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22 November 2019

EMA/CHMP/302620/2017 Rev. 2*

Annex to the European Commission guideline on


‘Excipients in the labelling and package leaflet of
medicinal products for human use’ (SANTE-2017-11668)

Excipients and information for the package leaflet

Agreed by CHMP Excipients Drafting Group 6 July 2017

Adopted by EMA Committee for Medicinal Products for Human Use (CHMP) 20 July 2017

Endorsed by European Commission's Notice to Applicants Group 4 October 2017

Date of publication 22 November 2019

This document replaces the Annex previously included in the Guideline CPMP/463/00 Rev. 1.

It is an integral part of the European Commission guideline on ‘Excipients in the labelling and package
leaflet of medicinal products for human use’ (SANTE-2017-11668).

Keywords Excipient, Package Leaflet, Labelling

*Rev. 2 includes an update of boric acid

Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands


Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us
Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union

© European Medicines Agency, 2022. Reproduction is authorised provided the source is acknowledged.
Excipients and information for the package leaflet
Name Updated on Route of Threshold Information for the Package Comments
Administration Leaflet

Aprotinin Topical Zero May cause hypersensitivity or The topical route in this case refers to
severe allergic reactions. sites that may have access to the
circulation (e.g. wounds, body cavities
etc.).
Arachis oil (peanut oil) All Zero <Medicinal product> contains Purified arachis oil may contain peanut
arachis oil (peanut oil). If you are protein. The PhEur monograph does
allergic to peanut or soya, do not not contain a test for residual protein.
use this medicinal product.
SmPC: contraindication.

Aspartame (E 951) 09/10/2017 Oral Zero This medicine contains x mg Aspartame is hydrolysed in the
aspartame in each <dosage gastrointestinal tract when orally
unit><unit volume> <which is ingested. One of the major hydrolysis
equivalent to products is phenylalanine.
x mg/<weight><volume>>.
Information to consider for the SmPC:
Aspartame is a source of Neither non-clinical nor clinical data
phenylalanine. It may be harmful are available to assess aspartame use
if you have phenylketonuria in infants below 12 weeks of age.
(PKU), a rare genetic disorder in
which phenylalanine builds up
because the body cannot remove
it properly.

EMA/655784/2022 Page 2/29


Azo colouring agents Oral Zero May cause allergic reactions.

e.g.:
Tartrazine (E 102)
Sunset yellow FCF (E
110)
Azorubine, carmoisine (E
122)
Amaranth (E 123)
Ponceau 4R, cochineal
Red A (E 124)
Brilliant black BN, black
PN (E 151)
Balsam of Peru Topical Zero May cause skin reactions.

Benzalkonium chloride 09/10/2017 All Zero This medicine contains x mg


benzalkonium chloride in each
<dosage unit><unit volume>
<which is equivalent to
x mg/<weight><volume>>.
Benzalkonium chloride 09/10/2017 Ocular Zero Benzalkonium chloride may be From the limited data available, there
absorbed by soft contact lenses is no difference in the adverse event
and may change the colour of the profile in children compared to adults.
contact lenses. You should
remove contact lenses before Generally, however, eyes in children
using this medicine and put them show a stronger reaction for a given
back 15 minutes afterwards. stimulus than the adult eye. Irritation
may have an effect on treatment
Benzalkonium chloride may also adherence in children.
cause eye irritation, especially if
you have dry eyes or disorders of Benzalkonium chloride has been
the cornea (the clear layer at the reported to cause eye irritation,
front of the eye). If you feel symptoms of dry eyes and may affect
abnormal eye sensation, stinging the tear film and corneal surface.
or pain in the eye after using this Should be used with caution in dry eye
medicine, talk to your doctor. patients and in patients where the
cornea may be compromised.

EMA/655784/2022 Page 3/29


Patients should be monitored in case of
prolonged use.

Benzalkonium chloride 09/10/2017 Nasal Zero Benzalkonium chloride may cause Long-term use may cause oedema of
irritation or swelling inside the the nasal mucosa.
nose, especially if used for a long
time.
Benzalkonium chloride 09/10/2017 Inhalation Zero Benzalkonium chloride may cause
wheezing and breathing
difficulties (bronchospasm),
especially if you have asthma.
Benzalkonium chloride 09/10/2017 Cutaneous Zero Benzalkonium chloride may Use during pregnancy and lactation is
irritate the skin. not expected to be associated with
harmful effects to the mother as
You should not apply this cutaneous absorption of benzalkonium
medicine to the breasts if you are chloride is minimal.
breast-feeding because the baby
may take it in with your milk. Not for application to mucosa.
Benzalkonium chloride 09/10/2017 Oromucosal, Zero Benzalkonium chloride may cause
rectal and local irritation.
vaginal

EMA/655784/2022 Page 4/29


Benzoic acid (E 210) 09/10/2017 All Zero This medicine contains x mg
and benzoates <benzoic acid/benzoate salt> in
each <dosage unit><unit
e.g.: volume> <which is equivalent to
Sodium benzoate (E 211) x mg/<weight><volume>>.
Potassium benzoate (E
212)

