Public Assessment Report

Scientific discussion

Helixor A 100 mg, 50 mg, 30 mg, 20 mg,

10 mg, 5 mg, 1 mg, solution for injection

Asp. no: 1981-6014 / 1981-6013 / 1981-6012 / 1981-6011 /

1981-6010 / 1981-6009 / 1981-6008 /1981-6007 /
1981-6006 / 1981-6005 / 1981-6002

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Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN

Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala
Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66
Internet: www.mpa.se E-mail: [email protected]
 LAY SUMMARY
The Medical Products Agency (Läkemedelsverket) has granted Helixor Heilmittel GmbH &
Co. KG, Germany, a well-established use approval for the herbal medicinal product Helixor A,
100 mg, 50 mg, 30 mg, 20 mg, 10 mg, 5 mg and 1 mg, solution for injection. Helixor A is
available on prescription and can be bought from pharmacies.

Helixor A 100 mg, 50 mg, 30 mg, 20 mg, 10 mg, 5 mg and 1 mg is used in individualised
palliative cancer care as an adjuvant to conventional therapy. The active ingredient is a liquid
water extract from fresh herb of mistletoe grown on silver fir. The approval is based upon data
from published scientific literature regarding mistletoe.

The chemical/pharmaceutical quality of the product is acceptable and no serious safety

concerns have been identified during the assessment. It was therefore decided that Helixor A,
100 mg, 50 mg, 30 mg, 20 mg, 10 mg, 5 mg and 1 mg could be approved as a herbal medicinal
product.

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I. INTRODUCTION
Helixor Heilmittel GmbH & Co. KG, Germany, has applied for a marketing authorisation for
Helixor A, 100 mg, 50 mg, 30 mg, 20 mg, 10 mg, 5 mg, 1 mg, solution for injection. The
active substance is Viscum album L. ssp. abietis (mistletoe) fresh herb; liquid extract (1:20)
0.09 % NaCl-solution.

The applications for all strengths of Helixor A were submitted under Article 10a Well-
established use approval for herbal medicinal products of the Directive 2001/83 EC, as
amended.

The assessment reports (i.e. Quality, Clinical and Non-clinical) for Helixor A apply to all
strengths of the product (i.e. 100, 50, 30, 20, 10, 5, 1 mg). Furthermore, Helixor A is packed in
packages containing ampoules of only one strength as well as packages containing ampoules
of different strengths.

For approved indication, see the Summary of Product Characteristics.

II. QUALITY ASPECTS

II.1 Introduction

Helixor A are presented in the form of solution for injection containing the active substance
Viscum album L. ssp. abietis (mistletoe) fresh herb; liquid extract (1:20) 0.09 % NaCl-solution.
The strengths 100 mg, 50 mg, 30 mg, 20 mg, 10 mg, 5 mg and 1 mg corresponds to
approximately 100 mg, 50 mg, 30 mg, 20 mg, 10 mg, 5 mg and 1 mg of fresh herb Viscum
album L. ssp. abietis growing on Abies alba Mill. (silver fir).

The excipients are water, sodium chloride and sodium hydroxide (pH-adjustment). The
solution for injection is packed in glass ampoules à 1 ml. Only Helixor A 100 mg is packed in
glass ampoules à 2 ml.

All manufacturers involved in the production operate in accordance with EU-GMP, or where
relevant, GACP (Good Manufacturing Practice, respectively Good Agricultural and Collection
Practice).

II.2 Drug Substance

The herbal substance is Viscum album L. ssp. abietis growing on Abies alba Mill.
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The harvesting of the mistletoe plant materials is performed over four seasons. Relevant
information on growing conditions and controls of the herbal substance (such as residues of
heavy metals and pesticides as well as microbiological quality) has been provided. The fresh
herb is shredded, diluted, blended and filtrated. The herbal preparation is a mixture of two
intermediate extracts to give the final extract Helixor A.

The route of administration is subcutaneous injection, hence water of very high purity (water
for injection) was used for the extraction. The manufacturing process has
been adequately described and satisfactory specifications have been provided for starting
materials and solvents.

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Control of the active substance (herbal preparation) Viscum album L. ssp. abietis (mistletoe)
fresh herb; liquid extract (1:20) 0.09 % NaCl-solution, has been adequately described.
Satisfactory specification has been provided.

The active substance specification includes relevant tests and the limits for impurities have
been justified. The analytical methods applied are suitably described and validated.

Stability studies under ICH conditions have been conducted and the data provided are
sufficient to confirm the retest period.

II.3 Medicinal Product

The medicinal product Helixor A is sterile solution for subcutaneous injection. Helixor A, 100
mg, 50 mg, 30 mg, 20 mg, 10 mg, 5 mg and 1 mg are formulated using excipients described in
the current European Pharmacopoeia (Ph. Eur.). All raw materials used in the product are safe
with view to possible TSE/BSE risk.

The manufacturing process has been sufficiently described and critical steps identified. Results
from the process validation studies confirm that the process is under control and ensure both
batch to batch reproducibility and compliance with the product specification.

The tests and limits in the specification are considered appropriate to control the quality of the
finished product in relation to its intended purpose.

Stability studies under ICH conditions have been performed and data presented support the
shelf-life claimed in the SPC.

III. NON-CLINICAL ASPECTS

III.1 Introduction
The long market presence and the high interest in mistletoe products has resulted in a high
number of published, peer reviewed, studies on the pharmacology and toxicology of Helixor A
as well as other mistletoe products.

III.2 Pharmacology
Mistletoe extract contains a range of substances with potential pharmacodynamic activity,
among which mistletoe lectins have been most widely investigated. Besides the lectins, also
viscotoxins, phenylpropanoids, phytosterols, triterpenes, saccharides, and polyalcohols may
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contribute to the pharmacodynamic properties of the extract.
The role of these different substances is currently not known.

