ml) 5 times daily
Thyme liquid extract Corresp. thyme Primula tincture Corresp. Primula root
Single dose 0.43 g
0.19 g
0.21 g
0.042 g
Daily dose
2.15 g
0.95 g
1.05 g
0.21 g
Primary endpoint: decrease of the BSS
Results: BSS decreased in the verum group from 12.0 ± 4.4 to 1.0 ± 2.1; in placebo group from
11.7 ± 4.3 to 6.5 ± 4.8. The difference between these groups is highly significant (p≤ 0.001). At the
end of the study significantly more patients were symptom free in the verum group (58.7%) compared
to the placebo group (5.3%).
Figure from Gruenwald
et al.
(2005)
A subgroup analysis revealed that patients with more severe symptoms benefit more from the study
medication compared to patients with less pronounced symptoms.
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
Figure from Gruenwald
et al.
(2005)
The mean reported onset of the treatment was in the verum group at day 3.4, in the placebo group at
day 5.6.
No serious adverse events were observed. 5 AE occurred in the placebo group, 2 in the verum group
(stomach ache and nausea were considered to be in possible connection to the study medication).
Herbal preparation H
(Liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution
10% m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109) and liquid extract from
Primula root (DER 1:2-2.5), extraction solvent ethanol 70% m/m)
Preparation:
100 g (=75.36 ml) liquid contain
5 g liquid extract from thyme and
2.5 g liquid extract from Primula root
Evaluation of the non-inferiority of a fixed combination of thyme fluid and Primula root extract in
comparison to a fixed combination of thyme fluid extract and primrose tincture in patients with acute
bronchitis
(Gruenwald
et al.
2006).
Single-blind, randomised, bi-centric, prospective study including 189 outpatients (≥ 18 years of age).
Inclusion criteria:
acute, not previously treated bronchitis, lasting less than 48 hours; BSS ≥ 5 points.
Exclusion criteria:
obstructive or non-obstructive chronic bronchitis; allergic asthma bronchiale;
simultaneous treatment with or indication for antibiotic treatment; treatment with antibiotics during
the past 4 weeks; concomitant treatment with corticoids, beta-2-mimetics, theophylline, expectorants
or anti-tussives or treatment with these medications during the past 7 days prior to the study; clinical
relevant deviations in laboratory parameters due to severe organ or systemic diseases; patients with
cancer or HIV; pregnancy and lactation; chronic alcohol abuse, medication or drug dependency.
Concomitant medications without influence on the results were allowed (e.g. paracetamol, maximum
3 g per day).
Duration of treatment: 7-9 days.
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
Posology:
5 ml herbal preparation WEU B 6 times daily
Thyme liquid extract Corresp. thyme Primula liquid
extract
Corresp. Primula root
Single dose 0.33 g
0.15 g
0.165 g
0.073 g
Daily dose
1.98 g
0.88 g
0.99 g
0.44 g
or: herbal preparation WEU A 30 drops 5 times daily
Thyme liquid extract Corresp. thyme Primula tincture Corresp. Primula root
Single dose 0.43 g
0.19 g
0.21 g
0.042 g
Daily dose
2.15 g
0.95 g
1.05 g
0.21 g
Primary outcome criterion: change of the BSS at study end point compared to baseline.
Results
:
Reduction of bronchitis severity score from baseline 11.0 ± 5.0 to 2.6 ± 4.6 in the WEU B group
compared to a decrease from 11.0 ± 4.8 to 2.5 ± 4.2 in the WEU A group. The mean onset of the
treatment effect was at day 4 in both groups.
Figure from Gruenwald
et al.
(2006).
A statistically significant intergroup difference was not observed at any time point. The authors
conclude that the study medications showed comparable results regarding their efficacy.