Benzoic acid (E 210) 09/10/2017 Oral, parenteral Zero <Benzoic acid/Benzoate salt> Increase in bilirubinaemia following its
and benzoates may increase jaundice (yellowing displacement from albumin may
of the skin and eyes) in newborn increase neonatal jaundice which may
e.g.: babies (up to 4 weeks old). develop into kernicterus (non-
Sodium benzoate (E 211) conjugated bilirubin deposits in the
Potassium benzoate (E brain tissue).
212)

Benzoic acid (E 210) 09/10/2017 Topical Zero <Benzoic acid/Benzoate salt> May cause non-immunologic
and benzoates may cause local irritation. immediate contact reactions by a
possible cholinergic mechanism.
e.g.:
Sodium benzoate (E 211)
Potassium benzoate (E
212)

Benzoic acid (E 210) 09/10/2017 Topical Zero <Benzoic acid/Benzoate salt> Absorption through the immature skin
and benzoates may increase jaundice (yellowing of neonates is significant.
of the skin and eyes) in newborn
e.g.: babies (up to 4 weeks old).
Sodium benzoate (E 211)
Potassium benzoate (E
212)

Benzyl alcohol 09/10/2017 All Zero This medicine contains x mg


benzyl alcohol in each <dosage
unit><unit volume> <which is
equivalent to
x mg/<weight><volume>>.

EMA/655784/2022 Page 5/29


Benzyl alcohol may cause allergic
reactions.

Benzyl alcohol 09/10/2017 Oral, parenteral Zero Benzyl alcohol has been linked Intravenous administration of benzyl
with the risk of severe side effects alcohol has been associated with
including breathing problems serious adverse events and death in
(called “gasping syndrome”) in neonates (“gasping syndrome”). The
young children. minimum amount of benzyl alcohol at
which toxicity may occur is not known.
Do not give to your newborn baby
(up to 4 weeks old), unless Warning in section 4.4 in the SmPC
recommended by your doctor. should be given if used in neonates.
Benzyl alcohol 09/10/2017 Oral, parenteral Zero Do not use for more than a week Increased risk due to accumulation in
in young children (less than 3 young children.
years old), unless advised by your
doctor or pharmacist.
Benzyl alcohol 09/10/2017 Oral, parenteral Zero Ask your doctor or pharmacist for
advice if you are pregnant or
breast-feeding. This is because
large amounts of benzyl alcohol
can build-up in your body and
may cause side effects (called
“metabolic acidosis”).
Benzyl alcohol 09/10/2017 Oral, parenteral Zero Ask your doctor or pharmacist for High volumes should be used with
advice if you have a liver or caution and only if necessary,
kidney disease. This is because especially in subjects with liver or
large amounts of benzyl alcohol kidney impairment because of the risk
can build-up in your body and of accumulation and toxicity (metabolic
may cause side effects (called acidosis).
“metabolic acidosis”).
Benzyl alcohol 09/10/2017 Topical Zero Benzyl alcohol may cause mild
local irritation.
Bergamot oil Topical Zero May increase sensitivity to UV Does not apply when bergapten is
(containing light (natural and artificial shown to be absent from the oil.
bergapten) sunlight).

EMA/655784/2022 Page 6/29


Boric acid (and 29/03/2022 All 1 mg This medicine should not be given * 1 mg B (Boron) = 5.7 mg boric acid.
borates) B/day* to a child younger than 2 years
without medical advice, as it See Q&A document
contains boron and may impair (EMA/CHMP/619104/2013 Rev.2) for
fertility in the future. further calculations.

Amount of boron per age group which


may impair fertility if exceeded:

Age Safety limit


< 2 years 1 mg B/day
< 12 years 3 mg B/day
< 18 years** 7 mg B/day
≥ 18 years** 10 mg B/day

** This amount may also cause harm


to the unborn child.

Based on the information included in


the table above, warnings in the
sections 4.4 and 4.6 (if relevant) of the
SmPC should be given accordingly.
Boric acid (and 29/03/2022 All 3 mg This medicine should not be given See comments above.
borates) B/day* to a child younger than 12 years
without medical advice, as it
contains boron and may impair
fertility in the future.
Boric acid (and 29/03/2022 All 7 mg This medicine should not be given See comments above.
borates) B/day* to a child younger than 18 years
without medical advice, as it
contains boron and may impair
fertility in the future.

If you are pregnant, talk to your


doctor before taking this medicine
as it contains boron which may be
harmful to your baby.
Bronopol Topical Zero May cause local skin reactions
(e.g. contact dermatitis).

EMA/655784/2022 Page 7/29


Butylated Topical Zero May cause local skin reactions
hydroxyanisole (E 320) (e.g. contact dermatitis), or
irritation to the eyes and mucous
membranes.
Butylated Topical Zero May cause local skin reactions
hydroxytoluene (E (e.g. contact dermatitis), or
321) irritation to the eyes and mucous
membranes.
Cetostearyl alcohol Topical Zero May cause local skin reactions
including Cetyl alcohol (e.g. contact dermatitis).

