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FOR USE BY HEALTHCARE PROFESSIONALS ONLY
Kaloba (EPs 7630)
®
®
PELARGONIUM SIDOIDES
For Relieving the Symptoms of Upper Respiratory
Tract Infections Including the Common Cold
PRODUCT MONOGRAPH
From Nature. For Health.
The Medicines and Healthcare Products Regulatory Agency (MHRA) granted
Dr Willmar Schwabe & Co. KG a Traditional Herbal Registration Certificate for the
traditional herbal medicinal product Kaloba® (EPs®7630) Oral Solution (Traditional
Herbal Registration Number THR 05332/0003) on 26th March 2008. This product is
available without a prescription and can be bought from pharmacies and other outlets.
CONTENTS
Further registration approvals for the Kaloba® (EPs®7630) range, all containing the
Pelargonium extract EPs® 7630, have been obtained. Kaloba® (EPs®7630) film-coated
tablets received approval on 31st March 2009, and Kaloba® (EPs®7630) syrup on
11th June 2010.
1. Introduction to Schwabe Pharma
The active ingredient of the product Kaloba® (EPs®7630) comes from the roots of
the plant Pelargonium sidoides DC (Pelargonium). Kaloba® (EPs®7630) is a traditional
herbal medicinal product used to relieve the symptoms of upper respiratory
tract infections including the common cold, such as sore throat, cough and blocked
or runny nose, based on traditional use only.
This registration is based exclusively upon longstanding use of the extract from the
roots of the plant and not upon data generated from clinical trials. This is because
there is no requirement under the Traditional Herbal Registration Scheme to prove
scientifically that the product works.
However, there is a large body of published clinical and pre-clinical evidence relating
to Pelargonium sidoides DC (Pelargonium) that forms the basis of this monograph,
which should be read in conjunction with the current Summary of Product
Characteristics. Most of the available published clinical trials have been conducted
with Kaloba® (EPs®7630) extract.
2. Regulation and Quality of Herbal Medicines
2.1 Quality of Herbal Starting Material
2.2 Growing and Harvesting Herbs – and Protecting the Environment
2.3 EU Herbal Monographs – Quality Signposting
2.4 The Difference between “traditional use” and “clinical evidence”
3. Introduction to Acute Upper Respiratory Tract Infections (URTIs)
3.1 Pathophysiology of URTIs
3.2 Current Treatments and Related Problems
3.3 Problems of Antibiotic Resistance
4. Kaloba® (EPs®7630) - Quality Information
4.1 Introduction
4.2 Qualitative and Quantitative Information
5. Pharmacology
5.1 Mode of Action
5.2 Clinical Information
5.2.1 Clinical Studies
5.2.2 Pre-clinical Studies
5.3 General Safety Information on Kaloba® (EPs®7630)
6. Kaloba® (EPs®7630) - Frequently Asked Questions
7. Core Summary of Product Characteristics
7.1 Kaloba® (EPs®7630) oral drops
7.2 Kaloba® (EPs®7630) tablets
7.3 Kaloba® (EPs®7630) syrup
8. References
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
1. INTRODUCTION TO SCHWABE PHARMA
2. REGULATION AND QUALITY OF HERBAL MEDICINES
Leading the World in Herbal Medicine Self-Care
2.1 Quality of Herbal Starting Material
For more than 140 years, the Dr Willmar Schwabe group of companies has been
committed to improving people’s health and wellbeing. We do so by proving through
research and development, that plant based medicines offer a safe, efficacious alternative
to conventional medicines.
It is important that consumers are able to choose to purchase herbal medicines as part
of their self-care programme, that are of a consistently high quality from batch to batch.
This consistent quality standard can only be achieved if the herbs used in the herbal
medicine meet certain quality standards. These quality standards for the herbal starting
material are described in reference texts which we call pharmacopoeial monographs.
These herbal monographs describe in detail the European quality standards which must
be met, ranging from all components allowable in the herb to the consistent amount
of certain marker compounds characteristic to a particular herb that must be present.
Schwabe Pharma (UK) Ltd produces a range of registered traditional herbal remedies
(THRs) used to relieve or prevent the symptoms of common minor ailments including
coughs & colds, stress, low mood, muscle and joint pain, digestive disorders, menopause,
migraine and premenstrual syndrome. We are leading the way in registering herbal
medicines approved for both quality and safety by the Medicines and Healthcare
Products Regulatory Agency (MHRA).
Dr Willmar Schwabe Pharmaceuticals is the leading manufacturer of herbal medicines
worldwide and is committed to four key values:
Reliable and reproducible quality can only be achieved where the herbal starting
material complies with these herbal monograph standards.
2.2 Growing and Harvesting Herbs – and Protecting the Environment
1. Innovation - we take people’s needs seriously and research them
with passion and commitment, every day, every month, every year.
2. Reliability - it’s in our nature. For more than 140 years, the family owned
company has been dedicated to providing innovative traditional herbal
medicines across the globe.
Controlled cultivation on managed farms of medicinal herbs will clearly lead to a more
reliable quality than herbs that have been collected and harvested in the wild. In addition,
controlled cultivation helps to ensure that consumer demand for a herb does not put
survival of the herb at risk. Therefore, great efforts are taken to support the controlled
cultivation of herbs worldwide. For example, Dr Willmar Schwabe owns and manages
controlled cultivation of Pelargonium sidoides in South Africa, Rhodiola rosea in Canada
and Ginkgo biloba in France and China.
3. Responsibility - we are committed to environmental protection
and the conservation of our natural resources. Our cultivated plants on
managed farms assist in the preservation of natural habitats and protect native
plants from further decimation and potential extinction.
Although controlled cultivation has many advantages over wild collection of herbs,
there are some circumstances where only wild collection is possible. It is essential
that wild collection is managed with great care in order to protect the herb from
possible extinction.
4. Quality - we control the whole process from harvesting the plants to the
production of the finished herbal medicines and we ensure that only high
quality plant materials are used for the production of these unique products.
On our plantations, the raw materials for our products are grown under controlled
conditions, following Good Agricultural and Collective Practice (GACP)
guidelines.
A European Guideline entitled “Good Agricultural and Collective Practice” (GACP)
has been adopted throughout the EU and this Guideline describes a set of quality
standards which must be adopted in growing and collecting all herbs for the manufacture
of traditional herbal registered products. This European Guideline is very important
in helping to protect vulnerable plant species from extinction through exploitation
and market demands.
N.B. Unlicensed herbal medicines and herbal food supplements, often known as
“botanicals”, do not have to comply with this Guideline.
Our special extracts are prepared using modern pharmaceutical technology using
unique extraction processes to guarantee a concentrated and high quality end
product. All manufacturing stages, from raw plant material testing to final release
of the product are carried out to international requirements of the Good
Manufacturing Practice (GMP) guidelines.
At Schwabe Pharma we share a common vision: “From Nature. For Health”.
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Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
2.3 EU Herbal Monographs – Quality Signposting
2.4 The Difference between “traditional use” and “clinical evidence”
The quality of herbs used in manufacture of traditional herbal medicines are
characterised by the following parameters:
Conventional licensed medicines in the UK are always assessed for quality, safety and
efficacy by the Medicines and Healthcare Products Regulatory Agency (MHRA). Efficacy
is assessed by MHRA clinical assessors based on at least two pivotal clinical trials and
many related clinical trials that must comply with the European Clinical Trials Directive.
It will often cost several million pounds to complete just one clinical trial as part of
licensing a conventional medicine.
• A clear botanical and scientific definition
• Identification of the herb
• Purity
• Content
A clear botanical definition comprises the Latin and scientific names of the plant
and the part of the plant used. The identity and authentication of a herb is usually
based on the macroscopic (visual) and microscopic features. Additional tests, such
as thin-layer chromatography fingerprint analysis are often required as well. These
allow for identification on the basis of compounds always found in a particular herb.
Other tests are often included in the monograph to ensure that the herb meets
acceptable standards. For example, moisture content of the dried herb is often
stipulated, as moisture can affect the stability of some of the active compounds
found in a particular herb. Microbiological standards are also an important part
of a monograph, in order to ensure that the herb is safe to use.
Heavy metals such as lead, mercury, cadmium and arsenic can accumulate in some
plants, and heavy metal levels are therefore strictly controlled in herbal monographs.
Herbal monographs usually stipulate levels of specific marker compounds that
are characteristic of that particular herb. For example, the herb Feverfew contains
parthenolide; Chaste Tree or Agnus Castus contains casticin; and Milk Thistle contains
silymarins. The levels of these marker compounds, both in the harvested herb, and
the finished tablet or capsule must be achieved, otherwise the herb or finished tablet
or capsule cannot be sold and marketed.
04
The fragmented nature of the herbal products market, with many companies having
an annual turnover of less than the cost of a high quality clinical trial, has led to the
introduction of the European Traditional Herbal Medicinal Products Directive.
This Directive requires that in order to obtain a registered herbal medicine approval, the
company must demonstrate that the herb has been used for 30 years at the dosage in
the herbal product that is being registered, for the required indication. At least 15 years
of the 30 year period, must have been in an EU country and only indications that are
for self-limiting, over-the-counter, minor ailments are acceptable. So clinical efficacy, as for
conventional medicines, is not assessed – only traditional usage over a 30 year period.
Key Questions about the Traditional Herbal Medicinal Products Directive
Does “Traditional use” mean anything in evidence terms?
Yes. It is unlikely that sustained use of a herb for a particular indication would have survived
over a 30 year period unless the users had experienced benefit. It is for this reason that
traditional use for many people is a powerful reason for trying a herb to relieve a
particular ailment or complaint. Indeed, some herbs have been used in some ethnic cultures
for many hundreds of years, and have been passed down from generation to generation.
Do any traditional herbal registered products have clinical evidence of benefit?
Achieving the high quality necessary to achieve a herbal registration requires
competent scientific and technical skills. The herbal starting materials right through
to the manufacture of the finished tablet or capsule must comply with rigorous
manufacturing standards that are described in Good Manufacturing Practice
Guidelines (GMP). These Guidelines are positively regulated in the UK by the Medicines and
Healthcare Products Regulatory Agency who have GMP Inspectors who visit
manufacturers regularly to check manufacturing compliance.
Yes. Some products, including Pelargonium, do have clinical evidence that a particular
herb is of benefit in a specific herbal registered product, but this evidence has NOT
been assessed by the MHRA as part of the approval process. Schwabe Pharma has a
heritage of carrying out clinical trials as part of a programme of developing a robust
evidence base for herbal medicines both in the UK and in many countries throughout
the world. This programme will continue, but does not form part of the assessment
process for registering herbal medicines.
