AstraZeneca UK Limited

Section 4.1

Text added:

-                      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.

Text removed

-           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.

Section 4.2

Table updated and new lines added relating to procedures on newly shaven areas, paediatric, adult genital organs and leg ulcers.

New footnotes added to table:

1)         After > 5 hours application time anaesthesia decreases.

2)         Application for >1 hour has not been documented.
3)         Until further clinical data are available, EMLA 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)         EMLA 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, EMLA alone applied for 60 or 90 min does not provide sufficient anaesthesia for thermocautery or diathermy of genital warts.

Paediatric population and methods of dose estimation updated

Table 2: Dose, application time and dose interval by age and weight removed. Data incorporated into new table

Section 4.3

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

Section 4.4

Text amended (12 months to 3 months)

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 EMLA.

Text added

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 EMLA for heel lancing in neonates.

EMLA 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 EMLA on the prepuce has been proven to be safe.

Text amended re atopic dermatitis.

Text amended re eye contact.

Text amended re middle ear.

Following text added

EMLA Cream contains polyoxyethylene hydrogenated castor oil which may cause skin reactions.

Section 4.5

Text amended re systemic toxicity

Section 4.6

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For EMLA Cream no adequate clinical data on exposed pregnancies are available. 

Text re Pregnancy updated and new text added.

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.

Text added and amended re lactation

Section 4.7

Text ameded to EMLA has no influence on driving ability and the ability to operate machines when used at the recommended doses.

Section 4.8

Text removed

EMLA has no influence on driving ability and the ability to operate machines when used at the recommended doses.

Table updated, text removed and new text added.

1) Intact skin

2) Genital Mucosa

3) Leg ulcer

Section 4.9

Text amended and following new text added

; 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.

Section10

Date of revision of the text amended to 14^th July 2011.

Section 4.5

Additional new text last paragraph.

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.

Section 10

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.

Local anaesthetic for topical use to produce surface anaesthesia of the skin.

For topical use on the genital mucosa to facilitate the removal of warts in adults.

Until further clinical data are available, 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 123 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.

Clinical studies have been unable to demonstrate the efficacy of EMLA during the heel lancing of neonates.

In term newborn infants, infants and children, EMLA should only be used on intact skin and should not be applied to genital mucosa.

EMLA Cream should not be applied to genital mucosa in children.

Until further clinical experience is available, EMLA Cream should not be applied to wounds or in areas of atopic dermatitis.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 monitorcheck oxygen saturation by co-oximetry.

Care must be taken to limit the dose and area of application and to prevent accidental ingestion.

Until further clinical experience is available, EMLA Cream should not be applied to wounds or in areas of atopic dermatitis.

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.

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.

Paediatric populationChildren

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 (25–30%) 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.

In the study using a dose of 1 g the average concentrations of methaemoglobin up to 18 hours after administration were 1.31% (range 0-3.1%) in the EMLA group and 1.34% (range 1.0%-1.9%) in the placebo group (not significantly different).

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-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, tThe use of EMLA prior to measles-mumps-rubella or intramuscular diptheria-pertussis-tetanus-inactivated poliovirus-Haemophilus influenzae b or Hepatitis B vaccines does 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.

Paediatric populationChildren

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.

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

Pack containing 10 x 5 g tubes of EMLA and 2 occlusive dressings.

1 x 30 g tube with enclosed spatula

Section 4.2 -  Addition and Removal of text from table

Current text

Adults (including elderly) and children > 1 year:

New Text

Section 4.4

Spelling error of the word congenital

Removal of the word muscous membrane form the 2^nd paragraph

current text:  ‘applied to wounds, mucous membranes or in areas of atopic dermatitis.’

New text:  ‘applied to wounds or in areas of atopic dermatitis’

Addition of the paragraph after the 7^th paragraph

Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive

Section 4.5

addition of paragraph after the 3^rd paragraph:

‘Specific interaction studies with lidocaine/prilocaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see also section 4.4).’

Section 4.6

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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.

Removal of the first sentence from 2^nd and 3^rd paragraph

‘Lidocaine and prilocaine cross the placental barrier’

‘However, both drugs have been in widespread clinical use for many years and a large number of women of childbearing age have been exposed to them. No specific effects on the reproductive process have been reported. However,’

Removal of the sentence from the 3^rd paragraph

‘Lidocaine and prilocaine are excreted in breast milk in small amounts’

addition of text to 4^th paragraph

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.

Section 4.8

Removal of text:

Transient paleness, redness and oedema have been reported.

Prilocaine has been known to cause methaemoglobinaemia in children when given parenterally.

In rare cases local anaesthetics have been associated with allergic reactions including anaphylactic shock.

Rare cases of discrete local lesions at the application site, described as purpuric or petechial, have been reported, especially after longer application times in children with atopic dermatitis or mollusca contagiosa.

Corneal irritation after accidental eye exposure.

Addition of text:

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.

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).

Section 4.9

Removal of text

Overdosage with EMLA is unlikely but signs of systemic toxicity will be similar in nature to those observed after administration of other local anaesthetics

Addition of text

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.

Section 5.2

Addition of text after the 2^nd paragraph

After the application of EMLA cream to intact male genital skin for 15 minutes (median 1 g), plasma concentrations of lidocaine and prilocaine (mean 6.6 nanogram/ml and 4.1 nanogram/ml) were reached after approximately 1.5 hours.

Section10  Date of Revision of text changed to 21/06/2007