Chlorocresol Topical, Zero May cause allergic reactions.


parenteral
Cyclodextrins 09/10/2017 All 20 This medicine contains x mg Cyclodextrins (CDs) are excipients
mg/kg/day cyclodextrin(s) in each <dosage which can influence the properties
e.g.: unit><unit volume> <which is (such as toxicity or skin penetration) of
Alfadex equivalent to the active substance and other
Betadex (E 459) x mg/<weight><volume>>. medicines. Safety aspects of CDs have
γ-cyclodextrin been considered during the
Sulfobutyl-ether-β- Do not use in children less than 2 development and safety assessment of
cyclodextrin (SBE-β-CD) years old unless recommended by the drug product, and are clearly
Hydroxypropyl betadex your doctor. stated in the SmPC.
Randomly methylated β-
cyclodextrin (RM-β-CD) There is insufficient information on the
effects of CDs in children < 2 years
old. Therefore, a case by case
judgement should be made regarding
the risk/benefit for the patient.

Based on animal studies and human


experience, harmful effects of CDs are
not to be expected at doses below 20
mg/kg/day.

EMA/655784/2022 Page 8/29


Cyclodextrins 09/10/2017 Oral 200 Cyclodextrins may cause digestive At high doses cyclodextrins can cause
mg/kg/day problems such as diarrhoea. reversible diarrhoea and cecal
e.g.: enlargement in animals.
Alfadex
Betadex (E 459)
γ-cyclodextrin
Sulfobutyl-ether-β-
cyclodextrin (SBE-β-CD)
Hydroxypropyl betadex
Randomly methylated β-
cyclodextrin (RM-β-CD)

Cyclodextrins 09/10/2017 Parenteral 200 If you have a kidney disease, talk In children less than 2 years, the lower
mg/kg/day to your doctor before you receive glomerular function may protect
e.g.: and use for this medicine. against renal toxicity, but can lead to
Alfadex > 2 weeks higher blood levels of cyclodextrins.
Betadex (E 459)
γ-cyclodextrin In patients with moderate to severe
Sulfobutyl-ether-β- renal dysfunction accumulation of
cyclodextrin (SBE-β-CD) cyclodextrins may occur.
Hydroxypropyl betadex
Randomly methylated β-
cyclodextrin (RM-β-CD)

Dimethyl sulphoxide Topical Zero May be irritant to the skin.

EMA/655784/2022 Page 9/29


Ethanol 22/11/2019 Oral Zero This medicine contains x mg of Where ethanol is present as a
Parenteral alcohol (ethanol) in each <dosage processing agent (for example in tablet
Inhalation unit><unit volume> <which is coating) or extraction solvent and is
equivalent to x evaporated off (under the level of ICH
mg/<weight><volume>><(y% Q3C) there is no need to mention
w/<w><v>)>. The amount in ethanol in patient information.
<dose><volume> of this
medicine is equivalent to less than To calculate the equivalent volume of
A ml beer or B ml wine. beer and wine, assume the ethanol
content of beer to be 5% v/v (alcohol
The small amount of alcohol in by volume, ABV), which is equivalent
this medicine will not have any to 4% w/v, and of wine to be 12.5%
noticeable effects. v/v or 10% w/v (the specific gravity of
ethanol has been approximated as
0.8).

Volumes of beer and wine (A and B)


should be rounded up to the next
whole number.

EMA/655784/2022 Page 10/29


Ethanol 22/11/2019 Oral 15 mg/kg This medicine contains x mg of To calculate the equivalent volume of
Parenteral per dose alcohol (ethanol) in each <dosage beer and wine, assume the ethanol
Inhalation unit><unit volume> <which is content of beer to be 5% v/v (alcohol
equivalent to x by volume, ABV), which is equivalent
mg/<weight><volume>><(y% to 4% w/v, and of wine to be 12.5%
w/<w><v>)>. The amount in v/v or 10% w/v (the specific gravity of
<dose><volume> of this ethanol has been approximated as
medicine is equivalent to A ml 0.8).
beer or B ml wine.
Where relevant, the interactions of
The amount of alcohol in this ethanol should be stated in the SmPC
medicine is not likely to have an (section 4.5).
effect in adults and adolescents,
and its effects in children are not Suggestion for information in the
likely to be noticeable. It may SmPC:
have some effects in younger A dose of (select maximum dose) of
children, for example feeling this medicine administered to (a child
sleepy. A years of age and weighing B kg or an
adult weighing 70 kg) would result in
The alcohol in this medicine may exposure to C mg/kg of ethanol which
alter the effects of other may cause a rise in blood alcohol
medicines. Talk to your doctor or concentration (BAC) of about D
pharmacist if you are taking other mg/100 ml (see Appendix 1 of report
medicines. EMA/CHMP/43486/2018).

