Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anaesthetics, local; amides
ATC code: N01B B20
Mechanism of action
EMLA Cream provides dermal anaesthesia through the release of lidocaine and prilocaine from the cream into the epidermal and dermal layers of the skin and the vicinity of dermal pain receptors and nerve endings.
Lidocaine and prilocaine are amide-type local anaesthetics. They both stabilise neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of 

impulses, thereby producing local anaesthesia. The quality of anaesthesia depends upon the application time and the dose.

Skin
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 4.4).

Genital mucosa
Absorption from the genital mucosa is more rapid and onset time is shorter than after application to the skin.

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 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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
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

After the application of 10 g EMLA Cream for 10 minutes to vaginal mucosa, maximum plasma concentrations of lidocaine and prilocaine (mean 0.18 μg/ml and 0.15 μg/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.