III.3 Pharmacokinetics
Constituents responsible for the therapeutic effect of Helixor A are not entirely known,
and thus pharmacokinetic studies are not relevant.

III.4 Toxicology
Local reactions at the site of injection are frequently observed in animal studies.
Studies on reproductive and developmental effects are insufficient.
Published data on genotoxicity and carcinogenicity are not available.
Apart from this, available literature regarding safety pharmacology and toxicity reveals no
special hazard for humans.

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III.5 Ecotoxicity/environmental risk assessment
Helixor A is a herbal medicinal product. According to “Guideline on the environmental risk
assessment of medicinal products for human use (EMEA/CHMP/SW4447/00), herbal
medicinal products are exempted from the obligation to present an environmental risk
assessment due to the nature of their constituents.

III.6 Discussion on the non-clinical aspects

A detailed scientific bibliography addressing non-clinical characteristics has been submitted.
In accordance with article 10a of Directive 2001/83/EC as amended, for a herbal medicinal
product with well established use, the lack of conclusive data on the mechanism of action as
well as of pharmacokinetic data is acceptable. The basic requirements for authorisation as a
well-established herbal medicinal product from a non-clinical point of view are judged to be
fulfilled.

IV. CLINICAL ASPECTS

IV.1 Introduction
The treatment of cancer with mistletoe extracts was first introduced into anthroposophical
medicine by Rudolf Steiner around 1920. Mistletoe extract preparations are today the most
frequently used complementary and alternative methods (CAM) in the treatment of cancer
patients in German-speaking countries.
The Medical Products Agency (MPA) has decided to mainly base the evaluation of clinical
efficacy on the review by the Cochrane Collaboration of mistletoe therapy in oncology
published in 2008. The review contains assessment of clinical efficacy of mistletoe extracts in
general i.e. not of any particular mistletoe extract.

IV.2 Pharmacokinetics
Results from human pharmacokinetic studies with Helixor A or other mistletoe extracts are not
available. The total extract is regarded as the active substance, since the role of the individual
components of the extract has not been established. Thus the lack of pharmacokinetic studies is
acceptable.

IV.3 Pharmacodynamics
The mechanism of action has not been clarified.

IV.4 Clinical efficacy

A Cochrane review concerning mistletoe therapy in oncology was published in 2008
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(Horneber M, et al). It is a joint assessment of different mistletoe extracts, dosage and
treatment duration. The objective of the review was to determine the effectiveness, tolerability
and safety of mistletoe extracts given either as monotherapy or adjunct therapy, i.e. given
concomitantly with chemo- or radiotherapy, for patients with cancer.
The outcome measures assessed were survival time, tumour response, quality of life (QoL),
psychological distress, adverse effects from antineoplastic treatment and safety of mistletoe
extracts.
In the studies evaluated, 3484 cancer patients were included and randomised. In five studies
Helixor with varying dosage was used. The number of patients withdrawing or dropping out
was reported for all of the studies included in the Cochrane review.
In conclusion, the study results are seen as insufficient to provide clear guidelines for the use
of mistletoe extracts in oncological practice. There is some support as regards health-related

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QoL. There is no clear evidence for superiority of one preparation or treatment schedule over
the other.
Eight clinical studies were listed in the Cochrane review as studies to be assessed in an
upcoming update of the review. An assessment of these studies has been performed by the
MPA. None of these studies is judged to be of pivotal importance.

IV.5 Clinical safety

The MPA agrees with the Cochrane assessors and the applicant that mistletoe extracts are
usually well tolerated and have only few side effects. This is supported by the longstanding
and wide-spread use of mistletoe extracts in cancer therapy, especially in some European
countries.
Twelve studies included in the Cochrane review reported on adverse effects related to
treatment with mistletoe extracts. The local reactions most commonly reported were redness,
itching and induration at the injection site, appearing in up to one third of the patients. Among
systemic reactions, mild fever and flu-like symptoms were reported in 10% of the patients.
Adverse reactions known to be caused by mistletoe extract preparations, including
anaphylactic reactions, are formerly known to the MPA. No new safety issues have been
identified during the assessment procedure.

IV.6 Discussion on the clinical aspects

In the opinion of the MPA, due to longstanding and widespread use of mistletoe products in
cancer treatment in the European Union, mistletoe extract products should be available for
Swedish cancer patients in individualised palliative cancer care as an adjuvant to conventional
therapy.
Based on the proposed posology, there is insufficient evidence in support of tumour response,
delay in tumour progression and concerning survival benefit.
No studies of drug-drug interactions have been performed. As a precautionary measure, a
contraindication to concomitant treatment with immunomodulators (with the exception of
cytotoxic drugs) and immunostimulants is adviced.

V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT

AND RECOMMENDATION
The applicant has shown that the chemical/pharmaceutical quality is acceptable and can
confirm that the process is under control and ensure both batch reproducibility and compliance
with the product specification.
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The adverse reactions reported during an extensive use of mistletoe products are no cause for
safety concern. No new safety signals have been identified in the submitted documentation.

The benefit/risk ratio is considered positive and Helixor A, solution for injection, is
recommended for approval.

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VI. APPROVAL

Helixor A, 100 mg, 50 mg, 30 mg, 20 mg, 10 mg, 5 mg, 1 mg, solution for injection was
approved in the national procedure on 2013-12-06.

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Public Assessment Report – Update
Scope Procedure number Product Information Date of start of the Date of end of Approval/ Assessment report
affected procedure procedure non approval attached
Y/N (version)

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