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DENELA 5% CREAM

Active substance(s): LIDOCAINE / PRILOCAINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Denela 5% Cream

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Lidocaine 2.5% w/w (25 mg/g)
Prilocaine 2.5% w/w (25 mg/g)
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Cream
White soft cream.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Topical anaesthesia of the skin in connection with:
Intact skin prior to minor dermatological procedures (e.g. needle insertion and
surgical treatment of localised lesions) and prior to dermal procedures on
larger areas e.g. split skin grafting.
Dermal procedures on newly shaven skin of large body areas e.g. laser hair
removal
Topical anaesthesia of the genital mucosa, e.g. prior to superficial surgical
procedures or prior to infiltration anaesthesia of mucosa.
Topical anaesthesia of leg ulcers to facilitate mechanical
cleansing/debridement.
In term newborn infants and children under the age of 18 years, Denela is indicated
for local anaesthesia on intact skin prior to minor dermatological procedures. Studies
have failed to demonstrate efficacy of Denela for heel lancing in newborn infants.

4.2

Posology and method of administration
Surface/ Age

Procedure

Application

Skin

Apply a thick layer of cream on the
skin and cover it with occlusive
dressing.

Adults

Approx. 1.5 g/10 cm2
Minor procedures e.g.
needle insertion and
surgical treatment of
localised lesions.

2 g (approx. half a 5 g tube) for 1 to
5 hours1)

Dermal surgical
Approx. 1.5-2 g/10 cm2 for 2 to 5
procedures on larger
hours1)
areas in a hospital setting
e.g. split skin grafting.

Children

Dermal procedures on
newly shaven skin of
large body areas e.g.
laser hair removal (selfapplication by patient)

Maximum recommended dose: 60g.

Minor procedures, e.g.
needle insertion and
surgical treatment of
localised lesions

Approx. 1.0 g/10 cm2 for 1 hour
(see details below)

Maximum recommended treated
area: 600 cm2 for a minimum of 1
hour, maximum 5 hours.1)

Neonates 0-2
months3)

Up to 1.0 g and 10 cm2 2)

Infants 3-11
months3)

Up to 2.0 g and 20 cm2 4)

Children 1-5
years

Up to 10.0 g and 100 cm2 for 1-5
hours1)

Children 6-11
years

Up to 20.0 g and 200 cm2 for 1-5
hours1)

Children with
atopic dermatitis

Prior to removal of
mollusca.

Application time: 30 minutes

Genital mucosa

Surgical treatment of

Approx. 5-10 g Denela for 5-10

Adults

localised lesions, e.g.
removal of genital warts
(condylomata
accuminata) and prior to
injection of local
anaesthetics.

minutes1). No occlusive dressing is
required. Commence the procedure
immediately after removal of
cream.

Prior to cervical
curettage.
Administer 10 g of cream in lateral
vaginal fornices for 10 minutes.
Skin of male
genital organs
Adults
Skin of female
genital organs
Adults
Leg ulcer
Adults

Prior to injection of local Apply a thick layer of Denela cream
anaesthetics
(1 g/10cm2) with occlusive dressing
for 15 minutes
Prior to injection of local Apply a thick layer of Denela cream
anaesthetics7)
(1-2 g/10cm2) with occlusive
dressing for 60 minutes
Mechanical cleansing
/debridement of leg
ulcer(s).

Apply a thick layer of the cream,
approx. 1-2 g/10 cm2 up to a total of
10 g to the leg ulcer(s).5, 6) Cover
with an occlusive dressing.
Application time: 30 to 60 minutes.
Cleansing should start without
delay after removal of the cream.

1)

After > 5 hours application time anaesthesia decreases.

2)

Application for >1 hour has not been documented.

3)

Until further clinical data are available, Denela should not be used in infants up
to 12 months of age receiving treatment with methaemoglobin-inducing agents.

4)

No clinically significant increase in plasma methaemoglobin levels has been
observed after an application time of up to 4 hours on 16 cm2.

5)

Denela has been used for the treatment of leg ulcers up to 15 times over a period
of 1-2 months without loss of efficacy or increased number or severity of adverse
events.

6)

Plasma levels have not been determined in patients treated with doses of >10 g,
(See also Section 5.2).

7)

On female genital skin, Denela alone applied for 60 or 90 min does not provide
sufficient anaesthesia for thermocautery or diathermy of genital warts.

One gram of Denela cream pressed out of a tube of 30 g is approximately 3.5 cm.

Persons frequently applying or removing cream should ensure that contact is avoided
in order to prevent the development of hypersensitivity.

