EUROPEAN COMMISSION
ENTERPRISE DIRECTORATE-GENERAL
Single market : management & legislation for consumer goods
Pharmaceuticals : regulatory framework and market authorisations
Brussels,
ENTR/F2/BL D(2003)
Revision 1
NOTICE TO APPLICANTS
VOLUME 3B
Guidelines
Medicinal products for human use
Safety, environment and information
Excipients in the label and package leaflet of
medicinal products for human use
July 2003
Rue de la Loi 200, B-1049 Bruxelles/Wetstraat 200, B-1049 Brussel - Belgium - Office: AN88 1/3.
Telephone: direct line (+32-2)295.53.71, switchboard 299.11.11. Fax: 296.15.20.
Telex: COMEU B 21877. Telegraphic address: COMEUR Brussels.
CPMP/463/00
Final
EXCIPIENTS IN THE LABEL AND PACKAGE LEAFLET OF
MEDICINAL PRODUCTS FOR HUMAN USE
INTRODUCTION
This is a Commission guideline pursuant to Article 65 of Directive 2001/83/EC. It contains warning
statements relating to the presence of certain excipients in medicinal products. Homeopathic
medicinal products authorised through a special simplified registration procedure are not addressed in
this guideline since for these homeopathic products there are specific labelling requirements
according to Article 69.
.
Article 54(c) requires that all excipients need to be declared on the labelling if the medicinal product
is an injectable or a topical, or an eye preparation. Furthermore, Article 54 (1)(c) provides that:
excipients known to have a recognised action or effect, and included in the guidelines published by
the Commission pursuant to Article 65, need to be declared on the labelling of all other medicinal
products.
Article 59 (1)(a) 2nd indent requires a full statement of the active substance and excipients in the
package leaflet. Article 59 (1)(c) states that the package leaflet must include a list of information
which is necessary before taking the medicinal product. Article 59(1)(c), 7th indent provides that the
aforementioned information should include information on those excipients, knowledge of which is
important for the safe and effective use of the medicinal product and included in the guidelines
published by the Commission pursuant to Article 65.
Article 59(1) requires that the package leaflet must be in accordance with the SPC and shall be drawn
up in accordance with the SPC. Therefore, consistent information should be stated in both documents.
PURPOSE
This guideline is for use by competent authorities, applicants for a Marketing Authorisation and
Marketing Authorisation Holders. The Annex provides a list of the excipients which should be stated
on the labelling and outlines the information which should appear in the package leaflet, for these
excipients. This guideline does not apply to these substances when they are used as active substances.
DEFINITIONS AND EXAMPLES
In general, excipients may be defined as the constituents of the pharmaceutical form that is taken by
or administered to the patient, other than the active substance.
According to the Annex of Directive 2001/83/EC, such constituents may include:
colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and
aromatic substances, etc.,
the constituents intended to be ingested or otherwise administered to the patient, of the outer
covering of the medicinal products capsules, gelatine capsules, rectal capsules etc.
Further examples may include:
excipient mixtures, e.g. those used for example in direct compression or in a film coat or polish
for an ingested dose form.
Page 1
pH adjusters
the constituents of printing inks used to mark the ingested dose form
diluents present, for example in herbal extracts or vitamin concentrates
the constituents present in a mixture of chemically related components ( e.g. preservatives )
However, in the context of this guideline, residues of substances arising from the manufacturing
process, impurities, residual solvents, degradation products etc. are not included in this definition.
In general, excipients are considered to be inert. Whilst it is desirable that excipients should have
little or no pharmacological action of their own, some do indeed have a recognised action or effect in
certain circumstances. Therefore Marketing Authorisation applicants and holders should ensure that
excipients are used appropriately in the formulation of their medicinal products, with regard to the
information contained in the Annex.
NOMENCLATURE
The following applies to the names of all excipients on the labelling, package leaflet and in the SPC.
1.
Proprietary names should not be used for individual excipients. Excipients should be referred to
by their recommended international nonproprietary name (INN), the European Pharmacopoeia
name, or failing this, their usual common name.
