EMLA^® Cream 5%

Lidocaine 2.5% w/w (25 mg/g)

Prilocaine 2.5% w/w (25 mg/g)

For excipients, see 6.1

White soft cream.

In adults, EMLA is indicated for local anaesthesia

- on 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.

- on genital mucosa prior to surgical treatment of localised lesions.

In adult men, EMLA is indicated for local anaesthesia on genital skin prior to injection of local anaesthetics.

In term newborn infants and children under the age of 18 years, EMLA is indicated for local anaesthesia on intact skin prior to minor dermatological procedures. Studies have failed to demonstrate efficacy of EMLA for heel lancing in newborn infants.

Paediatric population

Adolescents 12 years:

As for adults (approximately 2 g EMLA applied under an occlusive dressing for a minimum of 60 minutes, maximum 5 hours).

Term newborn infants, infants and children 11 years:

For dose, application area, application time and dose interval by age and weight see Table 2 below.

Table 2: Dose, application time and dose interval by age and weight

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 EMLA in pre-term newborn infants has not been established. Use of EMLA is not recommended in pre-term infants.

Use of EMLA is not recommended in infants less than 12 months of age receiving treatment with methaemoglobin-inducing drugs (see section 4.4).

Prior to curettage of mollusca in children with atopic dermatitis, an application time of 30 minutes is recommended.

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

EMLA is available in 5 g and 30 g tubes. To dispense 1 g of EMLA 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 EMLA 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.

Known hypersensitivity to anaesthetics of the amide type or to any other component of the product.

EMLA 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 12 months a transient, clinically insignificant increase in methaemoglobin level is commonly observed up to 12 hours after an application of EMLA.

Patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methaemoglobinaemia are more susceptible to drug induced methaemoglobinaemia.

In term newborn infants, infants and children, EMLA 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, EMLA should not be applied to open wounds.

Care should be taken when applying EMLA to patients with atopic dermatitis. A shorter application time, 15-30 minutes, may be sufficient (see section 5.1 Pharmacodynamic properties). Prior to curettage of mollusca in children with atopic dermatitis, an application time of 30 minutes is recommended.

Care should be taken not to allow EMLA to come in contact with the eyes as it may cause eye irritation. Also the loss of protective reflexes may allow corneal irritation and potential abrasion. If contact with the eye occurs, immediately rinse the eye with water or sodium chloride solution and protect it until sensation returns.

EMLA, like other local anaesthetics may be ototoxic and should not be instilled in the middle ear nor should it be used for procedures which might allow penetration into the middle ear.

Although the systemic availability of prilocaine by percutaneous absorption of EMLA 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 under close surveillance and ECG monitoring considered, since 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 is not affected when EMLA Cream is used prior to BCG vaccination, the results of intracutaneous injections of live vaccines should be monitored.

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.

The risk of additional systemic toxicity should be considered when large doses of EMLA are applied to patients already using other local anaesthetics or structurally related drugs e.g. class I anti-arrhythmics such as mexiletine.

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, EMLA cream) at recommended doses.

For EMLA Cream no adequate clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. In both animals and humans, lidocaine and prilocaine cross the placental barrier and may be absorbed by the foetal tissues. Caution should be exercised when used in pregnant women.

Lidocaine and 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.

None known.

Transient local reactions at the application site, most commonly erythema, paleness and/or oedema, may occur in>1% of patients treated with EMLA. Other types of reactions, such as allergic reactions or methaemoglobinaemia, occur in <0.1% of patients.

Paediatric population

In clinical trials 298 neonates and infants aged up to 12 months were treated with EMLA (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

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 EMLA, 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).

Rare cases of clinically significant methaemoglobinaemia have been reported in children. Prilocaine in high doses may cause an increase in the methaemoglobin level particularly in conjunction with methaemoglobin-inducing agents (e.g. sulphonamides). Clinically significant methaemoglobinaemia should be treated with a slow intravenous injection of methylthioninium chloride.

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. 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.

Pharmacotherapeutic group: Local anaesthetics

ATC Code: N01B B20

EMLA Cream provides dermal analgesia. The depth of analgesia depends upon the application time and the dose. EMLA 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 Cream 5%. 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 EMLA.

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 was no significant differences with placebo in assessment of pain performed by evaluating facial expressions or heart rate, respiratory rate, oxygen saturation, nor 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 60180 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-tetanus-inactivated 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.

Systemic absorption of lidocaine and prilocaine from EMLA 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, EMLA 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 EMLA 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.

Lidocaine and prilocaine are well established active ingredients.

Polyoxyethylene hydrogenated castor oil, Carbomer 974P, sodium hydroxide and water purified.

None known.

3 years.

Do not store above 30°C, do not freeze.

“Pre-medication pack” containing 5 x 5 g tubes EMLA and 12 occlusive dressings.

Pack containing 1 x 5 g tube of EMLA and 2 occlusive dressings.

1 x 30 g tube with enclosed spatula

1 x 5 g tube

Not applicable.

AstraZeneca UK Limited

600 Capability Green

Luton

LU1 3LU, UK

PL 17901/0120

First Authorisation: 16^th May 1996

Renewal of Authorisation: 5^th July 2002

28^th September 2009