Paediatric population
Adolescents

12 years:

As for adults (approximately 2 g Denela applied under an occlusive dressing for a
minimum of 60 minutes, maximum 5 hours).
Term newborn infants, infants and children

11 years:

In term newborn infants and infants < 3 months, only one single dose should be
applied in any 24 hour period.
For children aged 3 months and above, a maximum of 2 doses, separated by at least
12 hours can be given within any 24 hour period. If, based on clinical need, a decision
is nevertheless taken to use two applications in children under the age of 3 months,
see sections 4.4 and 4.8.
The safety of Denela in pre-term newborn infants has not been established. Use of
Denela is not recommended in pre-term infants.
Use of Denela is not recommended in infants less than 3 months of age receiving
treatment with methaemoglobin-inducing drugs (see section 4.4).
For all age groups analgesic efficacy may decline if the skin application time is more
than 5 hours. Procedures on intact skin should begin soon after the occlusive dressing
is removed.
On the genital mucosa analgesic efficacy declines after 10-15 minutes and therefore
the procedure should be commenced immediately.

Methods of dose estimation
Denela is available in 5 g and 30 g tubes. To dispense 1 g of Denela from either tube
size, apply the cream to a circular area with a diameter of approx. 18 mm (a 1 pence
coin) and depth of approx. 4 to 5 mm.

If high levels of accuracy in dosing are required to prevent overdose (i.e. at doses
approaching the maximum in neonates or if two applications may be required in a 24
h period), a syringe can be used where 1 ml = 1 g.
A string of cream can be used to define the quantity of Denela administered from the
30 g tube where 1 g = 3.5 cm; however, a string of cream may not be appropriate for
all application needs, e.g. when administering a low dose to small surface areas.

4.3

Contraindications
Hypersensitivity to the amide-type local anaesthetics or to any other component of the
product.

4.4

Special warnings and precautions for use
Denela should not be used in the following cases:
(a)

in pre-term neonates i.e. gestational age less than 37 weeks.

(b)

in infants/neonates between 0 and 12 months of age receiving treatment with
methaemoglobin-inducing agents due to the possible additive effects.

In infants/neonates younger than 3 months a transient, clinically insignificant increase
in methaemoglobin level is commonly observed up to 12 hours after an application of
Denela.
Patients with defective glucose-6-phosphate dehydrogenase, hereditary or idiopathic
methaemoglobinaemia are more susceptible to drug induced signs of
methaemoglobinaemia.
In term newborn infants, infants and children, Denela should only be used on intact
skin and should not be applied to genital mucosa.
In term neonates and infants < 3 months, only one single dose should be applied in
any 24 hour period. If, based on clinical need, a decision is nevertheless taken to use
two applications in children under the age of 3 months, the child should be clinically
monitored for systemic adverse reactions (see sections 4.8 and 4.9).
Consideration should be given to the fact that pulse oximeter values may overestimate
the actual oxygen saturation in case of increased methaemoglobin fraction; therefore,
in cases of suspected methaemoglobinaemia, it may be more helpful to monitor
oxygen saturation by co-oximetry.

Care must be taken to limit the dose and area of application and to prevent accidental
ingestion.
Due to insufficient data on absorption of active substances, Denela should not be
applied to open wounds (excluding leg ulcers).
Due to the potentially enhanced absorption on newly shaven skin, it is important to
adhere to the recommended dosage, area and time of application (see Section 4.2).
Studies have been unable to demonstrate the efficacy of Denela for heel lancing in
neonates.
Denela should not be applied to the genital mucosa of children owing to insufficient
data on absorption of active substances. However, when used in neonates for
circumcision, a dose of 1.0 g Denela on the prepuce has been proven to be safe.
Care should be taken when applying Denela to patients with atopic dermatitis. A
shorter application time, 15-30 minutes, may be sufficient (see Section 5.1).
Application times of longer than 30 minutes in patients with atopic dermatitis may
result in an increased incidence of local vascular reactions, particularly application
site redness and in some cases petechiae and purpura (see Section 4.8 Undesirable
effects). Prior to removal of mollusca in children with atopic dermatitis, it is
recommended to apply cream for 30 minutes.
When applied in the vicinity of the eyes, Denela cream should be used with particular
care since it may cause eye irritation. Also the loss of protective reflexes may allow
corneal irritation and potential abrasion. If eye contact occurs, immediately rinse the
eye with water or sodium chloride solution and protect the eye until sensation returns.
Denela should not be applied to an impaired tympanic membrane. Tests on laboratory
animals have shown that Denela cream has an ototoxic effect when instilled into the
middle ear. Animals with an intact tympanic membrane, however, show no
abnormality when exposed to Denela cream in the external auditory canal.
Although the systemic availability of prilocaine by percutaneous absorption of Denela
is low, caution should be exercised in patients with anaemia, congenital or acquired
methaemoglobinaemia or patients on concomitant therapy known to produce such
conditions.
Patients treated with anti-arrhythmic drugs class III (eg, amiodarone) should be
carefully monitored and ECG monitoring considered as cardiac effects may be
additive.
Lidocaine and prilocaine have bacteriocidal and antiviral properties in concentrations
above 0.5 – 2%. For this reason, although one clinical study suggests that the