If you are pregnant or breast- For comparison, for an adult drinking a


feeding, talk to your doctor or glass of wine or 500 ml of beer, the
pharmacist before taking this BAC is likely to be about 50 mg/100
medicine. ml.

If you are addicted to alcohol, talk Co-administration with medicines


to your doctor or pharmacist containing e.g. propylene glycol or
before taking this medicine. ethanol may lead to accumulation of
ethanol and induce adverse effects, in
particular in young children with low or
immature metabolic capacity.

When a dose is given over prolonged


period (e.g. by slow infusion over
several hours), the rise in BAC will be
less and the effects of ethanol may be

EMA/655784/2022 Page 11/29


reduced. In such cases the package
leaflet and SmPC should include a
statement such as: Because this
medicine is usually given slowly over
XX hours, the effects of alcohol may be
reduced.

Ethanol 22/11/2019 Oral 75 mg/kg This medicine contains x mg of See comments above.
Parenteral per dose alcohol (ethanol) in each <dosage
Inhalation unit><unit volume> <which is
equivalent to x
mg/<weight><volume>> (y%
w/<w><v>). The amount in
<dose><volume> of this
medicine is equivalent to A ml
beer or B ml wine.

The alcohol in this preparation is


likely to affect children. These
effects may include feeling sleepy
and changes in behaviour. It may
also affect their ability to
concentrate and take part in
physical activities.

The amount of alcohol in this


medicine can affect your ability to
drive or use machines. This is

EMA/655784/2022 Page 12/29


because it may affect your
judgement and how fast you
react.

If you have epilepsy or liver


problems, talk to your doctor or
pharmacist before taking this
medicine.

The amount of alcohol in this


medicine may alter the effects of
other medicines. Talk to your
doctor or pharmacist if you are
taking other medicines.

If you are pregnant or breast-


feeding, talk to your doctor or
pharmacist before taking this
medicine.

If you are addicted to alcohol, talk


to your doctor or pharmacist
before taking this medicine.
Ethanol 22/11/2019 Cutaneous Zero This medicine contains x mg In neonates (pre-term and term
alcohol (ethanol) in each <dosage newborn infants), high concentrations
unit><unit volume> <which is of ethanol may cause severe local
equivalent to x reactions and systemic toxicity due to
mg/<weight><volume>> (y% significant absorption through
w/<w><v>). immature skin (especially under
occlusion). The corresponding warning
It may cause burning sensation in the SmPC/PL should be added if
on damaged skin. appropriate.

Depending on the product and


concentration of ethanol, the warning
“flammable” may be necessary.
Inclusion of warnings on use near an
open flame, lit cigarette or some
devices (e.g. hairdryers) should be
considered.

EMA/655784/2022 Page 13/29


Formaldehyde Topical Zero May cause local skin reactions
(e.g. contact dermatitis).

Formaldehyde Oral Zero May cause stomach upset and


diarrhea.
Fragrances containing 09/10/2017 Topical Zero This medicine contains fragrance *< >: fragrance allergens listed in
allergens* with <allergen(s)>*. appendix.

(See appendix) <Allergen(s)>* may cause In addition to allergic reactions in


allergic reactions. sensitised patients, non-sensitised
patients may become sensitised.

Benzyl alcohol is listed as one of the


26 fragrance allergens but can also be
used as an excipient. When benzyl
alcohol is used as an excipient (in
addition to a fragrance or not), the
label of this excipient applies.
Fructose 09/10/2017 Oral, parenteral Zero This medicine contains x mg The additive effect of concomitantly
fructose in each <dosage administered products containing
unit><unit volume> <which is fructose (or sorbitol) and dietary
equivalent to intake of fructose (or sorbitol) should
x mg/<weight><volume>>. be taken into account.

Fructose 09/10/2017 Oral Zero [If the medicine is in contact with Oral products used frequently or over a
teeth (e.g. oral liquids, lozenges long period of time, e.g. for two weeks
or chewable tablets) and is or longer.
intended for long term use:]
Fructose may damage teeth.

EMA/655784/2022 Page 14/29


Fructose 09/10/2017 Intravenous (IV) Zero If you (or your child) have Patients with hereditary fructose
hereditary fructose intolerance intolerance (HFI) must not be given
(HFI), a rare genetic disorder, you this medicine unless strictly necessary.
(or your child) must not receive
this medicine. Patients with HFI Babies and young children (below 2
cannot break down fructose in this years of age) may not yet be
medicine, which may cause diagnosed with hereditary fructose
serious side effects. intolerance (HFI). Medicines
(containing fructose) given
You must tell your doctor before intravenously may be life-threatening
receiving this medicine if you (or and must be contraindicated in this
your child) have HFI or if your population unless there is an
child can no longer take sweet overwhelming clinical need and no
foods or drinks because they feel alternatives are available.
sick, vomit or get unpleasant
effects such as bloating, stomach A detailed history with regard to HFI
cramps or diarrhoea. symptoms has to be taken of each
patient prior to being given this
medicinal product.
Fructose 09/10/2017 Oral, parenteral 5 If your doctor has told you that Patients with hereditary fructose
(other than IV) mg/kg/day you (or your child) have an intolerance (HFI) should not take/be
intolerance to some sugars or if given this medicinal product.
you have been diagnosed with
hereditary fructose intolerance
(HFI), a rare genetic disorder in
which a person cannot break
down fructose, talk to your doctor
before you (or your child) take or
receive this medicine.
Galactose Oral, parenteral Zero If you have been told by your SmPC proposal: Patients with rare
doctor that you have an hereditary problems of galactose
intolerance to some sugars, intolerance e.g. galactosaemia<, or
contact your doctor before taking glucose-galactose malabsorption>
this medicinal product. should not take this medicine.
Galactose Oral, parenteral 5g Contains x g galactose per dose.
This should be taken into account
in patients with diabetes mellitus.