This type of positive regulation and Inspection does not take place with either
unlicensed herbal medicines or herbal food supplement (“botanical”) type products, and
is essential in giving patients and healthcare professionals assurance about the quality of
traditional herbal registered medicines.
Are traditional herbal registered products of the same quality as conventional
medicines?
Yes. The quality requirements for registered herbal products are strictly controlled and
the same high standards of manufacture are required as for conventional medicines.
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Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
The manufacturing standards are strictly enforced through a rolling two year MHRA
Inspection programme of the manufacturing facility.
N.B. Herbal food supplements (“botanicals”) and unlicensed herbal medicine
manufacturing procedures are not regulated in this way.
Many conventional medicines have information leaflets with the medicine.
What is the situation with traditional herbal registered products?
The situation is identical. All traditional herbal registered products have an MHRA
approved patient information leaflet which describes useful information for the
patient, including when and how to take the product, and any contra-indications
on when the product should not be taken – such as pregnancy or breast-feeding.
N.B. Herbal food supplements (“botanicals”) and unlicensed herbal medicines do
NOT have information leaflets that have been approved as described above.
3.1 Pathophysiology of Upper Respiratory Tract Infections
A disrupted immune balance is the basis of any infection. The immune system can
no longer protect the body from an increased pathogenic burden. This is primarily
the case with particularly aggressive viruses that are unknown to the immune system,
particularly in patients in vulnerable groups or where the immune system is already
affected by stress, anxiety or other debilitating diseases.
The nasal cavity/pharynx is generally the starting point for an upper respiratory tract
infection. This is where rhinopharyngitis, which is characterised by the initial symptoms
of sore throat, rhinitis (runny nose) and lethargy, actually develops.
Pathogen ascendance subsequently triggers sinusitis whilst pathogen descendance
causes tonsillitis, laryngitis and frequently acute tracheobronchitis. This also explains
why acute bronchitis is virtually always associated with other symptoms caused by the
inflammatory processes in the nasal cavities and pharynx (Figure 1)4.
3. INTRODUCTION TO ACUTE UPPER RESPIRATORY
TRACT INFECTIONS
The onset of infection with reference
to interaction with epithelial cells is
completed in three stages:
Acute upper respiratory tract infections (URTIs) are the most common diseases treated
in general and paediatric primary care practice and affect all age groups, particularly
during the winter months. During a cold or flu epidemic, they can account for up to
50% of all GP consultations1. GP consultations for colds and flu alone cost between 600
and 800 million pounds every year2. This is a significant challenge for GPs working in
primary care, both clinically and in terms of managing patient expectations, because the
majority of infections are virus-mediated3.
1. Adhesion – pre-requisite for infection
2. Internalisation – pathogen proliferation and reservoir for recurrence
3. Paracellular translocation – spread of infection in the deep tissues
Acute upper respiratory tract infections are diseases which are generally self-limiting
in nature. However, if left untreated, there is a risk that the clinical course of the
symptoms may be considerably prolonged. This can lead to extended time off work
or away from school, which often causes difficulties for families in an increasingly
challenging and demanding work environment. Complications can occur in children, the
elderly and vulnerable groups such as diabetics or asthmatics. These vulnerable patients
are at particular risk of developing bronchitis, with an increased likelihood of developing
an acute, serious infection such as, for example, pneumonia.
Figure 1: Spread of infectious
pathogens in the respiratory tract
Internalised and paracellularly translocated pathogens in the deeper cell layers can often
not be reached by substances with a direct, antimicrobial effect. Thus it is even more
important to protect the mucosal cells and to activate the non-specific immune system,
especially the natural killer cells, which are the first line of defence.
In conclusion, it should be emphasised that even respiratory tract infections which
appear harmless at first sight should be treated, particularly in vulnerable patients.
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Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Adhesion
Viruses are by far the most important group of
pathogens associated with URTIs, accounting for
90 – 95% of upper respiratory tract infections
(Table 1). Conversely, primary bacterial pathogens
are only seldom detected in acute sinusitis.
Internalisation
The current incidence of this particular risk was quantified by Adam6 in a 2001
study: Even in 1980, only one case of rheumatic fever occurred during the working
life of 12 general practitioners. Based on this minimal risk, the authors concluded
that immediate antibiotic treatment should not be recommended. However, it is
generally accepted that patients presenting with acute symptomatic streptococcusinduced infection should receive antimicrobial therapy7,8. However, this treatment
is still effective when started (with a delay of up to 9 days). According to Adam, this
means that treatment can be delayed until laboratory test results of a throat swab
have been received and an appropriate antibiotic can then be prescribed for the
pathogen spectrum identified through the swab result.
3.2 Current Treatments and Related Problems
Although 9 out of 10 upper respiratory tract infections are caused by viruses,
antibiotics are prescribed in over 80% of cases9. However, clinical and scientific
evidence to support the use of antibiotics in upper respiratory tract infections is poor,
as detailed below:
Translocation
Pathogen
Significance
Severity
Viruses:
Adenovirus (types 1-7, 12)
Rhinovirus
Coxsackie virus
Other enteroviruses
Influenza virus A and B
Influenza virus C
Parainfluenza virus 1,2
Parainfluenza virus 3
RSV (respiratory-syncytial virus)
+++
++
+
+
+++
+
++
+++
+++
+ to +++
+ to ++
+
+
+ to ++++
+
++
+++
+ to +++
Bacteria
Mycoplasma pneumoniae
Chlamydia pneumoniae
+++
+
+ to +++
++
Table 1: Overview of pathogens involved in acute tracheobronchitis
Tonsillitis causality is less clearly defined. Although simple catarrhal, mostly viral-induced
tonsillitis can occur, a streptococcal sore throat that in general has to be treated with
antibiotics, can occur as well. The treatment of acute tonsillitis therefore falls into the
medical domain, although the risk of developing post-streptococcal complications in
countries with a good standard of hygiene is extremely low. The post-streptococcal
risk described in many textbooks is most probably a “phantom risk” in Germany5
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Antibiotics in the treatment of Non-A-Streptococcal Pharyngitis
A meta-analysis of 27 studies involving 2,835 patients conducted by the Cochrane
Collaboration (2006) led to the conclusion that antibiotic therapy in this indication only
shortens symptoms by 16 hours and that most patients do not benefit at all from this
form of treatment10.
Antibiotics in the treatment of laryngitis
The Cochrane Review (2007) authored by Reveiz et al. of 206 adult patients did not
show a clinically significant benefit. The authors concluded that antibiotics in the
management of acute laryngitis did not improve symptoms and should therefore
not to be recommended as a first-line treatment for acute laryngitis11.
Antibiotics in the treatment of otitis media (inflammation of the middle ear)
Similarly, a meta-analysis was carried out by the Cochrane Collaboration (2003). The
examination of 8 studies involving a total of 2,287 children led Glasziou et al. to
the conclusion that the prescribing of antibiotics in the treatment of otitis media is
only slightly beneficial to children and should be carefully evaluated in view of the
side effects, particularly since otitis media is a clinical condition that spontaneously
heals in most cases12.
Antibiotics in the treatment of colds and acute purulent rhinitis
In a Cochrane Review of six studies with a total of 1,147 patients, Arroll and Kenealy
(2005) concluded that there is inadequate evidence regarding the use of antibiotics
in this indication and that the routine administration of these substances cannot be
recommended13.
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Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Antibiotics in the treatment of acute sinusitis
A Cochrane Review by Williams et al. (2003) (meta-analysis of 49 studies involving
a total of 13,660 patients) revealed that there is only very limited evidence regarding
the beneficial use of antibiotics and that doctors should consider carefully the limited
therapeutic effect against the existing potential for side effects14.
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Antibiotics in the management of acute bronchiolitis
Bronchiolitis is a serious and often life-threatening disease of the lower respiratory
tract that mainly affects babies. The disease is caused by the RSV (Respiratory Syncytial
Virus). A Cochrane analysis (2007) did not reveal any significant difference between
placebo andantibiotics16 when considering the primary end points of disease
duration and death.
In conclusion, antibiotic therapy was only statistically significant and clinically relevant
in relation to increased frequency of side effects, especially allergic exanthema,
gastrointestinal disorders and fungal infections.
It should be noted that almost 8 out of 10 children will be treated at least once with
antibiotics between the 2nd and 4th year of their life. The average duration of treatment
is 17.6 days/child/year17.
The uncontrolled administration of antibiotics in children is of particular concern,
particularly as asthma is 2.5 times more prevalent in 7 year-old children given
antibiotics at an early age compared to their untreated peers. Moreover, allergies
are twice as prevalent in this same patient category18.
-1
In ([R /1-R])
Antibiotics in the treatment of acute bronchitis
In the Cochrane meta-analysis (2004) of 9 studies involving a total of 750 adults and
children, the authors concluded that antibiotics only have a minimal benefit in the
treatment of acute bronchitis. The use of antibiotics should be weighed against the
broad spectrum of side effects. In addition, the significant risk of antibiotic resistance
development, and the high cost of this therapy should also be taken into consideration15.
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DDD beta-lactam antibiotics / 1.000 population
Figure 2: Resistance as a function of antibiotic consumption
The speed of development of bacterial resistance that may develop in individuals using
antibiotics was confirmed in a study by Malhotra-Kumar et al. (2007) published in The
Lancet. Even the short-term use of antibiotics resulted in a significant, sustained
increase in bacterial resistance. The results were obtained in a double-blind, placebocontrolled study of 224 subjects receiving either the macrolides azithromycin,
clarithromycin or placebo. A resistance of over 80% in the streptococcal strains tested
was found during the first examination one day after the final dose of the antibiotics
was given. This resistance continued with a very gradual reduction throughout the
whole 180-day observation period (Figure 3)20.
3.3 Problems of Antibiotic Resistance
Another side effect of antibiotic treatment is bacterial (antibiotic) resistance, which has
become a major international problem.
Bronzwaer (2002) highlighted the correlation between the frequency of the use of
antibiotics and the proportion of resistant bacterial strains in the overall European
population19. This study showed that the number of prescribed daily doses of
antibiotics is positively correlated with the occurrence of bacterial resistance in different
Member States (Figure 2).
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Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Rate of resistance to macrolides (%)
100
Azithromycin
Clarithromycin
Placebo 1
Placebo 2
80
resistant influenza type viral infections.
Bacterial and viral resistance cannot be considered merely as a governmental or global
problem. Particular attention should be paid to the fact that resistant pathogens are
rapidly transmitted between people and can pose a threat to young children and/or
vulnerable groups such as pregnant or elderly relatives.