immunization response, as assessed by local wheal formation, is not affected when
Denela Cream is used prior to BCG vaccination, the results of intracutaneous
injections of live vaccines should be monitored.
Denela 5% Cream contains macrogolglycerol hydroxystearate (hydrogenated
polyoxyl castor oil) which may cause skin reactions.

4.5

Interaction with other medicinal products and other forms of interaction
Methaemoglobinaemia may be accentuated in patients already taking drugs known to
induce the condition, e.g. sulphonamides, acetanilid, aniline dyes, benzocaine,
chloroquine, dapsone, metoclopramide, naphthalene, nitrates and nitrites,
nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminosalicylic acid,
phenacetin, phenobarbital, phenytoin, primaquine, quinine.
With large doses of Denela, consideration should be given to the risk of additional
systemic toxicity in patients receiving other local anaesthetics or agents structurally
related to local anaesthetics, since the toxic effects are additive.
Specific interaction studies with lidocaine/prilocaine and anti-arrhythmic drugs class
III (eg, amiodarone) have not been performed, but caution is advised (see also Section
4.4).
Drugs that reduce the clearance of lidocaine (eg, cimetidine or betablockers) may
cause potentially toxic plasma concentrations when lidocaine is given in repeated
high doses over a long time period. Such interactions should therefore be of no
clinical importance following short-term treatment with lidocaine (eg, Denela cream)
at recommended doses.

4.6

Fertility, pregnancy and lactation
Animal studies do not indicate any direct or indirect harmful effects on pregnancy,
embryo-foetal development, parturition or postnatal development.
Pregnancy
Lidocaine and prilocaine cross the placental barrier and may be absorbed by the foetal
tissues. It is reasonable to assume that lidocaine and prilocaine have been used in a
large number of pregnant women and women of childbearing age. No specific
disturbances to the reproductive process have so far been reported, e.g. an increased
incidence of malformations or other directly or indirectly harmful effects on the
foetus. However caution should be exercised when used in pregnant women.

Lactation
Lidocaine and, in all probability, prilocaine are excreted in breast milk, but in such
small quantities that there is generally no risk of the child being affected at
therapeutic dose levels.

4.7

Effects on ability to drive and use machines
Denela has no influence on driving ability and the ability to operate machines when
used at the recommended doses.

4.8

Undesirable effects
Common

Skin

(>1/100)

Transient local reactions at the application
site such as paleness, erythema (redness) and
oedema. 1,2,3)
An initial and usually mild sensation of
burning, itching or warmth at the application
site2,3)

Uncommon

Skin

(1/1000 to 1/100)

An initial mild burning, itching sensation or
warmth at the application site1)
Local paresthesia at the application site, e.g.
tingling sensation2)
Skin irritation at the application site3)

Rare
(<1/1000)

General

Methaemoglobinaemia.1)
Rare cases of discrete local lesions at site of
administration such as purpuric or petechial,
especially at longer application time in
children with atopic dermatitis or mollusca
contagiosa1)
Corneal irritation after accidental eye
exposure1)
In rare cases, local anaesthetic preparations
have been associated with allergic reactions
(in the most severe cases anaphylactic
shock)1,2,3)

1) Intact skin
2) Genital Mucosa
3) Leg ulcer

Paediatric population
In clinical trials 298 neonates and infants aged up to 12 months were treated with
Emla Cream (Table 3). A large number of infants and children aged 1 year and older
have been treated with Emla in clinical trials and in clinical practice since 1984.
Table 3. Number of paediatric patients, up to 12 months old, included in clinical
studies with Emla, by age group
Group

Number of patients

Pre-term neonates

21

Age 0–1 months

148

Age 1–3 months

55

Age 3–12 months

74

Total number

298

Frequency, type and severity of adverse reactions are similar in the paediatric and
adult age groups, except for methaemoglobinaemia, which is more frequently
observed, often in connection with overdose, in neonates and infants aged 0 to 12
months.
Rare cases of clinically significant methaemoglobinaemia in children have been
reported in literature. Prilocaine, one of the components of Denela, may in high doses
cause an increase in the methaemoglobin level, particularly in susceptible individuals
(Section 4.4) and in conjunction with other methaemoglobin-inducing agents.
Clinically significant methaemoglobinaemia should be treated with a slow
intravenous injection of methylthioninium chloride (Section 4.9).