EMA/655784/2022 Page 15/29


Glucose Oral Zero If you have been told by your SmPC proposal: Patients with rare
doctor that you have an glucose-galactose malabsorption
intolerance to some sugars, should not take this medicine.
contact your doctor before taking
this medicinal product.
Glucose Oral, parenteral 5g Contains x g glucose per dose.
This should be taken into account
in patients with diabetes mellitus.

Glucose Oral liquids, Zero May be harmful to the teeth. Information to be included only when
lozenges and the medicinal product may be intended
chewable tablets for chronic use, e.g. for two weeks or
more.
Glycerol (E 422) Oral 10 g per May cause headache, stomach
dose upset and diarrhea.
Glycerol (E 422) Rectal 1g May have a mild laxative effect.

Heparin (as an Parenteral Zero May cause allergic reactions and


excipient) 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.
Invert sugar Oral Zero If you have been told by your SmPC proposal: Patients with rare
doctor that you have an hereditary problems of fructose
intolerance to some sugars, intolerance or glucose-galactose
contact your doctor before taking malabsorption should not take this
this medicinal product. medicine.
Invert sugar Oral 5g Contains x g of a mixture of
fructose and glucose per dose.
This should be taken into account
in patients with diabetes mellitus.
Invert sugar Oral liquids, Zero May be harmful to the teeth. Information to be included only when
lozenges and the medicinal product may be intended
chewable tablets for chronic use, e.g. for two weeks or
more.

EMA/655784/2022 Page 16/29


Lactitol (E 966) Oral Zero If you have been told by your SmPC proposal: Patients with rare
doctor that you have an hereditary problems of fructose
intolerance to some sugars intolerance, galactose intolerance,
contact your doctor before taking galactosaemia or glucose-galactose
this medicinal product. malabsorption should not take this
medicine.
Lactitol (E 966) Oral 10 g May have a mild laxative effect.

Calorific value 2.1 kcal/g lactitol.

Lactose Oral Zero If you have been told by your SmPC proposal: Patients with rare
doctor that you have an hereditary problems of galactose
intolerance to some sugars, intolerance, total lactase deficiency or
contact your doctor before taking glucose-galactose malabsorption
this medicinal product. should not take this medicine.
Lactose Oral 5g 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.
Latex All Zero The container of this medicinal Not a typical excipient, but a warning
Natural Rubber (latex) product contains latex rubber. is considered necessary.
May cause severe allergic
reactions.
Macrogolglycerol Parenteral Zero May cause severe allergic
ricinoleate (castor oil reactions.
polyoxyl)
Macrogolglycerol
hydroxystearate (castor
oil polyoxyl
hydrogenated)

Macrogolglycerol Oral Zero May cause stomach upset and


ricinoleate (castor oil diarrhea.
polyoxyl)
Macrogolglycerol
hydroxystearate (castor
oil polyoxyl
hydrogenated)

EMA/655784/2022 Page 17/29


Macrogolglycerol Topical Zero May cause skin reactions.
ricinoleate (castor oil
polyoxyl)
Macrogolglycerol
hydroxystearate (castor
oil polyoxyl
hydrogenated)

Maltitol (E 965) Oral Zero If you have been told by your SmPC proposal: Patients with rare
Isomalt (E 953) doctor that you have an hereditary problems of fructose
(isomaltitol) intolerance to some sugars, intolerance should not take this
Maltitol liquid contact your doctor before taking medicine.
(hydrogenated glucose this medicinal product.
syrup)

Maltitol (E 965) Oral 10 g May have a mild laxative effect.


Isomalt (E 953)
(isomaltitol) Calorific value 2.3 kcal/g
Maltitol liquid <maltitol><isomalt>.
(hydrogenated glucose
syrup)

Mannitol (E 421) Oral 10 g May have a mild laxative effect.