Medically supervised watchful waiting is not a recommended option either. Altina
(2001) reported that 50% of all untreated patients presenting with acute bronchitis still
coughed on observation day 21, 25% on observation day 30 and 2 – 5% even after 6
months25. The most serious acute complication is pneumonia, which mainly affects
young children due to their incompletely developed immune system, and immunocompromised subjects such as the elderly or diabetic patients. The mortality rate of
community acquired pneumonia in Germany is currently estimated at approximately
11%26.
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Observation days
The risk of developing a chronic disease condition is of both individual and economic
significance. One in three patients presenting with acute bronchitis that is inadequately
treated will develop chronic bronchitis27, which accounts for 5% of all deaths28.
Figure 3: Development of resistance to macrolides
In practical terms, this means that an antibiotic administered at the beginning of the
infectious season in the Autumn can trigger resistance which is sustained throughout
the winter months through to Spring.
As a result of increasing antimicrobial resistance, a switch to so-called reserve antibiotics
or to combination therapies with a significant synergistic potential is increasingly required.
This treatment regimen not only generates enormous budgetary health service costs, but
also means that a significant number of pathogens lose their sensitivity to antibiotics.
The outcome of the above is that every year, 50,000 people in Europe die from
antibiotic resistant infections that can no longer be treated adequately with
existing antibiotics21.
Antiviral agents in the treatment of respiratory tract infections?
Neuraminidase inhibitors, such as oseltamivir (Tamiflu), which are authorised for use
in the management of influenza mediated infections, are not a therapeutic alternative
in the treatment of all upper respiratory tract infections. The benefits of using
neuraminidase inhibitors to treat what are mainly self-limiting infections are far
outweighed by the risk of increasing viral resistance, along with significant budgetary
costs to already overstretched health services. The extent of resistance development
already exceeds previous expectations22. In 2005 and 2001, up to 18% of
children23 and up to 4% of adults24, respectively, were already experiencing oseltamivir12
4. KALOBA® (EPs®7630) – QUALITY INFORMATION
4.1 Introduction
The active drug substance contained in Kaloba® (EPs®7630) is a patented dry root extract
of the herb Pelargonium sidoides DC. The extract is known by the name EPs® 7630 and
it has a herb-extract ratio of 1:8-10. The extract solvent is 11% (v/v) ethanol. Schwabe
Pharma (UK) Ltd distributes three different preparations: Kaloba® (EPs®7630) oral drops,
Kaloba® (EPs®7630) tablets and Kaloba® (EPs®7630) syrup. The three preparations
all contain the Pelargonium patented extract EPs®7630 but in different dosage forms.
For a full list of excipients refer to Section 7.
For centuries, medicine men of South African tribes have used decoctions obtained from
Pelargonium sidoides to cure various infections including tuberculosis. The Zulu word for
the plant is “Umckaloabo” and it means “bad cough” indicating its use in traditional Zulu
medicine.
In 1897, the Englishman Major Charles H. Stevens, who was suffering from pulmonary
tuberculosis, travelled to South Africa where he was cured with this traditional medicine
after 4 months of treatment. He introduced this herbal remedy into the UK under the
name of “Stevens’ Consumption Cure”.
The identity of the root drug contained in Stevens Consumption Cure, Pelargonium
sidoides, a South African plant belonging to the Pelargonium genus, Geraniaceae family,
was first identified in Germany in 1972. As time went by, modern medical researchdiscovered many of the numerous mechanisms of action of this unique plant extract.
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Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
4.2 Qualitative and Quantitative Information
The drug substance, EPs®7630 extract is a complex mixture of constituents. The
pharmaceutically active substance in Kaloba® (EPs®7630), contains characteristic groups
of substances, namely
• Polyphenols (total phenols, 40%)
• Proteins (10%)
• Purines (2%)
• Minerals (12%)
• Saccharides (12%)
• 7-hydroxycoumarin derivatives, in lower concentrations
Figure 4: Pelargonium plant and flower (Pelargonium sidoides DC)
The plant grows to a height of 20 – 80 cm, has greyish green leaves and purple
flowers (Figure 4). The roots of Pelargonium sidoides provide the raw material used in
the manufacture of the extract EPs®7630, which is the active constituent of the
Kaloba® (EPs®7630) brand. Rhizomes and roots that are aged from 2 – 4 years contain
the optimal amount of effective substances. Nowadays, Pelargonium sidoides is grown on
specialised managed farms using ecological and sustainable cultivation methods. These
methods ensure that wild habitats remain intact addressing sustainability of the species.
Occasionally, the raw material is collected in the wild with special permits from the
authorities. The whole process through from ground cultivation, seeding, harvesting and
collection is carried out in compliance with European Guidelines on Good Agricultural
and Collective Practice (GACP).
This sustainable approach is an essential element to the growing and harvesting of
all herbal extracts that are used in the manufacture of licensed herbal medicines. The
manufacture of the extract to GACP Guidelines, as well as ensuring sustainability of the
species, gives valuable employment to a significant number of farm workers in what is
a relatively poor area of Southern Africa. The starting material is not treated with
fumigants. The dried herb is tested macroscopically, microscopically and using TLC
(thin layer chromatography) for identity according to the European Pharmacopoeia
(Ph. Eur.). Purity testing is carried out for pesticide residues, heavy metals, aflatoxins and
microbial contamination. When all these tests comply with the Ph. Eur. the dried herbal
material is then processed to EPs® 7630 extract using specialised patented techniques.
All the stages of manufacture follow strict Good Manufacturing Practice (GMP) and
Good Agricultural and Collective Practice (GACP) Guidelines from starting material to
the finished product to ensure ongoing sustainability and consistent reproducible quality
of the finished product.
Kaloba® (EPs®7630) is approved in the UK as a traditional herbal medicinal product
to relieve the symptoms of upper respiratory tract infections including the common cold,
such as sore throat, cough and blocked or runny nose, based on traditional use only.
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The polyphenols mainly comprise the monomeric flavan-3-ols catechin and
gallocatechin. All 7-hydroxycoumarin derivatives including umckalin (7-hydroxy-5,6dimethoxycoumarin), which is found in the largest quantity and is typical of this plant
species, significantly differ in terms of chemical structure from the known anticoagulant
coumarins28. Some of the substances contained in Pelargonium sidoides have not yet
been identified – a typical feature of phytopharmaceuticals (Figure 5).
unknown to date
22%
minerals
12%
saccharides
12%
purines
2%
proteins
10%
coumarins
2%
total phenols
40%
Figure 5: Chemical composition of Kaloba® (EPs®7630)
Tests carried out with the individual chemical compounds compared to the whole
extract show that only the whole extract possesses an optimal, therapeutic effect.
The isolated individual compounds displayed very weak effects, if, indeed, any29. 15
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
5. PHARMACOLOGY
3. Secretomotory properties
5.1 Mode of Action
• Stimulation of the ciliary beat frequency of the respiratory ciliated epithelium
Kaloba® (EPs®7630) has a multi-faceted mode of action. The following mechanisms
of action for Kaloba® (EPs®7630) have been found to be relevant in the treatment of
respiratory tract infections:
4. Inhibition of “sickness behaviour”
1. Antiviral and cytoprotective properties
• Modulation of the production of interferons, pro-inflammatory cytokines and defensins
• Anti-oxidant properties
• Inhibition of leukocyte elastase
2. Antibacterial properties
• Increased adhesion of bacteria to dead epithelial cells of the respiratory tract mucosa
• Inhibition of adhesion of bacteria to living epithelial cells in the respiratory tract mucosa
• Stimulation of phagocytosis and chemotaxis
Infection
Virus replication
Viruses
Cilia
These modes of action are involved in every stage of respiratory tract infections, as
shown in Figure 6, and are described separately in the following.
5.1.1 Antiviral and cytoprotective properties
The cytoprotective effect of Kaloba® (EPs®7630) and the various compounds contained
in the extract against virus-induced cell destruction was confirmed in the following
model: Fibroblasts were incubated with macrophage residues (interferon induction
by control substance / EPs®7630) and infected with the encephalomyocarditis
virus (EMCV).
The survival capacity of the cells increased with greater concentrations of EPs®7630 up
to twice that recorded in the control group incubated only with the test compounds i.e.
the whole extract and not individual compounds was responsible for the cell-protective
effect (Figure 7)29.
Stimulation of
ciliated epithelium
200
P. sidoides
Respiratory tract epithelium
Bacterial adhesion
Internalisation
Activation of
host defence
Bacterial superinfection
(recurrence)
Type 1 interferons
Pro-inflammatory
Cytokines
Macrophage activation
Cell damage
CD8+-T-cells
Bacteria
Recovery
Phagocytosis
Oxidative burst
Intracellular killing
Phagocyte
Debris
Sickness behaviour
Capacity for survival (% of controls)
Polyphenols
Umckalin
150
100
50
0
0.8
1.6
3.12
6.25
12.5
25
50
100
150
200
250
μg/ ml
Figure 7: Increase in cell vitality with Kaloba® (EPs®7630)
Figure 6: Pathogenesis of respiratory tract infections and mechanisms of
action of Kaloba® (EPs®7630).
16
17
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Kaloba® (EPs®7630) also increases the release of antimicrobial peptides, the so-called
defensins, from neutrophilic granulocytes30. Defensins were initially discovered
in plants, which, unlike mammals, have no specific immune system, and which have
successfully defended themselves for millions of years against attack from microorganisms. In humans, defensins have been detected on the surface of CD4 cells in
the skin. These are said to play an essential role in the defence against pathogens.
Current research is focusing on discovering the underlying mechanism.
The antiviral effect of Kaloba® (EPs®7630) is principally derived from the modulation
of the non-specific immune system.
Increase in interferon synthesis
Kaloba® (EPs®7630) triggers stimulation of interferon (INF)-β production (Figure 8).This is
particularly relevant because the type 1 interferon INF-β not only protects cells against
virus-mediated destruction, but also has a direct antiviral effect and activates natural killer
cells31. The latter play an important role in the initial stages of infection as immune
cells of the first line of defence.
A study carried out with EPs®7630 on human cell cultures using the viral dsRNA
analogue polyl:polyC confirms this effect31.
Moreover, Kaloba® (EPs®7630) induces the other type-1-interferons, IFN-α and INF-γ,
which also possess cytoprotective properties32, 33.