Herbal preparation I
(Dry extract from thyme (DER 6-10:1), extraction solvent ethanol 70% v/v and
dry extract from Primula root (DER 6-7:1), extraction solvent ethanol 47.4% v/v)
Evaluation of efficacy and tolerability of a fixed combination of dry extracts of thyme herb and
primrose root in adults suffering from acute bronchitis with productive cough
(Kemmerich 2007)
Placebo-controlled, double-blind multicentre phase IV study.
361 outpatients (adults only), 23 study centres.
Inclusion criteria:
acute bronchitis with ≥ 10 coughing fits per day, onset of bronchial mucus
production up at a maximum of 2 days prior to recruitment, bronchitis severity score ≥5, maximum
BSS 20 points.
Exclusion criteria:
concomitant fever (> 39°C), pneumonia, history of chronic bronchial or pulmonary
disease such as chronic bronchitis, chronic obstructive pulmonary disease (including acute episode),
bronchiectasis, bronchial asthma, mucoviscidosis, history of clinically relevant chronic cardiovascular,
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
kidney, gastrointestinal or liver disease, malignant growth, any severe somatopathic, neurological
and/or psychiatric disease, pregnancy lactation.
Responders were defined as patients with no or improved symptoms at visit 2 and 3 compared to visit
1. Patients whose symptoms were unchanged or deteriorated were classified as ‘non-responders’.
Duration of treatment: 11 days, 1 tablet 3 times daily
Thyme dry extract Corresp. thyme Primula dry extract Corresp. Primula root
Single dose 160 mg
1.28 g
60 mg
0.39 g
Daily dose
480 mg
3.84 g
180 mg
1.17 g
Baseline examination, control examinations on day 4 and day 10/end of treatment.
Evaluation:
Manual count of coughing fits per day by the patients.
Investigator’s assessment of the bronchitis severity score (at baseline: 7.9 in the verum group, 7.6 in
the placebo group).
Primary outcome criterion: change in mean frequency of coughing fits during the daytime of days 7 to
9 as documented in the patient diary divided by the baseline value of day 1.
Results:
Reduction of coughing fits compared to baseline:
67.1% in verum, 51.3% in placebo group.
A 50% reduction of coughing fits was reached in the verum
group 2 days earlier compared to placebo group.
Figure from
Kemmerich
et
al.
(2007)
The bronchitis severity score improved in both groups rapidly, but responder rates were higher in the
verum group (visit 2: verum 77.5%, placebo 60.1%; visit 3: verum 92.9%, placebo 75.8%)
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
Figure from Kemmerich
et al.
(2007)
No difference in the frequency or severity of adverse events was observed. Severe or serious adverse
events were not reported. In the verum group 1 case with Eustachian tube disorder and 1 case of back
pain were labelled as moderate, 1 case of otitis externa as mild.
A controlled multi-centre study of herbal versus synthetic secretolytic drugs for acute bronchitis
(Ernst
et al.
1997).
Controlled, multi-centre (771 general physicians), post-marketing surveillance study.
7783 patients were included. 1490 children 5.7 ± 2.9 years of age and 3139 adults 40.9 ± 18.6 years
of age were included in the study group which received the fixed combination of thyme and Primula
root. The other patients received Ambroxol (n=479 children, 590 adults), N-Acetylcysteine (n=299
children, 1044 adults) or other herbal medicinal products (n=207 children, 183 adults, e.g. extracts of
Hederae folium, thyme, combination of essential oils).
The study was neither randomised nor placebo-controlled.
The calculation of the odds ratios revealed that for any parameter (e.g., auscultation, coughing during
day/night, pain while coughing, quantity of sputum, viscosity of sputum) the treatment was better with
the fixed combination of thyme and Primula root compared to the other groups. This was true for both
age groups.
The rate of adverse events was clearly below 1% (in 3140 adults 0.64%, in 1490 children 0.60%).
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
Herbal preparation C
(Liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution
10% m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109) and soft extract from Primula
root (DER 1-2:1), extraction solvent ethanol 55% v/v).