Organic mercury Ocular Zero May cause allergic reactions. See EMEA Public Statement, 8 July
compounds 1999, Ref. EMEA/20962/99

e.g.:
Thiomersal
Phenylmercuric
nitrate/acetate/borate

EMA/655784/2022 Page 18/29


Organic mercury Topical Zero May cause local skin reactions
compounds (e.g. contact dermatitis) and
discolouration.
e.g.:
Thiomersal
Phenylmercuric
nitrate/acetate/borate

Organic mercury Parenteral Zero This medicinal product contains See EMEA Public Statement, 8 July
compounds (thiomersal) as a preservative and 1999, Ref. EMEA/20962/99
it is possible that <you/your
e.g.: child> may experience an allergic
Thiomersal reaction. Tell your doctor if
Phenylmercuric <you/your child> have/has any
nitrate/acetate/borate known allergies.

Organic mercury Parenteral Zero Tell your doctor if you/your child Additional statement to be mentioned
compounds have/has experienced any health for vaccines.
problems after previous
e.g.: administration of a vaccine.
Thiomersal
Phenylmercuric
nitrate/acetate/borate

EMA/655784/2022 Page 19/29


Parahydroxybenzoates Oral Zero May cause allergic reactions
and their esters Ocular (possibly delayed).
Topical
e.g.:
Ethyl p-hydroxybenzoate
(E 214)
Sodium ethyl p-
hydroxybenzoate (E 215)
Propyl p-hydroxybenzoate E 216
Sodium propyl p-
hydroxybenzoate
E 217
Methyl p-
hydroxybenzoate (E 218)
Sodium methyl p-
hydroxybenzoate (E 219)

Parahydroxybenzoates Parenteral Zero May cause allergic reactions


and their esters Inhalation (possibly delayed), and
exceptionally, bronchospasm.
e.g.:
Ethyl p-hydroxybenzoate
(E 214)
Sodium ethyl p-
hydroxybenzoate (E 215)
Propyl p-hydroxybenzoate E 216
Sodium propyl p- E 217
hydroxybenzoate
Methyl p-
hydroxybenzoate (E 218)
Sodium methyl p-
hydroxybenzoate (E 219)

EMA/655784/2022 Page 20/29


Phenylalanine 09/10/2017 All Zero This medicine contains x mg
phenylalanine in each <dosage
Corrigendum unit><unit volume> <which is
19/11/2018 equivalent to
x mg/<weight><volume>>.

Phenylalanine may be harmful if


you have phenylketonuria (PKU),
a rare genetic disorder in which
phenylalanine builds up because
the body cannot remove it
properly.
Phosphate buffers 09/10/2017 Ocular Zero This medicine contains x mg Corresponding SmPC statement in
phosphates in each <dosage Section 4.8 (Undesirable effects):
unit><unit volume> <which is “Cases of corneal calcification have
equivalent to been reported very rarely in
x mg/<weight><volume>>. association with the use of phosphate
containing eye drops in some patients
If you suffer from severe damage with significantly damaged corneas.”
to the clear layer at the front of
the eye (the cornea), phosphates
may cause in very rare cases
cloudy patches on the cornea due
to calcium build-up during
treatment.
Potassium Parenteral Less than 1 This medicine contains potassium, Information relates to a threshold
mmol per less than 1 mmol (39 mg) per based on the total amount of K+ in the
dose <dose>, i.e. essentially medicinal product.
‘potassium-free’.
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.
Potassium Oral, parenteral 1 mmol per This medicine contains x mmol (or
dose y mg) potassium per <dose>. To
be taken into consideration by
patients with reduced kidney
function or patients on a
controlled potassium diet.

EMA/655784/2022 Page 21/29


Potassium Intravenous (IV) 30 mmol/l May cause pain at the site of
injection.
Propylene glycol (E 09/10/2017 All 1 This medicine contains x mg
1520) and esters of mg/kg/day propylene glycol in each <dosage
propylene glycol unit><unit volume> <which is
equivalent to
x mg/<weight><volume>>.
Propylene glycol (E 09/10/2017 Oral, parenteral 1 If your baby is less than 4 weeks Co-administration with any substrate
1520) and esters of mg/kg/day old, talk to your doctor or for alcohol dehydrogenase such as
propylene glycol pharmacist before giving them ethanol may induce serious adverse
this medicine, in particular if the effects in neonates.
baby is given other medicines that
contain propylene glycol or
alcohol.
Propylene glycol (E 09/10/2017 Oral, parenteral 50 If your child is less than 5 years Co-administration with any substrate
1520) and esters of mg/kg/day old, talk to your doctor or for alcohol dehydrogenase such as
propylene glycol pharmacist before giving them ethanol may induce adverse effects in
this medicine, in particular if they children less than 5 years old.
use other medicines that contain
propylene glycol or alcohol.
Propylene glycol (E 09/10/2017 Oral, parenteral 50 If you are pregnant or While propylene glycol has not been
1520) and esters of mg/kg/day breast-feeding, do not take this shown to cause reproductive or
propylene glycol medicine unless recommended by developmental toxicity in animals or
your doctor. Your doctor may humans, it may reach the foetus and
carry out extra checks while you was found in milk. As a consequence,
are taking this medicine. administration of propylene glycol to
pregnant or lactating patients should
be considered on a case by case basis.
Propylene glycol (E 09/10/2017 Oral, parenteral 50 If you suffer from a liver or kidney Medical monitoring is required in
1520) and esters of mg/kg/day disease, do not take this medicine patients with impaired renal or hepatic
propylene glycol unless recommended by your functions because various adverse
doctor. Your doctor may carry out events attributed to propylene glycol
extra checks while you are taking have been reported such as renal
this medicine. dysfunction (acute tubular necrosis),
acute renal failure and liver
dysfunction.