4.9

Overdose
Rare cases of clinically significant methaemoglobinaemia have been reported.
Prilocaine in high doses may cause an increase in the methaemoglobin plasma levels
particularly in conjunction with methaemoglobin-inducing agents (e.g.
sulphonamides).
Clinically significant methaemoglobinaemia should be treated with a slow
intravenous injection of methylene blue.
Should other symptoms of systemic toxicity occur, the signs are anticipated to be
similar in nature to those following the administration of local anaesthetics by other
routes of administration. Local anaesthetic toxicity is manifested by symptoms of

nervous system excitation and, in severe cases, central nervous and cardiovascular
depression.
Severe neurological symptoms (convulsions, CNS depression) must be treated
symptomatically by respiratory support and the administration of anticonvulsive
drugs; circulatory signs are treated in line with recommendations for resuscitation.
Since the rate of absorption from intact skin is slow, a patient showing signs of
toxicity should be kept under observation for several hours following emergency
treatment.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Local anaesthetics
ATC Code: N01B B20
Denela Cream provides dermal analgesia. The depth of analgesia depends upon the
application time and the dose. Denela causes transient local peripheral
vasoconstriction or vasodilation at the treated area.
In patients with atopic dermatitis, a similar but shorter vascular reaction is seen, with
erythema occurring after 30-60 minutes, indicating more rapid absorption through the
skin (see section 4.5 Special precautions and special warnings for use).

Paediatric population
Clinical safety studies
Methaemoglobin formation after the use of Emla in term infants was studied with the
aim to establish the safety of 1 g Emla 5% Cream. Forty-seven neonates and infants,
aged 0-3 months, with a post conceptual age of 37 weeks were included in a double
blind, randomized, placebo-controlled study. Methaemoglobin concentrations before
treatment with Emla and placebo were in the range 0.67-1.57% and 0.50-1.53%,
respectively. After treatment with 1 g Emla /placebo for 60-70 min methaemoglobin
concentrations were 0.50-2.53% for Emla and 0.50-1.53% for placebo. From 3.5 to
13 h after application the concentrations were significantly higher with Emla than
with placebo, but were clinically insignificant. One sample, in the Emla group
(2.53%), had a methaemoglobin concentration above the reference value of 2%.

Altogether, data from eleven clinical studies in neonates and infants showed that peak
methaemoglobin concentrations occur about 8 hours after epicutaneous Emla
administration, are clinically insignificant with recommended dosage, and return to
normal values after about 12-13 hours. Methaemoglobin formation is related to the
cumulative amount of prilocaine percutaneously absorbed, and may therefore increase
with prolonged application times of Denela.
Physiological methaemoglobin concentrations in both paediatric patients and adults
are normally maintained below 2%. A major increase in methaemoglobin (to a
concentration of 25-30%) will cause signs and symptoms of hypoxaemia. In neonates
elevated methaemoglobin levels up to 5–6% are not regarded as clinically significant.
Circumcision
In two randomized, double-blind, placebo-controlled studies in full-term neonates
aged 1 to 4 days Emla Cream (0.5 or 1 g) was applied on the prepuce for one hour
before circumcision, covered with an occlusive dressing. In the study using 0.5 g
Emla there were no significant differences with placebo in assessment of pain
performed by evaluating facial expressions or heart rate, respiratory rate, oxygen
saturation, or in general skin colour.
Emla Cream (1 g) significantly reduced the pain during parts of the circumcision
procedure, as demonstrated by less facial activity, reduction in duration of cry and
lower heart rates. No differences were found for oxygen saturation, respiratory rate
and Neonatal Infant Pain Scale (NIPS) – which includes facial expression, cry,
breathing pattern and state of arousal.
Vaccination
Two randomized double-blind, placebo-controlled studies in infants and neonates
looked at anaesthetic efficacy of Emla Cream in vaccinations and the effect on the
immunogenicity of live vaccines.
The first study used Emla Cream prior to subcutaneous measles-mumps-rubella
vaccine, in patients aged 12-15 months, where 1g of cream was applied for 60 180
minutes. Emla significantly reduced vaccination pain versus placebo, demonstrated
by difference between the pre- and post-vaccination total score on the Modified
Behavioural Pain Scale (MBPS - includes measurement of facial expression, cry and
body movement). No difference versus placebo was seen with the separate
assessment of proportion of patients that cry and duration of cry.
The second used Emla Cream prior to intramuscular diptheria-pertussis-tetanusinactivated poliovirus-Haemophilus influenzae b or Hepatitis B vaccines in patients
aged 0-6 months, where 1 or 2g of cream was applied to patients aged 0-4 and 6
months respectively, for 60-180 minutes. Emla significantly reduced vaccination pain
versus placebo, demonstrated as above, for the 6 month-old group, however in the 0-4
month old group there was high variation in treatment response. In the 2 and 4 month-