Treatment of acute cold in children – results of an observational study with a Primula – thyme –
preparation
(Fasse
et al.
2006).
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
Non interventional study in 98 children (0-<3 years of age), 112 children (≥3-≤6 years of age), and
90 children (>6-≤12 years of age).
Preparation:
100 g (=77.5 ml) contain:
12 g liquid extract of thyme
1.8 g soft extract of Primula root
Posology:
<3 years: 3 times daily 2.5-3 ml
3-6 years: 3 times 5 ml
6-12 years: 3-4 times 5 ml
Side effects: no data, the authors state an ‘excellent tolerability’. In 4 children vomiting occurred (2
children <3 years, 1 in group 3-6, 1 in group 6-12).
Assessor’s comment:
No control group, therefore no judgement of the efficacy of the treatment
possible.
Treatment of acute cold in children – results of an observational study with a Primula – thyme –
preparation
(Bässler & Zieseniß 2005)
Assessor’s comment:
No control group, therefore no judgement of the efficacy of the treatment
possible. This study is published as congress abstract only. This paper seems to be the abstract of the
paper by Fasse
et al.
(2006, see above).
Herbal preparation G
(Liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution
10% m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109) and tincture from Primula
root (Ratio herbal substance to extraction solvent 1:5), extraction solvent ethanol 50% v/v.
Preparation:
100 g (=92.081 ml) liquid contain
40 g liquid extract from thyme and
20 g tincture from Primula root
Efficacy and tolerability of liquid dosage forms of a fixed combination of thyme and primrose in children
with acute bronchitis
(Nauert & Grünwald 2005, Grünwald
et al.
2006a).
Non-interventional study in 110 children (6-12 years of age).
Posology: 25 drops up to 6 times daily.
The authors state an ‘excellent tolerability’ of the herbal preparation.
Assessor’s comment:
This study is published as congress abstract only. No control group was included.
Therefore no judgement of the efficacy of the treatment is possible. However, the study can be used
for the demonstration of safety of the herbal preparation in children from 6 years up.
Herbal preparation H
(Liquid extract from thyme (DER 1:2-2.5), extraction solvent ammonia solution
10% m/m : glycerol 85% m/m : ethanol 90% v/v : water (1:20:70:109) and liquid extract from
Primula root (DER 1:2-2.5), extraction solvent ethanol 70% m/m).
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
Preparation:
100 g (=75.36 ml) liquid contain
5 g liquid extract from thyme and
2.5 g liquid extract from Primula root
Efficacy and tolerability of liquid dosage forms of a fixed combination of thyme and primrose in children
with acute bronchitis
(Nauert & Grünwald 2005, Grünwald
et al.
2006a).
Non-interventional study in 111 children (1-4 years of age) and 109 children (5-12 years of age).
Posology:
1-4 years: 2.5 ml, up to 6 times daily.
4-12 years: 5 ml up to 6 times daily.
The authors state an ‘excellent tolerability’ of the herbal preparation.
Assessor’s comment:
This study is published as congress abstract only. No control group was included,
therefore no judgement of the efficacy of the treatment is possible. However, the study can be used
for the demonstration of safety of the herbal preparation in children from 1 year up.
Fixed combination of thyme liquid extract and Primula root liquid extract for the oral treatment of
children with cough and bronchial catarrh
(Nauert & Eckert 2003, Grünwald
et al.
2006a).
Non interventional study in 312 children (1-4 years of age) and 324 children (4-12 years of age).
Posology:
1-4 years: 2.5 ml 6 times daily
4-12 years: 5 ml 6 times daily.
The onset of the treatment effect was observed at day 3-4.
The authors state an ‘excellent tolerability’ of the herbal preparation.
Assessor’s comment:
This study is published as congress abstract only. No control group was included,
therefore no judgement of the efficacy of the treatment is possible. However, the study can be used
for the demonstration of safety of the herbal preparation in children from 1 year up.