EMA/655784/2022 Page 22/29


Propylene glycol (E 09/10/2017 Oral, parenteral 500 Propylene glycol in this medicine Various adverse events, such as
1520) and esters of mg/kg/day can have the same effects as hyperosmolality, lactic acidosis; renal
propylene glycol drinking alcohol and increase the dysfunction (acute tubular necrosis),
likelihood of side effects. acute renal failure; cardiotoxicity
(arrhythmia, hypotension); central
Do not use this medicine in nervous system disorders (depression,
children less than 5 years old. coma, seizures); respiratory
depression, dyspnoea; liver
Use this medicine only if dysfunction; haemolytic reaction
recommended by a doctor. Your (intravascular haemolysis) and
doctor may carry out extra checks haemoglobinuria; or multisystem
while you are taking this organ dysfunction, have been reported
medicine. with high doses or prolonged use of
propylene glycol.

Therefore doses higher than 500


mg/kg/day may be administered in
children > 5 years old but will have to
be considered case by case.

Adverse events usually reverse


following weaning off of propylene
glycol, and in more severe cases
following hemodialysis.

Medical monitoring is required.


Propylene glycol (E 09/10/2017 Cutaneous 50 Propylene glycol may cause skin
1520) and esters of mg/kg/day irritation.
propylene glycol
Do not use this medicine in babies
less than 4 weeks old with open
wounds or large areas of broken
or damaged skin (such as burns)
without talking to your doctor or
pharmacist.

EMA/655784/2022 Page 23/29


Propylene glycol (E 09/10/2017 Cutaneous 500 Propylene glycol may cause skin
1520) and esters of mg/kg/day irritation.
propylene glycol
Because this medicine contains
propylene glycol, do not use it on
open wounds or large areas of
broken or damaged skin (such as
burns) without checking with your
doctor or pharmacist.
Sesame oil All Zero May rarely cause severe allergic
reactions.
Sodium 09/10/2017 Oral, parenteral Less than This medicine contains less than 1 1 mmol of sodium (Na) = 23 mg Na =
1 mmol mmol sodium (23 mg) per 58.4 mg salt (NaCl).
(23 mg) <dosage unit><unit volume>,
per dose that is to say essentially ‘sodium- Information relates to a threshold
free’. based on the total amount of sodium in
the medicinal product.

It is especially relevant to products


used in children or in patients on a low
sodium diet, to provide information to
prescribers and reassurance to parents
or patients concerning the low level of
sodium in the product.
Sodium 09/10/2017 Oral, parenteral 1 mmol This medicine contains x mg For parenterals with variable (e.g.
(23 mg) sodium (main component of weight-based) dosing sodium content
per dose cooking/table salt) in each may be expressed in mg per vial.
<dosage unit><unit volume>.
This is equivalent to y% of the Proposed wording for SmPC:
recommended maximum daily “This medicinal product contains x mg
dietary intake of sodium for an sodium per <dosage unit>, equivalent
adult. to y% of the WHO recommended
maximum daily intake of 2 g sodium
for an adult.”

EMA/655784/2022 Page 24/29


Sodium 09/10/2017 Oral, parenteral 17 mmol Talk to your doctor or pharmacist This applies only to products for which
(391 mg) in if you need <Z> or more <dosage the labelled posology allows the
the units> daily for a prolonged product to be taken on a daily basis for
maximum period, especially if you have > 1 month or repeated use for more
daily dose been advised to follow a low salt than 2 days every week.
(sodium) diet.
17 mmol (391 mg) is approximately
20% of the WHO adult recommended
maximum daily dietary intake of 2 g
sodium and is considered to represent
‘high’ sodium.

This is also relevant for children, where


the maximum daily intake is
considered to be proportional to adults
and based on energy requirements.

<Z doses> reflects the lowest number


of dosage units for which the threshold
of 17 mmol (391 mg) of sodium is
reached/ exceeded. Round down to the
nearest whole number.

For SmPC wording please refer to


PRAC recommendation: “1.3. Sodium-
containing effervescent, dispersible
and soluble medicines – Cardiovascular
events” (EMA/PRAC/234960/2015).

EMA/655784/2022 Page 25/29


Sodium laurilsulfate 09/10/2017 Cutaneous Zero This medicine contains x mg The thickness of the skin varies
sodium laurilsulfate in each considerably according to the body site
Corrigendum <dosage unit><unit volume> and with age and can be an important
19/11/2018 <which is equivalent to x factor in the sensitivity to sodium
mg/<weight><volume>>. laurilsulfate (SLS).