2.
The name of an excipient appearing in the Annex must be accompanied by the E number if it
exists. The E number alone may be used for an excipient on the labelling, provided that the full
name and the E number are stated in the user package leaflet, in the section where the full
qualitative composition is given.
3.
Proprietary flavours or fragrances may be declared in general terms (e.g. 'orange flavour,
'citrus fragrance/perfume'); any known major components or those with a recognised action or
effect should be declared specifically.
4.
Chemically modified excipients should be declared in such a way as to avoid confusion with
the unmodified excipient (e.g. pre-gelatinised starch).
5.
pH adjusters should be mentioned by name and their function may also be stated, e.g.
hydrochloric acid for pH adjustment.
6.
All components of compound excipients or mixtures should be declared, listed under a general
descriptive term e.g. printing ink containing x, y, z. A general descriptive term may be used on
the labelling provided more information is given in the package leaflet. Any component with a
recognised action or effect should be mentioned on the labelling.
EXCIPIENTS IN THE LABELLING
According to Directive 2001/83/EC, all excipients in parenteral, ophthalmic and topical medicinal
products must appear on the labelling. Topical medicinal products can be taken to include those
medicinal products applied externally to the skin, respiratory products delivered to the lung by
inhalation and any medicinal product delivered to the oral, nasal, rectal or vaginal mucosae, i.e. where
the delivery may be local or transdermal.
For all other medicinal products, only those excipients known to have a recognised action or effect,
included in the Commissions guideline, should be declared on the labelling. Such excipients are
listed in Annex.
When a medicinal product contains any of these, the name of the excipient must be stated on the
Page 2
labelling, together with a statement such as 'see leaflet for further information'.
EXCIPIENTS IN THE PACKAGE LEAFLET
According to Article 59(1)(a) 2nd indent, of Directive 2001/83/EC, all of the excipients must be stated
on the package leaflet by name. Thus, all excipients, as indicated in the section on Definitions and
Examples above, should be declared according to the nomenclature defined in this guideline.
In line with the provisions of Article 59(1)(c) 4th and 7th indents of Directive 2001/83/EC, the fourth
column in the Annex provides information corresponding to each excipient. The text of this
information is in clear and understandable terms for the patient. However, taking into account that
applicants may have different house styles for their package leaflets, it is not required that the
information in the Annex should be applied verbatim to the package leaflet, so applicants may choose
their own style to present this information to the patient, e.g. in a direct or indirect style. The
content or meaning of the text must not be changed.
When a warning or information statement is required according to the Annex, it must be clear in the
package leaflet and SPC that the statement is linked to the presence of a particular excipient. The
patient should not be left in any doubt as to whether the warning relates to the excipient or the active
substance.
For some of the excipients in the Annex, the information to be included in the package leaflet may
relate to more than one section of the leaflet, e.g. effects on ability to drive and operate machinery,
pregnancy and lactation, undesirable effects. To simplify the presentation of the package leaflet, this
information should appear only once. However, in order that the patient does not miss important and
relevant information, it may be necessary to refer back to the excipient warnings section from other
sections in the package leaflet. For example in the case of ethanol, it will be necessary to refer back to
the excipient warnings section from those sections relating to effects on ability to drive, pregnancy
and lactation, information for children, etc.
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ANNEX: Excipients and Information for the Package Leaflet
Explanatory Notes
The Annex is structured as follows:
Name
This is the name of the excipient using INN or PhEur nomenclature where possible, including a
reference to E-numbers where relevant
Route of administration
This is necessary because the information may depend upon the route of administration, e.g. for
benzalkonium chloride the information relating to bronchospasm is relevant only for the respiratory
route.
Threshold
It is accepted that excipients may only show an effect above a certain dose.
Except where otherwise stated, thresholds are expressed as Maximum Daily Doses of the excipient
in question, taken as part of a medicinal product.
The threshold is a value, equal to or above which it is necessary to provide the information stated.