A fixed combination of thyme and primrose for the treatment of cough
(Schmidt 2008).
Non-interventional study in 199 children 6-12 months of age.
Posology: 6 times 1 ml per day
Mean duration of treatment: 6.4 days
Inclusion criterion
: acute disorders of the upper respiratory tract with cough, catarrh and mucous
obstruction of the bronchia.
Rating of symptoms like ‘severity of cough’, ‘number of coughing fits per day’, ‘number of coughing fits
during night’, ‘impairment of sleep quality’.
Side effects: 1 adverse event with possible causal relationship to the study medication (perioral
eczema). 1 adverse event (vomiting, diarrhoea) was interpreted as correlated with the underlying
disease.
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
Ethanol: 1 ml of the study medication results in a blood ethanol concentration of 0.008‰. The
metabolism in children in this age group is about 0.06‰-0.09‰ per hour. Therefore no accumulation
was to be expected.
Assessor’s comment:
No control group was included, therefore no judgement of the efficacy of the
treatment is possible. Although the ethanol content is very low, the herbal preparation is not
recommended for children below 2 years of age (according to ‘Reflection paper on ethanol content in
herbal medicinal products’, EMA/HMPC/85114/2008).
Compliance, tolerability and efficacy of a fixed combination of thyme and Primula (T+P) in 200 infants
with acute bronchitis
(Nauert & Bentley 2008).
200 infants (6-12 months of age) treated in 6 centres in Germany.
The study medication was given in a dosage of 1 ml, 6 times daily, over a period of 7 days.
The authors state an ‘excellent tolerability’ of the herbal preparation.
Assessor’s comment:
This study is published as congress abstract only. No control group was included.
Therefore no judgement of the efficacy of the treatment is possible. This paper seems to be the
abstract of the paper by Schmidt (2008, see above).
Assessor’s general comments on the studies with the fixed combination WEU B including children:
Parts of the studies are published as abstracts. Grünwald
et al.
2006a combined the data obtained until
2006. The numbers of included children differ between the publications.
Herbal preparation I
(Dry extract from thyme (DER 6-10:1), extraction solvent ethanol 70% v/v and
dry extract from Primula root (DER 6.0-7.0:1), extraction solvent ethanol 47.4% v/v).
A controlled multi-centre study of herbal versus synthetic secretolytic drugs for acute bronchitis
(Ernst
et al.
1997).
Controlled, multi-centre (771 general physicians), post-marketing surveillance study.
1490 children 5.7 ± 2.9 years of age were included in the study group which received the fixed
combination of thyme and Primula root. The other patients received Ambroxol (n=479 children), N-
Acetylcysteine (n=299 children) or other herbal medicinal products (n=207 children, e.g. extracts of
Hederae folium, thyme, combination of essential oils).
The study was neither randomised nor placebo-controlled.
The calculation of the odds ratios revealed that for any parameter (e.g., auscultation, coughing during
day/night, pain while coughing, quantity of sputum, viscosity of sputum) the treatment was better with
the fixed combination of thyme and Primula root compared to the other groups.
The rate of adverse events was clearly below 1% (in 1490 children 0.60%).
Assessor’ comments on the proposed age limit for the monograph:
Although there are data on the safe use of some fixed combinations even in children below 1 year of
age available the age limit should be set with 4 years for those fixed combinations where data on the
safe use in the paediatric population are available. Medicinal products containing such a fixed
combination will be available without prescription. Therefore the use will be without medical
supervision. For safety reasons the use of expectorants in children below 4 years of age has to be
restricted, the treatment has to be performed under medical control. Moreover, recent guidelines for
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
the management of cough in children recommend a ‘wait, watch, review’ approach instead of an
intervention by medication (Kelley & Allen 2007).
All other traditional fixed combinations should be limited for adolescents above 12 years of age and
adults like it was agreed for the Community monographs on the single active ingredients thyme and
Primula root.
4.3.