Improvement of phagocyte function
Increased phagocytosis and the intracellular destruction of microorganisms (intracellular
killing) is another pharmacological property of Kaloba® (EPs®7630) in preventing the
progress of infection. A significant improvement in the function of human phagocytes in
peripheral blood was detected in corresponding flow-cytometry assays using Candida
albicans as the target organism34.
In addition to phagocytosis per se, the formation of reactive oxygen species – the socalled oxidative bursts that damage the phagocytosed (internalized) pathogens directly
- is decisive for the activity of these immune cells.
At clinically relevant concentrations, Kaloba® (EPs®7630) increased both the active
phagocyte count (p < 0.002) as well as the proportion of burst-active phagocytes
(p < 0.001)(Figures 9 and 10).
The convergence of the four groups at the end of the test series is due to the fact that
all pathogens are phagocytosed at this point.
pl:pC(4 µg/ ml)
pl:pC(8 µg/ ml)
50
450
400
40
350
(%)
Stimulation of interferon (INF)-β-synthesis (%)
500
300
30
30 µg/ml
10 µg/ml
3 µg/ml
0 µg/ml
250
200
20
150
10
100
p < 0.002, repeated measurements
(SD < 50% of the mean value)
20
0
0
0
0.1
0.3
1
0.3 (µg/ml) Kaloba®
Figure 8: Effect of Kaloba® (EPs®7630) on INF- β -synthesis
18
Phagocytosis-active PBP
60
pl:pC(2 µg/ ml)
3
10
0
2
4
6
10
30
Minutes
Figure 9: Increase in phagocytosis with Kaloba® (EPs®7630)
19
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Burst-active PBP
90
5.1.2 Antibacterial properties
30 µg/ml
10 µg/ml
3 µg/ml
0 µg/ml
80
70
The direct bacteriostatic effect of Kaloba® (EPs®7630) is inferior to that of conventional
antibiotics35.
However, it is interesting to note that in a study carried out with multiresistant strains
of Staphylococcus aureus (MRSA), the susceptibility of these strains to Kaloba® (EPs®7630),
was comparatively favourable when compared to the non-resistant reference strain,
St. aureus ATCC 2592336.
(%)
60
50
40
30
The indirect antibacterial effects are more important.
20
Kaloba® (EPs®7630) inhibits the adhesion of bacteria to healthy mucosal cells and thus
counteracts a key mechanism in the pathogenesis of bacterial respiratory tract infections.
p < 0.001, repeated measurements
(SD < 50% of the mean value)
10
0
0
2
4
6
10
30
Adhesion to HEp-2-cells
85
Minutes
Figure 10: Increase in oxidative burst with Kaloba® (EPs®7630)
EPs® 7630
0 µg/ml
80
In another study, Conrad et al. (2007) showed an increase in intracellular
(intraphagocytic) killing with Kaloba® (EPs®7630). The number of surviving target
organisms was reduced by a maximum of 31% (p < 0.001)34.
0.3 µg/ml
3 µg/ml
75
10 µg/ml
30 µg/ml
70
5.6
60
55
50
0 µg/ml EPs® 7630
10 µg/ml EPs® 7630
30 µg/ml EPs® 7630
5.5
5.4
p < 0.001
Repeated measurements
ANOVA
5.3
5.2
Log10
%
65
Research into the mechanisms of action is continuing but it can already be said that
the anti-infective effects determined so far are directed against a broad spectrum of
pathogens. They play a crucial role especially in the management of viral infections.
45
p < 0.001
Repeated measurements
ANOVA
40
0
30
60
120
180
Minutes
Figure 12: Kaloba® (EPs®7630) inhibits the adhesion of A-streptococci
5.1
5.0
The effect of EPs®7630 on the adhesion of bacteria to 90% vital human HEp-2 cells,
a cell line of the larynx, was investigated in an in vitro study by means of flow cytometry.
A-streptococci (Streptococcus pyogenes) were used as the test organism. Clinically
relevant concentrations ranging from 0 to 30 μg EPs®7630 led to a significant
reduction in the adhesion of A-streptococci to these cells by up to 46% (p < 0.001)
(Figure 12)37.
4.9
4.8
4.7
4.6
0
15
30
60
120
Minutes
20
Figure 11: Increase in intracellular killing with Kaloba® (EPs®7630):
Increase in oxidative burst with Kaloba®
21
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
EPs® 7630
6,000
5,000
0 µg/ml
p = 0.067,
Repeated measurements
ANOVA
30 µg/ml
A-streptococci
Calcein AM-stained
HEp-2-cells
0 µg/ml Kaloba®
HEp-2-cells
(cfu)
4,000
3,000
30 µg/ml Kaloba®
2,000
Figure 13a: Adhesion of A-streptococci
Figure 13b: Kaloba® (EPs®7630) inhibits
adhesion
This reduction in adhesion was confirmed by fluorescence microscopy (Figure 13a/b).
In the same adhesion test, the identical test procedure was carried out using 90% dead
epithelial cells of the oral mucosa. This test showed that streptococcal adhesion to these
dead cells increased 7-fold with Kaloba® (EPs®7630) (p < 0.001). Pathogenic organisms
can therefore be trapped and eliminated in this way. The result was confirmed in
additional tests.
The internalisation of bacteria in the host cells plays a decisive role in the development
of recurrent infections because internalised bacteria evade the immune system’s defence
mechanisms. The intracellular proliferation of micro-organisms remaining after the initial
infection results in a renewed bout of infection.
The effect of extract EPs® 7630 on the penetration of pathogens into HEp-2 cells was
therefore investigated.
1,000
0
0
30
60
Minutes
120
180
Figure 14: Inhibition of internalisation with Kaloba® (EPs®7630)
5.1.3 Secretomotory properties
The recovery or stimulation of mucociliary clearance is a decisive factor in the defence
against respiratory tract infections. Kaloba® (EPs®7630) stimulates this mechanism, as
shown in an in vitro study with human nasal epithelial cells. EPs® 7630 increased the
ciliary beat frequency in a dose-dependent manner by 23% and 33% at 30 μg/ml and
100 μg/ml, respectively (Figure 15)38.
The result of this study showed a significant reduction in internalisation at test times 60,
120 and 180 minutes (Figure 14)37.
22
23
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
10.0
8.4
8.0
Hz
6.0
150
9.1
125
7.0
7.2
5.0
4.0
3.0
2.0
Time spent in the light field (sec.)
9.0
7.0
*
*
*
*
100
75
50
25
1.0
0
0.0
0 µg/ml
1 µg/ml
30 µg/ml
100 µg/ml
Control
Kaloba®
(400mg/kg)
Kaloba®
(0mg/kg)
Concentration of Kaloba®
Kaloba®
(400mg/kg)
Kaloba®
(200mg/kg)
Kaloba®
(100mg/kg)
LPS (0.4 mg/kg)
* statistically significant
Figure 15: Increase in ciliary activity with Kaloba® (EPs®7630)
5.1.4 Inhibition of “sickness behaviour”
Infections are frequently accompanied by non-specific changes in behaviour and both
physical and mental symptoms (weakness, fatigue, lack of interest and drive, anorexia,
social isolation, poor concentration, sleep disorders, anxiety, depression, etc.), which are
mediated by the effect of pro-inflammatory cytokines (e.g. IL - 1β, TNF-α and IL-6) on
the central nervous system.
The effect of Kaloba® (EPs®7630) on sickness behaviour triggered by
lipopolysaccharide (LPS) injection was tested in mice using a highly sensitive model to
detect behavioural changes – the light/dark box. Laboratory animals given EPs® 7630
after LPS administration remained substantially longer in the dark section of the box than
those animals in the control group.
* statistically significant
Figure 16: Effect of Kaloba® (EPS®7630) on the length of time spent in the light field
This prolonged stay in the dark section is indicative of an improvement in disease-induced
behavioural changes because these nocturnal animals spend longer in the light
section if they are feeling sick or unwell.
Kaloba® (EPs®7630) inhibited the LPS-mediated behavioural changes in a significant, dosedependent manner (Figure 16). This test result means that the positive effect on sickness
behaviour could play a crucial role in the therapeutic effects of Kaloba® (EPs®7630)39.
5.2 Clinical Information
5.2.1 Clinical Studies
Clinical studies of acute bronchitis in adults
Two placebo-controlled, double-blind studies were pivotal for an identical product to
gain a marketing authorization for the indication “acute bronchitis” in Germany. The
most important results of these studies are summarised below.
The Bronchitis Severity Score (BSS), the expression of symptom severity and thus of
the disease-mediated impact, was used, amongst others, to assess efficacy. This score is
calculated from the sum of the key symptoms – cough, expectoration, rales, chest pain
on coughing and dyspnoea, as evaluated by the investigating physician on a scale of 0
(not present) to 4 (very severe).
24
25
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Secondary outcome criteria included remission of the individual symptoms, time to onset
of action, patient compliance, tolerability, evaluation of therapeutic success by doctor
and patient using the Integrative Medicine Outcomes Scale (IMOS) and parameters
recorded in patient diaries such as intensity of symptoms, general wellbeing and
health-related quality of life.