A threshold of zero means that it is necessary to state the information in all cases where the
excipient is present in the medicinal product.
Information for the Package Leaflet
The information is presented here in a simple form, in clear and understandable terms for the patient.
The text often refers to the term per dose meaning dose of the medicinal product.
Since doses may be extremely variable, applicants must take into account
the maximum single dose of the medicinal product, as defined in the SPC, Section 4.2.
For this reason the information sometimes contains the expression
up to x mg per dose, for example.
If the pharmaceutical form is a solid form, e.g. tablet, capsule, suppository, powder in a sachet, it may
be better to refer to the amount per tablet, capsule etc.
Comments
Text in this column is not for the patient.
It is intended to give further information on the text in the preceding column, for the benefit of
applicants and the competent authorities.
In some cases these comments may appear as a contraindication in the SPC, worded in an appropriate
style.
page 4
ANNEX: Excipients and Information for the Package Leaflet
Name
Threshold
Aprotinin
Route of
Administration
Topical
Arachis oil (peanut oil)
All
Zero
Aspartame (E951)
Oral
Zero
Contains a source of phenylalanine. May be harmful for
people with phenylketonuria
Azo colouring agents:
Oral
Zero
May cause allergic reactions
Topical
Zero
May cause skin reactions
Zero
Information for the Package Leaflet
May cause hypersensitivity or severe allergic reactions
The topical route in this case
refers to sites that may have
access to the circulation (e.g.
wounds, body cavities etc.)
(Medicinal product) contains arachis oil (peanut oil). If Purified arachis oil may contain
you are allergic to peanut or soya, do not use this peanut protein. The PhEur
medicinal product.
monograph does not contain a
test for residual protein.
SPC: contraindication
For example,
E102, tartrazine
E110, susnset yellow FCF
E122, azorubine,
carmoisine
E123, amaranth
E124, ponceau 4R red,
cochineal red A
E151 brilliant black BN,
black PN
Balsam of Peru
Comments
page 5
Benzalkonium chloride
Ocular
Zero
Topical
Respiratory
Benzoic acid and
benzoates:
May cause eye irritation.
Avoid contact with soft contact lenses.
Remove contact lenses prior to application and wait at
least 15 minutes before reinsertion.
Known to discolour soft contact lenses.
Irritant, may cause skin reactions.
Topical
10 micrograms
/ delivered
dose
Zero
May cause bronchospasm.
Parenteral
Zero
May increase the risk of jaundice in newborn babies
Parenteral
Exposures less
than 90
mg/kg/day
Must not be given to premature babies or neonates.
Mildly irritant to the skin, eyes and mucous membranes.
for example:
E210 benzoic acid
E211 sodium benzoate
E212 potassium benzoate
Benzyl alcohol
May cause toxic reactions and allergic reactions in infants
and children up to 3 years old..
SPC: allergic should be
expressed as anaphylactoid
The amount of benzyl alcohol in
mg per <volume> should be
stated in the package leaflet and
SPC.
page 6
90mg/kg/day
Must not be given to premature babies or neonates.
Due to the risk of fatal toxic reactions arising from
exposure to benzyl alcohol in excess of 90 mg/kg/day,
this product should not be used in infants and children up
to 3 years old.
Bergamot oil
Bergapten
Topical
Zero
Bronopol
Topical
Zero
Butylated hydroxyanisole
(E320)
Topical
Zero
May cause local skin reactions (e.g.contact dermatitis), or
irritation to the eyes and mucous membranes.
Butylated
hydroxytoluene
(E321)
Castor oil polyoxyl and
castor oil polyoxyl
hydrogenated
Topical
Zero
May cause local skin reactions (e.g. contact dermatitis), or
irritation to the eyes and mucous membranes.
Parenteral
Oral
Zero
Zero
May cause severe allergic reactions
May cause stomach upset and diarrhoea
Topical
Zero
May cause skin reactions
Topical
Zero
May cause local skin reactions (e.g. contact dermatitis).