old groups, Emla gave reduced pain versus placebo, however statistical significance
was not shown (p=0.120 and 0.225 respectively).
Within both studies, the use of Emla did not affect mean antibody titres, rate of
seroconversion, or the proportion of patients achieving protective or positive antibody
titres post immunization, as compared to placebo treated patients.

5.2

Pharmacokinetic properties
Systemic absorption of lidocaine and prilocaine from Denela Cream is dependent
upon the dose, application time, and the thickness of the skin, which varies between
different areas of the body.
Intact skin: In order to provide reliable dermal analgesia, Denela Cream should be
applied under an occlusive dressing for at least 1 hour. The duration of analgesia after
an application time of 1-2 hours is at least 2 hours after removal of the dressing.
After the application of Denela Cream to intact male genital skin for 15 minutes
(median 1g), plasma concentrations of lidocaine and prilocaine (mean 6.6
nanogram/ml and 4.1 nanogram/ml) were reached after approximately 1.5 hours.
After application to the thigh in adults (60 g cream/400 cm2 for 3 hours) the extent of
absorption was approximately 5% of lidocaine and prilocaine. Maximum plasma
concentrations (mean 0.12 and 0.07 μg/ml) were reached approximately 2-6 hours
after the application.
The extent of systemic absorption was approximately 10% following application to
the face (10 g/100 cm2 for 2 hours). Maximum plasma levels (mean 0.16 and 0.06
μg/ml) were reached after approximately 1.5-3 hours.
Genital mucosa: Absorption from the genital mucosa is more rapid than after
application to the skin. After the application of 10 g Emla Cream for 10 minutes to
vaginal mucosa maximum plasma concentrations of lidocaine and prilocaine (mean
0.18 micrograms/ml and 0.15 micrograms/ml respectively) were reached after 20-45
minutes.

Paediatric population
Following the application of 1 g Emla Cream in infants/neonates below 3 months of
age, to approx 10 cm2 for one hour, the maximum plasma concentrations of lidocaine
and prilocaine were 0.135 micrograms/ml and 0.107 micrograms/ml respectively.
Following the application of 2 g Emla Cream in infants between 3 and 12 months of
age, to approx 16 cm2 for four hours, the maximum plasma concentrations of

lidocaine and prilocaine were 0.155 micrograms/ml and 0.131 micrograms/ml
respectively.
Following the application of 10 g of Emla Cream in children between 2 and 3 years of
age, to approx 100 cm2 for two hours, the maximum plasma concentrations of
lidocaine and prilocaine were 0.315 micrograms/ml and 0.215 micrograms/ml
respectively.
Following the application of 10-16 g Emla Cream in children between 6 and 8 years
of age, to approx 100-160 cm2 for two hours, the maximum plasma concentrations of
lidocaine and prilocaine were 0.299 micrograms/ml and 0.110 micrograms/ml
respectively.

5.3

Preclinical safety data
Lidocaine and prilocaine are well established active ingredients.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Macrogolglycerol hydroxystearate
Carbomer
Sodium hydroxide
Purified water

6.2

Incompatibilities
None known.

6.3

Shelf life
24 months
In-use shelf life: 3 months

6.4

Special precautions for storage
Store below 25°C, do not freeze.

6.5

Nature and contents of container
Collapsible white aluminum tubes internally coated with an epoxy resin-based
lacquer and closed with a white polypropylene cap.
There are four different pack types in total. The 5 g packs are supplied with or
without CE marked occlusive dressings for use with the cream. The 30 g packs are
supplied with a sterile CE marked wooden spatula, to facilitate the application and
spreading of the cream. The pack variants are listed below.
5 g Packs:





5 by 5 g tubes with 12 occlusive dressings – also referred to as a ‘premedication pack’
1 by 5 g tube with 2 occlusive dressings
1 b 5 g tube

30g Packs:



6.6

1 by 30 g tube with a sterile wooden spatula – also referred to as a
‘surgical pack’

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Auden Mckenzie (Pharma Division) Ltd
McKenzie House
Bury Street
Ruislip
Middlesex
HA4 7TL

UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 17507/0119

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30/04/2013

10

DATE OF REVISION OF THE TEXT
30/04/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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