Overall conclusions on clinical pharmacology and efficacy
Although there are promising results from randomised, placebo-controlled clinical trials published for
three of the fixed combinations the status of ‘well-established use’ cannot be established. A major
deficiency of the trials is the lack of validation of the bronchitis severity score. Additionally the validity
of the criterion ‘number of coughing fits’ taken from patient diaries or manual counts is questioned in
scientific literature (Irwin
et al.
2006, Morice
et al.
2007).
A recent Cochrane review on OTC medications for cough (Smith
et al.
2008) as well as the guideline on
diagnosis and treatment of cough from the German society for general medicine and family medicine
(DEGAM 2008) conclude that there is at the moment no sufficient evidence for the use of expectorants
for the treatment of acute cough provoked by different reasons.
Therefore the data from the clinical trials support the traditional use of these fixed combinations and
make the use in the proposed indication plausible.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
5.2.
Patient exposure
The fixed combinations included in the monograph are in medicinal use at least since 1976. No
concrete data on patient exposure are available.
5.3.
Adverse events and serious adverse events and deaths
No serious adverse events or deaths were either observed during the clinical trials or reported from the
medicinal use of the fixed combinations.
During clinical trials stomach ache, nausea, vomiting, diarrhoea and perioral eczema were observed
and interpreted as possibly caused by the study medication.
5.4.
Laboratory findings
No data available.
5.5.
Safety in special populations and situations
No serious adverse events or deaths were either observed during the clinical trials or reported from the
medicinal use of the fixed combinations in children.
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
During clinical trials in children gastrointestinal complaints like vomiting and diarrhoea as well as skin
reactions like pruritus and perioral eczema were observed and interpreted as possibly caused by the
study medication.
5.6.
Overall conclusions on clinical safety
No serious adverse events or deaths were either observed during the clinical trials or reported from the
medicinal use of the fixed combinations.
In clinical trials only mild to moderate, transient gastrointestinal complaints or skin reactions occurred.
Although the data from clinical trials suggest that use of some of the fixed combinations might be safe
in children down to 6 months of age, the use of this fixed combination as an expectorant without
supervision of a doctor should be restricted to children older than 4 years of age. In younger children
the diagnosis should be performed by a doctor.
No special risks are known for the single active ingredients or for the combination. Therefore the use of
the fixed combination of thyme and Primula root can be considered as safe when administered in the
specified posology.
6.
Overall conclusions
Both thyme and Primula root are traditionally used as expectorants in cough associated with cold. This
indication is also recommended for traditional herbal medicinal products containing a fixed combination
of these two herbs. The medicinal use in this indication is plausible due to the pharmacological
properties of thyme and Primula root and due to results of clinical trials. Although the clinical trials
report beneficial effects of some fixed combinations in the treatment of acute bronchitis all fixed
combinations are rated as traditional herbal medicinal products. The main reason is the lack of
validation of the parameters used for the evaluation of the efficacy (e.g., the bronchitis severity score)
All fixed combinations which are proposed for traditional use are in medicinal use at least since 1976
and fulfil therefore the criteria of 30 years of medicinal use.
For all combinations concrete data on the posology are available.
No special risks are known for the single active ingredients or for the combination. The type and
intensity of adverse events which were observed during clinical trials do not give reason for safety
concerns. Therefore the use of the fixed combination of thyme and Primula root can be considered as
safe when administered in the specified posology.
The contraindications and warnings from the monographs on the single active compounds are
sufficient.
Since the benefit of the medicinal use in the specified indication is plausible and no special risks are
known, the benefit/risk balance is clearly positive.
Due to the lack on adequate data on genotoxicity a Community list entry is not proposed.
Annex
List of references
Assessment report on
Thymus vulgaris
L. and
Thymus zygis
L., herba and
Primula veris
L. and
Primula elatior
(L.) Hill, radix
EMA/HMPC/130038/2010
Page
Source: European Medicines Agency
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