Topical
Parenteral
Topical
Zero
May cause allergic reactions
Zero
May be irritant to the skin.
Cetostearyl alcohol
including Cetyl alcohol
Chlorocresol
Dimethyl sulphoxide
The amount of benzyl alcohol
per <volume> should be stated
in the package leaflet and SPC.
May increase sensitivity to UV light (natural and artificial Does not apply when bergapten
sunlight).
is shown to be absent from the
oil
May cause local skin reactions (e.g. contact dermatitis).
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Ethanol
Oral and
Parenteral
Less than 100
mg per dose
This medicinal product contains small amounts of ethanol
(alcohol), less than 100mg per <dose>.
0__
1__
2__
100 mg 3g
per dose
Oral and
Parenteral
3 g per dose
This statement is to provide
reassurance to parents and
children concerning the low
levels of alcohol in the product.
This medicinal product contains ... vol % ethanol The package leaflet should give
(alcohol), i.e. up to ... mg per dose, equivalent to ... ml the equivalent volume of beer
and wine, nominally calculated
beer, ... ml wine per dose.
assuming 5 % vol and 12% vol
Harmful for those suffering from alcoholism.
To be taken into account in pregnant or breast-feeding ethanol respectively.
women, children and high-risk groups such as patients
Separate warning statements
with liver disease, or epilepsy.
may be needed in different parts
of the PL.
This medicinal product contains ... vol % ethanol
(alcohol), i.e. up to ... mg per dose, equivalent to ... ml
beer, ... ml wine per dose.
Harmful for those suffering from alcoholism.
To be taken into account in pregnant or breast-feeding
women, children and high-risk groups such as patients
with liver disease or epilepsy.
The amount of alcohol in this medicinal product may alter
the effects of other medicines.
The amount of alcohol in this medicinal product may
impair your ability to drive or use machines.
Formaldehyde
Topical
Zero
May cause local skin reactions (e.g. contact dermatitis).
page 8
Fructose
Galactose
Glucose
Oral
Zero
May cause stomach upset and diarrhoea
Oral
Parenteral
Zero
If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before
taking this medicinal product
5g
Contains x g fructose per dose.
This should be taken into account in patients with
diabetes mellitus.
Oral liquids,
lozenges and
chewable tablets
Zero
May be harmful to the teeth
Parenteral
Zero
If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before
taking this medicinal product
Oral
Zero
If you have been told by your doctor that you have an
intolerance to some sugars contact your doctor before
taking this medicinal product
Oral
Parenteral
5g
Contains x g galactose per dose.
This should be taken into account in patients with
diabetes mellitus
Oral
Zero
SPC proposal: Patients with rare
hereditary problems of fructose
intolerance should not take this
medicine.
Information to be included only
when the medicinal product may
be intended for chronic use, e.g.
for two weeks or more
SPC proposal: Patients with rare
hereditary problems of galactose
intolerance e.g. galactosaemia
should not take this medicine.
SPC proposal: Patients with rare
hereditary problems of galactose
intolerance e.g. galacotosaemia,
or glucose-galactose
malabsorption should not take
this medicine.
If you have been told by your doctor that you have an SPC proposal: Patients with rare
intolerance to some sugars, contact your doctor before glucose-galactose malabsorption
taking this medicinal product
should not take this medicine
page 9
Oral
Parenteral
5g
Oral liquids,
lozenges and
chewable tablets
Zero
Oral
10g/dose
Rectal
1g
Heparin
(as an excipient )
Parenteral
Zero
May cause allergic reactions and reduced blood cell
counts which may affect the blood clotting system.
Patients with a history of heparin-induced allergic
reactions should avoid the use of heparin-containing
medicines.
Hydrogenated Glucose
syrup
(or Maltitol Liquid)
Oral
Zero
If you have been told by your doctor that you have an SPC proposal: Patients with rare
intolerance to some sugars, contact your doctor before hereditary problems of fructose
taking this medicinal product
intolerance should not take this
medicine.