Sodium laurilsulfate may cause Sensitivity to SLS will also vary


local skin reactions (such as according the type of formulation (and
stinging or burning sensation) or effects of other excipients), the
increase skin reactions caused by concentration of SLS, contact time and
other products when applied on patient population (children, hydration
the same area. level, skin color and disease).

Patient populations with decreased


skin barrier functions such as in atopic
dermatitis are more sensitive to the
irritant properties of SLS.

Sorbic acid (E 200) and Topical Zero May cause local skin reactions,
salts (e.g. contact dermatitis).

Sorbitol (E 420) 09/10/2017 Oral, parenteral Zero This medicine contains x mg The additive effect of concomitantly
sorbitol in each <dosage administered products containing
unit><unit volume> <which is sorbitol (or fructose) and dietary
equivalent to intake of sorbitol (or fructose) should
x mg/<weight><volume>>. be taken into account.

The content of sorbitol in medicinal


products for oral use may affect the
bioavailability of other medicinal
products for oral use administered
concomitantly.

EMA/655784/2022 Page 26/29


Sorbitol (E 420) 09/10/2017 Intravenous (IV) Zero Sorbitol is a source of fructose. If Patients with hereditary fructose
you (or your child) have intolerance (HFI) must not be given
hereditary fructose intolerance this medicine unless strictly necessary.
(HFI), a rare genetic disorder, you
(or your child) must not receive Babies and young children (below 2
this medicine. Patients with HFI years of age) may not yet be
cannot break down fructose, diagnosed with hereditary fructose
which may cause serious side intolerance (HFI). Medicines
effects. (containing sorbitol/fructose) given
intravenously may be life-threatening
You must tell your doctor before and should be contraindicated in this
receiving this medicine if you (or population unless there is an
your child) have HFI or if your overwhelming clinical need and no
child can no longer take sweet alternatives are available.
foods or drinks because they feel
sick, vomit or get unpleasant A detailed history with regard to HFI
effects such as bloating, stomach symptoms has to be taken of each
cramps or diarrhoea. patient prior to being given this
medicinal product.
Sorbitol (E 420) 09/10/2017 Oral, parenteral 5 Sorbitol is a source of fructose. If Patients with hereditary fructose
(other than IV) mg/kg/day your doctor has told you that you intolerance (HFI) should not take/be
(or your child) have an given this medicinal product.
intolerance to some sugars or if
you have been diagnosed with
hereditary fructose intolerance
(HFI), a rare genetic disorder in
which a person cannot break
down fructose, talk to your doctor
before you (or your child) take or
receive this medicine.
Sorbitol (E 420) 09/10/2017 Oral 140 Sorbitol may cause
mg/kg/day gastrointestinal discomfort and
mild laxative effect.
Soya oil All Zero <Medicinal product> contains In line with Arachis oil.
Hydrogenated soya oil soya oil. If you are allergic to
peanut or soya, do not use this SmPC: contraindication.
medicinal product.
Stearyl alcohol Topical Zero May cause local skin reactions
(e.g. contact dermatitis).

EMA/655784/2022 Page 27/29


Sucrose Oral Zero If you have been told by your SmPC proposal: Patients with rare
doctor that you have an hereditary problems of fructose
intolerance to some sugars, intolerance, glucose-galactose
contact your doctor before taking malabsorption or sucrase-isomaltase
this medicinal product. insufficiency should not take this
medicine.
Sucrose Oral 5g Contains x g of sucrose per dose.
This should be taken into account
in patients with diabetes mellitus.

Sucrose Oral liquids, Zero May be harmful to the teeth. Information to be included only when
lozenges and the medicinal product may be intended
chewable tablets for chronic use, e.g. for two weeks or
more.
Sulphites including Oral Zero May rarely cause severe
metabisulphites Parenteral hypersensitivity reactions and
Inhalation bronchospasm.
e.g.:
Sulphur dioxide (E 220)
Sodium sulphite (E 221)
Sodium bisulphite (E 222)
Sodium metabisulphite (E
223)
Potassium metabisulphite
(E 224)
Potassium bisulphite (E
228)

EMA/655784/2022 Page 28/29


Wheat starch 09/10/2017 Oral Zero This medicine contains only very The name of the excipient on the
(containing gluten) low levels of gluten (from wheat packaging should be: ’Wheat starch’.
Corrigendum starch)<. It is regarded as
19/11/2018 ‘gluten-free’*> and is very
unlikely to cause problems if you
have coeliac disease.

One <dosage unit> contains no


more than x micrograms of
gluten.

If you have wheat allergy


(different from coeliac disease)
you should not take this medicine.

[* The statement ’gluten-free’


applies only if the gluten content
in the medicinal product is less
than 20 ppm.]
Wool fat (lanolin) Topical Zero May cause local skin reactions
(e.g. contact dermatitis).

Xylitol (E 967) Oral 10 g May have a laxative effect.

Calorific value 2.4 kcal/g xylitol.

EMA/655784/2022 Page 29/29

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