Study 1
Study of acute bronchitis in adults
AuthorChuchalin et al. 200540
Study design
Multicentre, prospective, randomised, double-blind,
placebo-controlled study
Investigational medicinal product
EPs® 7630 (Kaloba®) vs. placebo
Number of patients
124
Duration of treatment
7 days
Dosage
3 x 30 drops/day, optional 500 mg paracetamol
p.o. when body temperature rises to > 38.5°C
Target criteria
Proof of superiority of the active drug confirmed by a change in the BSS
Figure 17a: Improvement in bronchitis symptoms with Kaloba® (EPs®7630)
(p<0.0001)
Results
An improvement in BSS of 7.2 (active drug) vs. 4.9 (placebo) (p < 0.0001) was recorded on day 7. More rapid recovery of ability to work (84.4% vs. 45.0% on day 7)
Tolerability
98.4% of patients and 96.7% of doctors assessed the tolerability of Kaloba® (EPs®7630) as “very good” or “good”
Able to work
Unable to work
16%
55%
84%
45%
EPs® 7630
Placebo
Figure 17b: Reduction of inability to work with Kaloba (EPs®7630) on day 7
®
26
27
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Study 2
(EPS®7630)
EPs® 7630
Placebo
Difference
Cough
52
12
40
Symptom
Study of acute bronchitis in adults
Heger, 200741
Author
Matthys &
Rales
88
50
38
Study design
Multicentre, prospective, randomised, double-blind, placebo-controlled study
Weakness/fatigue
80
47
33
Investigationalmedicinal product
EPs® 7630 (Kaloba®) vs. placebo
Expectoration
68
40
28
Number of patients
217
Hoarseness
80
56
24
Duration of treatment
7 days
Headache
88
68
20
Dosage
3 x 30 drops/day, optional 500 mg paracetamol p.o. when body temperature rises to > 38.5°C
Dyspnoea
88
77
11
Target criteria
Proof of superiority of the active drug confirmed by a change in the BSS
Chest pain
93
86
7
Fever
98
91
7
Results
An improvement in BSS of 7.6 (active drug) vs. 5.3 (placebo) (p < 0.0001) was recorded on day 7
Joint pain
93
88
5
Tolerability
No serious adverse events same tolerability as placebo
Figure 18b: Improvement in individual symptoms of bronchitis with Kaloba® (EPs®7630)
Study 3
Study of acute bronchitis in adults
AuthorMatthys et al. 200342
Figure 18a: Improvement in bronchitis symptoms with
Kaloba® (EPs®7630) (p=0.0001)(p<0.0001)
28
Study design
Randomised, double-blind, placebo-controlled study
Investigational medicinal product
EPs® 7630 (Kaloba®) vs. placebo
Number of patients
468
Duration of treatment
7 days
Dosage
3 x 30 drops/day, optional paracetamol tablets
(500 mg) when body temperature rises to ≥ 39°C
Target criteria
Proof of superiority of the active drug over placebo
Results
Change of BSS on day 7, decrease in BSS of 5.9 ±
2.9 (active drug) vs. 3.2 ± 4.1(placebo) (p < 0.0001)
Tolerability
96.1% of patients assessed the tolerability of EPs® 7630 as “very good” or “good”
29
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Study 1
Study of acute bronchitis in children and adolescents
AuthorKamin, 200743
Study design
Multicentre, prospective, randomised, double-blind,
placebo-controlled study
Investigational medicinal product
EPs® 7630 (Kaloba®) vs. placebo
Number of patients
200 children between 1 and 18 years of age
Duration of treatment
7 days
Dosage
Patients between 1 and 6 years of age: 3 x 10 drops/day
Patients > 6 to 12 years of age: 3 x 20 drops/day
Patients > 12 to 18 years of age: 3 x 30 drops/day
Figure 19a: Improvement in bronchitis symptoms with Kaloba®
(EPs®7630)
Able to work
Unable to work
16%
Target criteria
Proof of superiority of the active drug confirmed by a change in the BSS
Results
An improvement in BSS of 3.4 (active drug) vs. 1.2 (placebo) (p < 0.001) was recorded on day 7
Clinical Outcome (IMOS)
43%
Data recorded on day 7 by the investigator responsible
100
Placebo
EPs® 7630
90
80
84%
Kaloba®EPs ® 7630
57%
Placebo
Figure 19b: Reduction of inability to work with Kaloba® (EPs®7630)
on day 7
Patients (%)
70
60
50
40
30
20
10
Clinical studies in acute bronchitis in children
Two placebo-controlled studies involving 200 and 220 patients were carried out to
assess the treatment of acute bronchitis in children and adolescents. The design and
results of these studies correlate with the studies described earlier that were carried
out in adults.
30
0
Complete
recovery
Significant
improvement
Moderate
improvement
No change
Deterioration
Figure 20: Investigator’s assessment of the efficacy of Kaloba® (EPs®7630)
31
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Changes in the Bronchitis Severity Score (BSS)
Changes in the Bronchitis Severity Score (BSS)
ITT analysis (n = 200)
ITT analysis (n = 220)
6
7
Placebo
EPs® 7630
p < 0.001
4
3
2
EPs® 7630
6
p < 0.001
Bronchitis Severity Score
(mean and 95% CI)
Bronchitis Severity Score
(mean and 95% CI)
5
Placebo
1
5
4
3
2
1
0
0
0
3-5
7
0
Figure 21: Investigator’s assessment of the efficacy of Kaloba® (EPs®7630)
7
3-5
Day
Day
Figure 22a: Improvement in bronchitis symptoms with Kaloba® (EPs®7630)
Study 2
Clinical Outcome (IMOS)
Study of acute bronchitis in children and adolescents
Data recorded on day 7 by the investigator responsible
AuthorKamin, 200743
Multicentre, prospective, randomised, double-blind, placebo-controlled study
Investigational medicinal product
EPs® 7630 (Kaloba®) vs. placebo
Number of patients
220 children between 1 and 18 years of age
Duration of treatment
7 days
Dosage
Patients between 1 and 6 years of age: 3 x 10 drops/day
Patients > 6 to 12 years of age: 3 x 20 drops/day
Patients > 12 to 18 years of age: 3 x 30 drops/day
32
Target criteria
Proof of superiority of the active drug confirmed by a change in the BSS
Results
An improvement in BSS of 4.4 (active drug) vs. 2.9 (placebo) (p < 0.001) was recorded on day 7
100
Placebo
EPs® 7630
90
80
70
Patients (%)
Study design
60
50
40
30
20
10
0
Complete
recovery
Significant
improvement
Moderate
improvement
No change
Deterioration
Figure 22b: Improvement in bronchitis symptoms with Kaloba® (EPs®7630)
33
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Study 3
Study of acute bronchitis in children and adults
Study design
Multicentre, prospective, open observational study
Investigational medicinal product
EPs® 7630 (Kaloba®)
Number of patients
2099 patients aged 0-93; 127 patients >
6 – 12 years; 241 patients ≤ 6 years
Duration of treatment
14 days
Dosage
Adults and children > 12 years of age: 3 x 30 drops/day
Children > 6-12 years of age: 3 x 20 drops/day
Children 6 years of age or less: 3 x 10 drops/day
7
6
5
4
3
2
0
Change of BSS
Results
In all patients: The BSS decreased from 7.1 ± 2.9 at baseline to 1.0 ± 1.9 at the last visit
Subgroup analysis: For children
(patients < 18 years, n = 498): The BSS decreased from 6.3 ± 2.8 to 0.9 ± 1.8 at the last visit
Subgroup of infants (patients < 3 years, n = 78): The BSS decreased from 5.2 ± 2.5 to 1.2 ± 2.1 at the last visit
Tolerability
8
1
The tolerability of EPs® 7630 was very good
Adverse events occurred in only 1.2% of the
patients, none of the events was serious
baseline
1st follow-up
2nd follow-up
3rd follow-up
Figure 23: BSS changes during the study period in children and infants
100
Patients (%) with remission at last
individual visit
Target criteria
all infants (n = 78)
9
Bronchitis Severity Score
(mean and standard deviation)
AuthorMatthys, et
all children (n = 498)
10
al. 200744
90
80
70
60
50
40
30
20
10
0
Cough
Sputum
Rales
Chest pain at
cough
Dyspnoea
Figure 24: Remission rates from baseline to last observation for bronchitis
specific symptoms in all patients (n = 2099)
34
35
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Additional studies
Changes in the Sinusitis Severity Score (SSS)
ITT analysis (n = 103)
Acute sinusitis
16
The efficacy of Kaloba® (EPs®7630) in the management of acute sinusitis was confirmed
in the following controlled double-blind study.
14
EPs® 7630
p < 0.0001
12
Sinusitis Severity Score
(mean and 95% CI)
The primary test criterion was the Sinusitis Severity Score (SSS), which comprised the
total score of the following symptoms: headache, pain in the upper jaw region,
percussion pressure on bending forward, pressure or pain on bending forward, blocked
nose, purulent nasal secretion and purulent discharge in the median nasal passage.
These symptoms were assessed on the scale of 0 (not present) to 4 (very severe).
The maximum cumulative score was therefore 24.
Placebo
10
8
6
4
X-rays of paranasal sinuses were taken at the beginning and end of the study in order to
confirm the diagnosis.
2
Study 1
0
0
7
Study of acute Sinusitis maxillaris in adults
21
Day
al. 200945
Study design
Multicentre, prospective, randomised, double-blind, placebo-controlled study
Investigational medicinal product
EPs® 7630 (Kaloba®) vs placebo
Number of patients
103
Duration of treatment
21 days
Dosage
3x60 drops per day
Target criteria
Proof of superiority of the active drug confirmed
by a change in the SSS
Results
An improvement in the SSS of 5.4 (active drug) vs. 2.5 (placebo) (p<0.0001) was recorded at the end of the double blind phase (day 21)
Figure 25a: Improvement in sinusitis symptoms with Kaloba® (EPs®7630)
% patients who improved / were symptom-free
AuthorBachert et
14
100
Placebo (n = 52)
EPs® 7630 (n = 51)
90
80
70
60
50
40
30
20
10
0
Headache
Maxillary
pain on
bending
Maxillary
pressure
Blocked nose
Purulent
nasal
secretion
Purulent
post-nasal
discharge
Figure 25b: Improvement in individual symptoms of sinusitis with Kaloba® (EPs®7630)
36
37
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Study 2
Decrease of the Tonsillopharyngitis Severity Score (TSS)
ITT analysis (n = 143)
Study of acute non-group A beta-haemolytic streptococcal (GABHS)
tonsillopharyngitis in children
12
AuthorBereznoy et al. 200346
10
Investigational medicinal product
EPs® 7630(Kaloba®) vs placebo
Number of patients
143 children between 6 and 10 years of age
Duration of treatment
6 days
Dosage
3x20 drops per day (Paracetamol suppositories (500mg) when body temperature rises to >38.5°C (day 0 to day 4))
Target criteria
Proof of superiority of the active drug confirmed by a change in the TSS
Results
Decrease in TSS of 7.1 ± 2.1 (active drug) vs. 2.5 ± 3.6 (placebo) (p<0.0001) was recorded on day 4
Tolerability
97.2% of patients and 97.3% of doctors assessed the tolerability of EPs® 7630 as “very good”
or “good”
EPs® 7630
Tonsillopharyngitis Severity Score
Study design
Multicentre, randomised, double-blind, placebo-
controlled study
Placebo
8
6
4
2
0
0
2
4
6
Day
Figure 26a: Improvement in individual symptoms of tonsillopharyngitis with
Kaloba® (EPs®7630)
Freedom from typical tonsillitis symptoms on day 4
(remission rates)
100
Placebo
90
Kaloba®
80
70
(%)
60
50
40
30
20
10
he
ac
ad
fe
ve
r
he
a
liv
sa
m
ou re
th dn
+ es
th s o
ro f
at
w
flo
at
ro
th
re
so
di
ff
sw icul
all tie
ow s i
in n
g
0
Figure 26b: Remission rates for tonsillitis specific symptoms
38
39
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Study 3
Study of common cold in adults
AuthorLizogub et al. 200747
Study design
Multicentre, prospective, randomised, double-blind, placebo-controlled study
Investigational medicinal product
EPs®7630 (Kaloba®) vs. placebo
Number of patients
103
Duration of treatment
10 days
Dosage
3 x 30 drops/day
Target criteria
Proof of superiority of the active drug over placebo
Results
Change in Cold Intensity Score (CIS), after 5 days the CIS decreased by 10.4 ± 3.0 in the EPs®7630 and by 5.6 ±4.3 in the placebo group
Tolerability
On day 5, more than 9 out of 10 patients
assessed the tolerability of EPs®7630 as “very good” or “good”, no adverse events were reported
Changes in the Cold Intensity Score (CIS)
ITT analysis (n = 103)
20
Placebo
18
EPs® 7630
Cold Intensity Score
(mean and 95% CI)
16
5.2.2 Pre-Clinical Studies
There are some more recent studies that have been carried out in order to investigate
further potential actions and indications for Kaloba® (EPs®7630). The two studies below
give details on the anti-viral effect of EPs®7630 on the Herpes virus and the influenza
virus strain H1N1.