Glycerol
Contains x g glucose per dose.
This should be taken into account in patients with
diabetes mellitus
May be harmful to the teeth
Information to be included only
when the medicinal product may
be intended for chronic use, e.g.
for two weeks or more
May cause headache, stomach upset and diarrhoea
May have a mild laxative effect
page 10
Invert sugar
Oral
10 g
May have a mild laxative effect
Calorific value 2.3 kcal/g of hydrogenated glucose syrup.
Zero
If you have been told by your doctor that you have an SPC proposal: Patients with rare
intolerance to some sugars, contact your doctor before hereditary problems of fructose
taking this medicinal product
intolerance or glucose-galactose
malabsorption should not take
this medicine
Contains x g of a mixture of fructose and glucose per
dose.
This should be taken into account in patients with
diabetes mellitus
5g
Lactitol, E966
Oral liquids,
lozenges and
chewable tablets
Zero
Oral
Zero
10 g
May be harmful to the teeth
Information to be included only
when the medicinal product may
be intended for chronic use, e.g.
for two weeks or more
If you have been told by your doctor that you have an SPC proposal: Patients with rare
intolerance to some sugars contact your doctor before hereditary problems of fructose
taking this medicinal product
intolerance, galactose
intolerance, galactosaemia or
glucose-galactose malabsorption
should not take this medicine.
May have a mild laxative effect
Calorific value 2.1 kcal/g lactitol
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Lactose
Oral
Zero
5g
If you have been told by your doctor that you have an SPC proposal: Patients with rare
intolerance to some sugars, contact your doctor before hereditary problems of galactose
taking this medicinal product
intolerance, the Lapp lactase
deficiency or glucose-galactose
malabsorption should not take
this medicine.
Contains x g lactose (x/2 g glucose and x/2 g galactose)
per dose. This should be taken into account in patients
with diabetes mellitus
Lanolin (see Wool Fat)
Topical
Zero
May cause local skin reactions (e.g. contact dermatitis)
Latex
Natural Rubber (latex)
All
Zero
The container of this medicinal product contains latex Not a typical excipient, but a
rubber. May cause severe allergic reactions.
warning is considered necessary
Maltitol E965 and
Isomaltitol E953,
Maltitol Liquid
Oral
Zero
If you have been told by your doctor that you have an SPC proposal: Patients with rare
intolerance to some sugars, contact your doctor before hereditary problems of fructose
taking this medicinal product
intolerance should not take this
medicine.
10 g
May have a mild laxative effect
Calorific value 2.3 kcal/g maltitol (or isomaltitol)
10 g
May have a mild laxative effect
(see Hydrogenated
Glucose Syrup )
Mannitol, E421
Oral
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Organic Mercury
compounds
Ocular
Zero
May cause allergic reactions.
For example
Topical
Zero
May cause local skin reactions (e.g. contact dermatitis)
and discolouration
Thiomersal
Phenylmercuric nitrate,
acetate, borate)
Parenteral
Zero
This medicinal product contains (thiomersal) as a
preservative and it is possible that <you/your child> may
experience an allergic reaction. Tell your doctor if
<you/your child> have/has any known allergies.
See EMEA Public Statement,
8 July 1999,
Ref. EMEA/20962/99
See EMEA Public Statement,
8 July 1999,
Ref. EMEA/20962/99
Tell your doctor if you/your child have/has experienced Additional statement to be
any health problems after previous administration of a mentioned for vaccines
vaccine.
Parahydroxybenzoates
and their esters
Oral
Ocular
Topical
Zero
May cause allergic reactions (possibly delayed).
Parenteral
Respiratory
Zero
May cause allergic reactions (possibly delayed), and
exceptionally, bronchospasm.
All
Zero
This medicine contains phenylalanine.