Study 1
14
Efficacy of an aqueous Pelargonium sidoides EPs® 7630 extract against herpes virus48
12
Schnitzler, P., Schneider, S., Stintzing, F. C., Carle, R., Reichling, J. Efficacy of an aqueous
Pelargonium sidoides extract against herpes virus.
Phytomedicine 2008. 15: 1108-1116.
10
8
6
4
2
0
1
3
5
Day
Figure 27a: Improvement in common colds symptoms with EPs®7630
40
Figure 27b: Changes of the individual common cold symptoms with
EPs®7630/Kaloba®
10
Abstract
The compounds of an aqueous root extract of the African medicinal plant Pelargonium
sidoides were analysed by LC-MS spectroscopy and antiviral effect of this extract against
herpes simplex virus was examined in cell culture. Besides predominant coumarins,
simple phenolic structures as well as flavonoid and catechin derivatives were identified
as major constituents in the Pelargonium extract. The inhibitory activity of this extract
against herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2)
was tested in vitro on RC-37 cells using a plaque reduction assay and exhibited high
antiviral activity against both herpes viruses in viral suspension tests.
41
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
The 50% inhibitory concentration (IC50)subscript of the aqueous Pelargonium
sidoides extract for herpes simplex virus plaque formation was determined at 0.00006%
and 0.000005% for HSV-1 and HSV-2, respectively. At maximum non-cytotoxic
concentrations of the extract, plaque formation was significantly reduced by more
than 99.9% for HSV-1 and HSV-2 and a clear concentration-dependant antiviral activity
against HSV could be demonstrated for this extract. In order to determine the mode
of antiviral action, the extract was added at different times to the cells or viruses during
the infection cycle. Both herpes viruses were significantly inhibited when pretreated with
the plant extract or when the extract was added during the absorption phase, whereas
aciclovir demonstrated antiviral activity only intracellularly during replication of HSV.
These results indicate that Pelargonium sidoides extract affected the virus before
penetration into the host cell and reveals a different mode of action when compared
to the classical drug aciclovir. Hence this extract is capable of exerting an antiviral effect
on herpes simplex virus and might be suitable for topical therapeutic use as an antiviral
drug both in labial and genital herpes infections.
Figure 28: Antiviral effect of Pelargonium sidoides extract against HSV-1. Dose-response
experiments were repeated independently 3 times and data presented are the average
of 4 experiments. Details of experiment: Cells were pre-treated with Pelargonium
sidoides extract prior to virus infection (pretreatment cells), viruses were pretreated
prior to infection (pretreatment virus), the Pelargonium sidoides extract was added
during the adsorption period (adsorption) or after penetration of the viruses into cells
(replication).
Figure 29: Antiviral activity of Pelargonium sidoides extract against
HSV-2. Data presented are mean of 4 experiments.
Study 2
EPs®7630 (Kaloba® (EPs®7630 )), an extract from Pelargonium sidoides roots, exerts
anti-influenza virus activity in vitro and in vivo49
Theisen, L. L. and Muller, C.P. EPs®7630 (Kaloba®), an extract from Pelargonium sidoides
roots, exerts anti-influenza virus activity in vitro and in vivo. Antiviral Research. 2012. 94:
147-156.
Abstract
A prodelphinidin-rich extract from Pelargonium sidoides DC, EPs®7630 (Kaloba®),
which is licensed to treat respiratory tract infections such as acute bronchitis, was
investigated for its antiviral effects. EPs®7630 showed dose-dependent anti-influenza
activity at non-toxic concentrations against pandemic H1N1, oseltamivir-sensitive
and - resistant seasonal H1N1, seasonal H3N2 and the laboratory H1N1 strain
A/PuertoRico/8/34, while it had no antiviral activity against adenovirus or measles virus.
Figure 28
42
The extract inhibited an early step of influenza infection and impaired viral
hemagglutination as well as neuraminidase activity. However, EPs®7630 did not exhibit
a direct virucidal effect, as virus preincubation (unlike cell preincubation) with the extract
did not influence infectivity. Importantly, EPs®7630 showed no propensity to resistance
development in vitro. Analysis of EPs®7630 constituents revealed that prodelphinidins
represent the active principle.
43
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Chain length influenced antiviral activity, as monomers and dimers were less
effective than oligo- and polymers. Importantly, gallocatechin and its stereoisomer
epigallocatechin exert antiviral activity also in their monomeric form. In addition, EPs® 7630
administered by inhalation significantly improved survival, bodyweight and body
temperature of influenza-infected mice, without obvious toxicity, demonstrating the
potential benefit of EPs® 7630 in treatment of influenza.
Figure 30a and b: Anti-influenza activity of EPs®7630 in mice. Infection of 10 mice per
group with 4 MLD50 or 1 MLD50 of A/Puerto Rico/8/34, treatment with EPs®7630 or
water by inhalation 3 times a day for 10 days. Numbers represent surviving animals
from a group of 10. Influence of EPs®7630 treatment on virus lung titers. Lungs were
removed on the day when less than 75% bodyweight was reached or on day 14 for
surviving mice. Homogenisation and titration on MDCK cells. MLD50, half maximal
mouse lethal dose.
,
Figure 30b
5.3 General Safety Information on Kaloba® (EPs®7630)
The favourable clinical safety profile of Kaloba® (EPs®7630) is corroborated by
toxicological investigations. All standard tests such as cytotoxicity, acute and
chronic toxicity in rats and dogs, genotoxicity studies (Ames test, chromosome
aberration test and micronucleus test) as well as tests for carcinogenic potential, local
tolerability, immunotoxicity and reproduction toxicity yielded no significant results50.
5.3.1 Coumarins in Kaloba® (EPs®7630) and Their Effects on the Hepatobiliary
System
Figure 30a
Coumarins represent a large group of compounds for which hepatotoxic potential has
been reported. It is known that some compounds in the large group of coumarin
derivatives may have hepatotoxic effects. However, these substances differ structurally
from the 7-hydroxycoumarins that are present in EPs® 7630 (Kaloba®).
There is no reference in the scientific literature to hepatotoxic effects with
7-hydroxycoumarins. On the contrary, the metabolism of coumarin compounds via
7-hydroxylation is viewed as a detoxification mechanism51 and there is evidence that
7-hydroxycoumarins (such as, for instance, 4-methylumbiliferone) may even have
hepatoprotective effects52.
Products containing 4-methylumbiliferone have been available since the 1990s in both
the USA and Europe as food supplements to improve liver function. They have also been
used in part as medicinal products owing to their spasmolytic and choleretic effects.
As expected, hepatotoxic effects were not observed in acute or chronic toxicity studies
in dogs and rats following oral administration of up to 3000 mg/kg of EPs® 7630. This is
confirmed in studies carried out on human hepatocytes and hepatoma cells53.
44
45
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
The species-specific metabolism of this substance group plays a crucial role in
determining whether or not coumarins develop any toxic effects. Highly toxic
epoxides are formed as metabolites in rats, for instance, but do not occur in humans54.
5.3.2 Coumarins in EPs® 7630(Kaloba®) and Their Effects on Blood Coagulation
In contrast to the well documented anticoagulant 4-hydroxycoumarins, the structurally
different coumarins contained in EPs®7630 (Kaloba®) do not cause inhibition of
vitamin-K-dependent synthesis of coagulation factors in the liver (Figure 31)56.
High-dose studies in rats carried out over 14 days with 10, 75 or 500 mg/kg EPs®7630
revealed no change in thrombin time, partial thrombin time and thromboplastin
time. No potentiation of the anticoagulant effect was observed following concomitant
administration of 0.05 mg/kg warfarin. The results suggest that neither direct effects on
haemostasis nor haemostatic effects due to interaction with anti-coagulants are likely
during treatment with Kaloba® (EPs®7630) (Figure 32)56.
Chemical structure of coumarins in EPs ® 7630
and coumarin-type anticoagulants
CH3
C
OCH3
CH2
O
O
O
4
H3CO
3
Warfarin (Marevan® )
7
HO
OH
8
O
O
OH
Umckalin
C2H5
CH
O
O
Phenprocoumon (Marcumar ®)
Figure 31: Chemical structure of coumarins in Kaloba® (EPs®7630)
compared to coumarins in anticoagulants
46
Control
EPs® 7630
EPs® 7630 + Warfarin
Warfarin
140
Percentage (control = 100)
Human primary hepatocytes (with normal and reduced CYP2A6-activity) were
incubated with the coumarin derivative umckalin (10 and 100 μm), which is contained in
EPs®7630 (Kaloba®). After up to four hours’ incubation, two metabolites were detected
in addition to the intact starting substance, namely glucuronide and sulphate conjugates
of umckalin55.
*
#
150
130
120
#
110
*
#
100
TPT
PTPT
TT
# p < 0,05 compared to control
* p < 0,05 compared to EPs ® 7630
Figure 32: Kaloba® (EPs®7630) does not significantly influence the
pharmacodynamics of coumarin type anticoagulants
5.3.3 Drug Interactions
Interactions with other medicinal products are generally not expected as EPs®7630
(Kaloba®) does not affect liver metabolism except for a clinically irrelevant inhibition
of CYP2C9. An effect on other tested cytochrome-P450 isoenzymes has not been
observed at relevant concentrations. This includes CYP3A4, which is responsible for the
metabolism of many pharmacologically active substances57. Similarly, no induction of
cytochrome-P450-isoenzymes has been observed in human hepatocytes58.
These results are supported by findings in an interaction study conducted by Roots et
al., who did not observe any relevant differences for the primary target criterion, AUC
(Area Under the Curve) of penicillin V with and without concomitant administration of
EPs®7630 (Kaloba®). The double-blind, randomised study was conducted in 2004 with
Kaloba® and penicillin V (3 x 30 drops EPs® 7630 (Kaloba®) vs. 3 x 1.2 mega Isocillin®
p.o.) for 7 days59.
5.3.4 Tolerability
Approximately 304 million daily doses of Kaloba® (EPs®7630) were sold between
1994 and 2006, predominantly in Germany. The incidence of side effects is extremely
low and equates to 0.53 per million defined daily doses (defined daily doses – DDD).
This means that only one in 189,000 patients will experience a side effect during an
average treatment period of 10 days. The rate of side effects is 0.27 per million DDD
for hypersensitivity reactions (especially redness and pruritus), 0.13 for gastrointestinal
disorders (such as stomach pain, heartburn, nausea or diarrhoea) and 0.05 for gingival
haemorrhaging and nose bleeds.
47
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
161 suspected cases of adverse drug reactions (ADRs) were reported spontaneously
and 96 ADRs were reported from clinical trials over the above period.
The principal side effects from both sources are listed in the package leaflet.
Overall, only 13 serious adverse drug reactions (ADRs) were reported between 1994
and 2006. The causal relationship of these with EPs®7630 was mostly classified as
unlikely. These figures confirm the excellent tolerability of Kaloba® treatment60.
The efficacy and safety of EPs®7630 (Kaloba®) in the treatment of respiratory tract
infections has been extensively investigated. Over 3,800 patients were recruited in
controlled double-blind studies and over 5,400 patients in open-label and noninterventional (post-marketing surveillance) studies.
The EPs®7630 (Kaloba®) study programme in children is significant, because the
anatomy and physiology of children differ from that of adults. There are differences in
the metabolism and in the responses of receptors and target organs. To date, specific
pharmacological studies have still not been carried out for up to 90% of all medicinal
products used in paediatric practice61. The consequences: every second medicinal
product has not been authorised for children and adolescents62, which means that
between 36 and 100% of hospital and 20 – 56% of outpatient prescriptions for children
are off-label prescriptions63.
6. KALOBA® (EPs®7630) - FREQUENTLY ASKED QUESTIONS
Drug interactions
No interactions with other medicinal products have been reported to date. However,
in view of the theoretical effect of Kaloba® (EPs®7630) on coagulation parameters,
enhancement of the effects of anticoagulant drugs such as phenprocoumon
and warfarin (e.g. Marevan®) cannot be excluded when these are administered
concomitantly with Kaloba® (EPs®7630).
Special patient groups and questions
Pregnancy/lactation
There is insufficient experience to date with regard to the use of Kaloba® (EPs®7630)
during pregnancy and lactation. For this reason, Kaloba® (EPs®7630) should not
be administered during pregnancy and lactation without seeking medical advice.
Auto-immune diseases
Kaloba® (EPs®7630) has an immuno-modulating effect rather than an immunostimulating effect and it therefore boosts the immune system only in the event of
infection. Consequently, there are no contra-indications on the use of Kaloba in patients
with auto-immune diseases, although there have been no studies carried out to date in
this patient group. Significantly, Kaloba can be used by asthmatics unlike Echinacea, which is
contra- indicated for use in both asthmatics and patients suffering from autoimmune diseases.
Children under 6 years of age
Kaloba® (EPs®7630) is not approved in the UK for use in children under 6 years of
age. However in Germany it is indicated from 1 year due to very good tolerability and
proven efficacy. Kaloba® (EPs®7630) oral drops and syrup are indicated from 6 years
onwards, and Kaloba® (EPs®7630) tablets from 12 years in the UK.
Alcoholics
Herbal remedies in liquid form such as Kaloba® (EPs®7630) Oral Solution, frequently
contain alcohol. This is used as an extraction agent, natural stabilising agent and
absorption-enhancing agent. The natural blood alcohol level in humans is 0.003%. This is
only slightly changed by the intake of a small quantity of alcohol such as that contained
in Kaloba® (EPs®7630) Oral Drops because these small quantities are metabolised very
quickly after ingestion. Many foodstuffs consumed in normal quantities contain as much
as or even more alcohol than that contained in a daily dose of Kaloba® (EPs®7630).
Similarly, there is no risk to children. A glass of apple juice (0.2l) contains more than
three times as much pure alcohol (0.76ml) than the maximum paediatric dose of 60
drops Kaloba® (EPs®7630). Regardless of this, the medicinal product can be administered
in a small glass or warm tea or juice. A large proportion of the alcohol evaporates
and the taste is also lost.
Diabetics
Kaloba® (EPs®7630) oral drops, tablets and syrup are suitable for diabetics. The amount
of sugar absorbed in the daily dose is clinically insignificant and need not be taken
into account in any daily sugar intake calculation.
Coeliac disease
Kaloba® (EPs®7630) does not contain gluten and can be administered to patients with
gluten-sensitive coeliac disease.
48
49
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
7. CORE SUMMARY OF PRODUCT CHARACTERISTICS
Contraindications
7.1 Kaloba® (EPs®7630) oral drops
Kaloba is not to be used in the following cases:
• hypersensitivity to the active substance or to the excipient,
• increased tendency to bleeding and application of coagulation-inhibiting drugs,
• severe hepatic and renal diseases, as no adequate data are available in these areas,
• pregnancy and lactation
• children < 6 years.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active substance:
10 g (= 9.75 mL) of oral solution contains 8.0 g extract from the roots of Pelargonium
sidoides DC (1 : 8 - 10) (EPs® 7630).
Extraction solvent: 11% ethanol (w/w).
1 ml (approximately 20 drops) of Kaloba Oral Drops, solution contains 120 mg ethanol
(alcohol) equivalent to 2.4 ml beer or 1.0 ml of wine.
CLINICAL PARTICULARS
Therapeutic indications
Traditional herbal medicinal product used to relieve the symptoms of upper respiratory
tract infections including common cold, such as sore throat, cough and blocked or runny
nose, based on traditional use only.
In the package leaflet, the patient is advised to consult a doctor immediately if his or her
condition does not improve within one week, in case of fever lasting for several days or
in case of shortness of breath or bloody sputum.
Kaloba oral solution contains 12 vol % ethanol (alcohol).
This corresponds to:
180 mg alcohol equivalent to 3.6 ml beer or 1.5 ml wine per adults´single dose •
(30 drops)
•
120 mg alcohol equivalent to 2.4 ml beer or 1.0 ml wine per children’s single dose (20 drops).
Posology and method of administration
Harmful for those suffering from alcoholism. To be taken into account in children and
high-risk groups such as patients with liver disease, or epilepsy.
Adults and adolescents over the age of 12:
Take 30 drops three times per day.
Interaction with other medicinal products and other forms of interaction
Children aged between 6-12 years:
Take 20 drops three times per day.
The necessary amount of drops may be taken directly from a spoon or, if preferred, can
be mixed with half a glass of water and the contents of the entire glass should be drunk
straightaway. The dose should be taken in the morning, at midday and in the evening.
20 drops is equivalent to approximately 1ml
30 drops is equivalent to approximately 1.5ml.
Duration of application
After relief of symptoms, continuation of treatment for further 2 – 3 days is
recommended in order to prevent a relapse, however treatment duration should not
exceed 2 weeks.
50
Special warnings and precautions for use
Drug interactions have not been reported to date.
However, due to the potential influence of Kaloba on coagulation parameters, the
possibility that this product enhances the effect of coagulation-inhibiting drugs such
as warfarin in cases of simultaneous intake cannot be excluded.
Pregnancy and lactation
This product should not be used in women who are pregnant or breast-feeding, as there
are no data available for these patient groups.
Effects on ability to drive and use machines
Kaloba has no or negligible influence on the ability to drive and use machines.
51
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Undesirable effects
7.2 Kaloba® (EPs®7630) tablets
The evaluation of adverse reactions is based on the following information on frequency:
Very common:Common:
more than 1 out of 100 treated persons
more than 1 out of 10 treated persons QUALITATIVE AND QUANTITATIVE COMPOSITION
1 film-coated tablet contains 20 mg of extract (as dry extract) from the roots of
Pelargonium sidoides DC (1 : 8 - 10) (EPs®7630)
Extraction solvent 11% ethanol (w/w).
Uncommon: Rare:
more than 1 out of 1000 treated persons more than 1 out of 10 000 treated persons
CLINICAL PARTICULARS
Therapeutic indications
Very rare:
1 or less out of 10 000 treated persons including single cases
Traditional herbal medicinal product used to relieve the symptoms of upper respiratory
tract infections including the common cold, such as sore throat, cough and blocked or
runny nose, based on traditional use only.
Gastro-intestinal complaints such as stomach pain, heartburn, nausea or diarrhoea may
occur uncommonly (≥ 1/1,000 to < 1/100) during treatment with Kaloba.
In rare cases (≥1/10,000 to ≤ 1/1,000), mild bleeding from the gingiva or nose
may occur. Furthermore, hypersensitivity reactions (e.g. exanthema, urticaria,
pruritus of skin and mucous membranes) have been described in rare cases. Such
reactions may already occur at the first intake of the pharmaceutical product.
In very rare cases (≤ 1/10,000), serious hypersensitivity reactions with swelling of the face,
dyspnea and drop of blood pressure may occur.
In single cases, signs indicating disturbances of liver function have been reported after
intake of Kaloba; the causal relationship between this effect and the application of the
product has not been demonstrated.
Overdose
The effects of overdose are unknown.
Although there are no data on cases of overdose, overdose is likely to increase side effects.
Thus, treatment should be symptomatic and as clinically indicated.
PHARMACEUTICAL PARTICULARS
List of excipients
Posology and method of administration
Adults and adolescents over 12 years of age:
Take 1 tablet three times daily (morning, midday, evening).
Tablets should be swallowed whole with a little water. The tablets should not be chewed.
The use in children under 12 years of age is not recommended (see section 4.4 `Special
warnings and precautions for use`).
Duration of use:
After relief of symptoms, continuation of treatment is recommended for a further 2 – 3
days in order to prevent a relapse. However, treatment duration should not exceed 2
weeks.
If the symptoms persist during the use of the medicinal product, a doctor or a qualified
health care practitioner should be consulted.
Contraindications
Kaloba is not to be used in the following cases:
• hypersensitivity to the active substance or to any of the excipients,
• increased tendency to bleeding,
• patients using coagulation-inhibiting drugs,
• severe hepatic and renal diseases, due to lack of adequate data.