May be harmful for people with phenylketonuria
For example
E214 Ethyl
hydroxybenzoate
E216
Propylhydroxybenzoate
E217 Sodium
propylhydroxybenzoate
E218
Methylhydroxybenzoate
E219 Sodium
methylhydroxybenzoate
Phenylalanine
page 13
Potassium
Parenteral
Less than
1 mmol per
<dose>
This medicine contains potassium, less than 1 mmol Information
relates
to
a
(39 mg) per <dose>, i.e. essentially potassium- free.
threshold based on the total
amount of K+ in the medicinal
product
It is especially relevant to
products used in paediatric
doses, to provide information to
prescribers and reassurance to
parents concerning the low level
of K+ in the product.
Propylene glycol and
esters
Parenteral
Oral
1 mmol per
<dose>
This medicine contains x mmol (or y mg) potassium per
<dose>. To be taken into consideration by patients with
reduced kidney function or patients on a controlled
potassium diet.
Parenteral
intravenous
Topical
30 mmol/l
May cause pain at the site of injection.
Oral
Parenteral
400mg/kg
adults
Zero
May cause skin irritation
May cause alcohol-like symptoms
200mg/kg
children
Sesame oil
All
Zero
May rarely cause severe allergic reactions.
page 14
Sodium
Parenteral
Less than
1 mmol per
<dose>
This medicinal product contains less than 1 mmol sodium Information
relates
to
a
(23 mg) per <dose>, i.e. essentially sodium- free.
threshold based on the total
amount of Na+ in the medicinal
product
It is especially relevant to
products used in paediatric
doses, to provide information to
prescribers and reassurance to
parents concerning the low level
of Na+ in the product.
Oral
Parenteral
1 mmol per
<dose>
This medicinal product contains x mmol (or y mg) sodium
per dose. To be taken into consideration by patients on a
controlled sodium diet
Sorbic acid and salts
Topical
Zero
May cause local skin reactions, (e.g. contact dermatitis).
Sorbitol E420
Oral
Parenteral
Zero
If you have been told by your doctor that you have an SPC proposal: Patients with rare
intolerance to some sugars, contact your doctor before hereditary problems of fructose
taking this medicinal product
intolerance should not take this
medicine.
Oral
10 g
May have a mild laxative effect
Calorific value 2.6 kcal/g sorbitol
Soya oil (and
Hydrogenated Soya oil)
All
Zero
(Medicinal product) contains soya oil. If you are allergic In line with Arachis oil.
to peanut or soya, do not use this medicinal product.
SPC: contraindication.
Stearyl alcohol
Topical
Zero
May cause local skin reactions (e.g. contact dermatitis)
page 15
Sucrose
Oral
Zero
5g
Sulphites including
metabisulphites
If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before SPC proposal: Patients with
taking this medicinal product
rare hereditary problems of
fructose intolerance, glucosegalactose malabsorption or
sucrase-isomaltase insufficiency
should not take this medicine.
Contains x g of sucrose per dose.
This should be taken into account in patients with
diabetes mellitus.
0__
1__
Oral liquids,
lozenges and
chewable tablets
Zero
May be harmful to the teeth.
Oral
Parenteral
Respiratory
Zero
May rarely cause severe hypersensitivity reactions and
bronchospasm
Oral
Zero
Suitable for people with coeliac disease.
Wheat Starch may contain
Patients with wheat allergy (different from coeliac gluten, but only in trace
disease) should not take this medicine.
amounts, and is therefore
2__
Information to be included only
when the medicinal product
may be intended for chronic
use, e.g. for two weeks or more
3__
For example:
E220 sulphur dioxide
E221 sodium sulphite
E222sodium bisulphite
E223 Sodium
metabisulphite
E224Potassium
metabisulphite
E228 Potassium
bisulphite
Wheat starch
page 16
considered safe for people with
coeliac disease. (Gluten in
wheat starch is limited by the
test for total protein described in
the PhEur monograph.)
Wool Fat
(Lanolin )
Topical
Zero
May cause local skin reactions (e.g. contact dermatitis)
Xylitol
Oral
10 g
May have a laxative effect
Calorific value 2.4 kcal/g xylitol
page 17