Glycerol 85%
Ethanol
52
53
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Special warnings and special precautions for use
In the patient information leaflet, the patient is advised to consult a doctor immediately
if his or her condition does not improve within one week, in case of fever lasting for
several days or in case of shortness of breath or blood in the sputum.
One film-coated tablet contains 20 mg lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
On theoretical grounds Kaloba should not be used where there is a likelihood of
increased tendency to bleeding or use of coagulation-inhibiting drugs.
Kaloba should not be used in case of severe hepatic and renal diseases, due to lack of
adequate data.
This formulation is not suitable for children under 12 years of age.
Interaction with other medicinal products and other forms of interaction
Very common:Common:
more than 1 out of 10 treated persons
more than 1 out of 100 treated persons
Uncommon:Rare:
more than 1 out of 1000 treated persons more than 1 out of 10 000 treated persons
Very rare:
1 or less out of 10 000 treated persons including single cases
Gastro-intestinal complaints such as stomach pain, heartburn, nausea or diarrhoea may
occur uncommonly (≥ 1/1,000 to < 1/100) during treatment with Kaloba.
In rare cases (≥1/10,000 to ≤ 1/1,000), mild bleeding from the gums or nose may
occur. Furthermore, hypersensitivity reactions (e.g. exanthema, urticaria, pruritus of skin and
mucous membranes) have been described in rare cases. Such reactions may occur after
the first intake of the product.
Drug interactions have not been reported to date.
In very rare cases (≤ 1/10,000), serious hypersensitivity reactions with swelling of the
face, dyspnoea and drop in blood pressure may occur.
However, due to the potential effect of Kaloba on coagulation parameters,
this product may enhance the effect of coagulation-inhibiting drugs such as
warfarin and should not be taken concomitantly with these drugs.
In single cases, signs indicating disturbances of liver function have been reported after
intake of Kaloba; the causal relationship between this effect and the use of the product
has not been demonstrated.
Pregnancy and lactation
If other adverse reactions not mentioned above occur, a doctor or a qualified health
care practitioner should be consulted.
Safety during pregnancy and lactation has not been established. In the absence of
sufficient data, the use during pregnancy and lactation is not recommended.
Effects on ability to drive and use machines
Overdose
The effects of overdose are unknown.
No studies on the effect on the ability to drive and use machines have been performed.
Although there are no data on cases of overdose, overdose is likely to increase sideeffects. Thus, treatment should be symptomatic and as clinically indicated.
Undesirable effects
PHARMACEUTICAL PARTICULARS
The evaluation of adverse reactions is based on the following information on frequency:
List of excipients
Extract:
Maltodextrin
54
55
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Tablet core:
Maltodextrin
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium,
Precipitated silica
Magnesium stearate
Film-coating:
Hypromellose 5 mPas
Macrogol 1500
Iron oxide yellow E172
Iron oxide red E172
Titanium dioxide E171
Talc
Simeticone
Methylcellulose
Sorbic acid.
7.3 Kaloba® (EPs®7630) syrup
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active substance:
100 g (= 93.985 ml) syrup contain 0.2506 g dried liquid extract from the roots of
Pelargonium sidoides DC (1 : 8 - 10) (EPs® 7630). The extraction agent is 11% ethanol
(w/w).
CLINICAL PARTICULARS
Therapeutic indications
Traditional herbal medicinal product used to relieve the symptoms of upper respiratory
tract infections including the common cold, such as sore throat, cough and blocked or
runny nose, based on traditional use only.
Posology and method of administration
For oral use
Shake the bottle well before use
Adults, the elderly and adolescents over 12 years of age:
Take 7.5 ml of the syrup three times per day.
56
Children aged between 6-12 years:
Take 5 ml of the syrup three times per day.
Syrup is to be taken in the morning, midday and evening.
The use in children under 6 years of age is not recommended (see section 4.4 “Special
warnings and precautions for use”.)
Duration of use
After relief of symptoms, continuation of treatment is recommended for a further 2 – 3
days in order to prevent a relapse. However, treatment duration should not exceed 2
weeks.
If the symptoms persist during the use of the medicinal product, a doctor or a qualified
health care practitioner should be consulted.
Contraindications
• hypersensitivity to the active substance or to any of the excipients
• increased tendency to bleeding
• patients using coagulation-inhibiting drugs
• evere hepatic and renal diseases due to lack of adequate data
Special warnings and special precautions for use
In the patient information leaflet, the patient is advised to consult a doctor immediately
if his or her condition does not improve within one week, in case of fever lasting for
several days or in case of shortness of breath or blood in the sputum.
On theoretical grounds Kaloba should not be used where there is a likelihood of
increased tendency to bleeding or use of coagulation-inhibiting drugs.
Kaloba should not be used in case of severe hepatic and renal diseases, due to lack of
adequate data.
The use of this product in children or adolescents under 6 years of age is not
recommended because data are not sufficient and medical advice should be sought.
Interaction with other medicinal products and other forms of interaction
Drug interactions have not been reported to date.
However, due to the potential effect of Kaloba on coagulation parameters, this product
may enhance the effect of coagulation-inhibiting drugs such as warfarin and should not
be taken concomitantly with these drugs.
57
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
Pregnancy and lactation
Safety during pregnancy and lactation has not been established. In the absence of
sufficient data use during pregnancy and lactation is not recommended.
Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
Undesirable effects
The evaluation of adverse reactions is based on the following information on frequency:
Very common:Common:
less than 1 out of 10 but more than
more than 1 out of 10 treated persons 1 out of 100 treated persons
Uncommon:Rare:
less than 1 out of 1000 but more than 1
less than 1 out of 100 but more out of 10 000 treated persons
than 1 out of 1000 treated persons Overdose
The effects of overdose are unknown.
Although there are no data on cases of overdose, overdose is likely to increase sideeffects. Thus, treatment should be symptomatic and as clinically indicated.
PHARMACEUTICAL PARTICULARS
List of excipients
Extract:
Maltodextrin
Syrup:
Xylitol
Glycerol 85%
Citric acid anhydrous
Potassium sorbate
Xanthan gum
Purified water Very rare:
less than 1 out of 10 000 treated persons including cases with unknown frequency
Gastro-intestinal complaints such as stomach pain, heartburn, nausea or diarrhoea may
occur uncommonly (≥ 1/1,000 to < 1/100) during treatment with Kaloba.
In rare cases (≥ 1/10,000 to ≤ 1/1,000) mild bleeding from the gums or nose may occur.
Furthermore, hypersensitivity reactions (e.g. exanthema, urticaria, pruritus of skin and
mucous membranes) have been described in rare cases. Such reactions may occur after
the first intake of the product.
In very rare cases (≤ 1/10,000) serious hypersensitivity reaction with swelling of the face,
dyspnoea and drop in blood pressure may occur.
In single cases, signs indicating disturbances of liver function have been reported after the
intake of Kaloba; the causal relationship between this effect and the use of the product
has not been demonstrated.
If other adverse reactions not mentioned above occur, a doctor or a qualified health
care practitioner should be consulted.
58
59
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
8. REFERENCES
1. Marre, R. and Merten, T. H. Klinische Infektiologie. Urban & Fischer. 2006. 296-297
2. Fintelmann, P. 6 KVN-Pressekonferenz 2005. Munchen (KVN=Komitee Forschung
Naturmeedizin e. V.)
3. DGPI Handbuch 2003
4. Hampl, W. and Mertens, T. Virale Atemweginfektionen bei Erwachsenen,
Bundesgesundheitsbl-Gesundheitsforsch-Gesundheitsschutz. 2003. 46: 488-498.
5. Porzsolt, F and Ohleyz, A. Kunstfehler und Phantom-Risiken. Deutsches Artzteblatt.
1999. 41: A-2575,B-2199, C-2063
6. Adam, D. et al. Kurtzzeittherapie der akuten Tonsillopharyngitis mit
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61
Kaloba® (EPs® 7630) PELARGONIUM SIDOIDES PRODUCT MONOGRAPH
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34. Conrad, A. et al. Extract of Pelargonium sidoides (EPs®7630) improves
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38. Neugebauer, P. et al. A new approach to pharmacological effects on ciliary beat
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by a Dry Extract from the Roots of Pelargonium Sidoides (EPs® 7630) in Mice,
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40. Chuchalin, A. G. et al. Treatment of acute bronchitis in adults with a Pelargonium
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Drug Preparation from Pelargonium sidoides (EPs® 7630): A Randomised, DoubleBlind, Placebo-Controlled, Multi-Centre Study, Curr Med Res Opin 2007; 23: 323–331.
62
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55. Dr. Willmar Schwabe Arzneimittel Karlsruhe, Präklinische Forschung, 2007: Xeno
Tech Study No. XT070007.
56. Koch, K. and Biber, A.Treatment of rats with the Pelargonium sidoides extract EPs® 7630
has no effect on blood coagulation parameters or on the pharmacokinetics of warfarin,
Phytomedicine 2007; 14 (Suppl. VI): 40–45.
57. Dr. Willmar Schwabe Arzneimittel Karlsruhe, Präklinische Forschung, 2005: Cerep
Study No. 9588.
58. Dr. Willmar Schwabe Arzneimittel Karlsruhe, Präklinische Forschung, 2005:
RCC-CCR Study N° 879701.
59. Roots, I. et al. Placebokontrollierte doppelblinde Interaktionsstudie mit Pelargoniumsidoides-Extrakt und Penicillin V bei gesunden Probanden, Phytopharmaka und
Phytotherapie 2004 – Forschung und Praxis, Berlin.
60. Buschulte, I. and Köhler, S. Periodic Safety Update Report on the tolerability of
Pelargonium sidoides Extract EPs® 7630, JSO Pharma, Ettlingen 2007.
61. Anonymus: Klinische Forschung mit Kindern vor dem Aus?, Pharm Ztg 2005; 24: 682.
62. Kanders, J. Off Label Use in der Kinderheilkunde – Ein heikles Thema, Ärztliche Praxis
09.02.2004.
63. Schweim, H.G. „off labeluse“... oder über die Notwendigkeit der Arzneimittelzulassung,
Vortrag Bundesinstitut für Arzneimittel und Medizinprodukte 2004, http://www.haraldschweim.de/off-label-neu.pdf.
64
65
www.kaloba.co.uk
MHRA Registration Number: THR 05332/0003
MHRA Registration Number: THR 05332/0005
AVAILABLE AS:
AVAILABLE AS:
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AVAILABLE AS:
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Part of the Taking Herbal Medicines Seriously series.