EMLA

1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
5. PHARMACOLOGICAL PROPERTIES
6. PHARMACEUTICAL PARTICULARS

Please consult full local prescribing information before using EMLA cream or EMLA patch.


1. NAME OF THE MEDICINAL PRODUCT

EMLA® Cream

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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active constituents:
1 g of EMLA Cream contains lidocaine 25 mg, prilocaine 25 mg.

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3. PHARMACEUTICAL FORM

Cream
EMLA Cream is an oil-in-water emulsion system in which the oil phase consists of a eutectic mixture of the base forms of lidocaine and prilocaine in the ratio 1:1.

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4. CLINICAL PARTICULARS

Topical anaesthesia of:
the skin in connection with
- needle insertion, e.g. i.v. catheters or blood sampling
- superficial surgical procedures;

the genital mucosa, e.g. prior to superficial surgical procedures or infiltration anaesthesia;

leg ulcers to facilitate mechanical cleansing/debridement.

4.2 Posology and method of administration

1) After a longer application time the anaesthesia decreases.
2) A longer application time than 1 hour has not been documented.
3) Until further clinical data is available, EMLA should not be used in infants between 0-12 months of age receiving treatment with methaemoglobin-inducing agents.
4) No clinically significant increase in 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 with no loss of efficacy or increase in local reactions.
6) The application of a larger dose than 10 g has not been studied with regard to plasma levels (see 5.2 “Phamacokinetics”).
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.

1 g of EMLA cream administered from the 30 g aluminium tube corresponds to a length of extruded cream of approximately 3.5 cm (ref 97 ).

4.3 Contraindications

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

4.4 Special warnings and special precautions for use

Patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methaemoglobinaemia are more susceptible to drug-induced methaemoglobinaemia (refs 81, 91).
Due to insufficient data on absorption, EMLA should not be applied to open wounds other than leg ulcers.

Studies have been unable to demonstrate the efficacy of EMLA for heel lancing in neonates (refs 59-61).

Care should be taken when applying EMLA to patients with atopic dermatitis. A shorter application time, 15-30 minutes, may be sufficient (see 5.1 "Pharmacodynamic properties"). Prior to curettage of mollusca in children with atopic dermatitis, an application time of 30 minutes is recommended (refs 30,31,54).

EMLA should not be applied to the genital mucosa of children owing to insufficient data on absorption. However, when used in neonates for circumcision, a dose of 1.0 g EMLA on the prepuce has proven to be safe (ref 20).

Care should be taken not to allow EMLA to come in contact with the eyes as it may cause eye irritation (see section 5.3). Also the loss of protective reflexes may allow corneal irritation and potential abrasion. If eye contact occurs, immediately rinse the eye in water or sodium chloride solution and protect it until sensation returns. (ref 32, 90).

EMLA should not be applied to an impaired tympanic membrane. Tests on laboratory animals have shown that EMLA Cream has an ototoxic effect when instilled into the middle ear. Animals with an intact tympanic membrane, however, show no abnormality when exposed to EMLA Cream in the external auditory canal (refs 33-35).

In children/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 (ref 20).

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. (ref 95)

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 is used prior to BCG vaccination, the results of intracutaneous injections of live vaccines should be monitored (ref 36,78,79).

Until further clinical data are available, EMLA should not be used in the following cases:

(a) in infants between 0 and 12 months of age receiving treatment with methaemoglobin-inducing agents (refs 20,21,25).

(b) in preterm infants with a gestational age less than 37 weeks (ref 20).

4.5 Interaction with other medicinal products and other forms of interaction

Prilocaine in high doses may cause an increase in the methaemoglobin level particularly in conjunction with methaemoglobin-inducing agents (eg, sulphonamides) (ref 37).

With large doses of EMLA, 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). (ref 95)
 

4.6 Pregnancy and lactation

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

In both animal and humans, 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 potential. No specific disturbances to the reproductive process have so far been reported, eg, 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. (refs 38,39, 89).

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 (ref 40).
 
4.7 Effects on ability to drive and use machines

Not applicable at the recommended dosage.


4.8 Undesirable effects
FREQUENCY OF ADVERSE EVENTS

Intact skin                                                               refs 1,2,41,42)

Genital mucosa

Leg ulcer

 
4.9 Overdose

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 (eg, sulphonamides) (ref 37). 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. 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.

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5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Local anaesthetics of the amide-type, ATC code: N01B B20

EMLA Cream 5% provides dermal anaesthesia through the release of lidocaine and prilocaine from the cream into the epidermal and dermal layers of the skin and the accumulation of lidocaine and prilocaine in the vicinity of dermal pain receptors and nerve endings. Lidocaine and prilocaine are amide-type local anaesthetic agents. They both stabilize 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 (refs 9,10,13).

EMLA Cream is applied to intact skin under an occlusive dressing. The time needed to achieve reliable anaesthesia of intact skin is 1-2 hours, depending on the type of procedure (refs 15,16,19).

In clinical studies of EMLA on intact skin, no differences in safety or efficacy (including anaesthetic onset time) were observed between geriatric patients (aged 65-96 years) and younger patients (refs 82,83,94).

The duration of anaesthesia following the application of EMLA Cream for 1-2 hours is at least 2 hours after removal of the dressing (refs 15,19).

The depth of cutaneous anaesthesia increases with application time. In 90% of patients the anaesthesia is sufficient for the insertion of a biopsy punch (4 mm diameter) to a depth of 2 mm after 60 min and 3 mm after 120 min EMLA treatment (ref 65). EMLA is equally effective and has the same anaesthetic onset time across the range of light to dark pigmented skin (skin types I to VI) (ref 80).

The use of EMLA prior to measles-mumps-rubella or intramuscular diphtheria-pertussis-tetanus-inactivated poliovirus-Haemophilus influenzae b or Hepatitis B vaccines does 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 (refs 78,79,84,85,92).

Absorption from the genital mucosa is more rapid and onset time is shorter than after application to the skin (refs 22,23).

After a 5-10 min application of EMLA to female genital mucosa the average duration of effective analgesia to an argon laser stimulus which produced a sharp, pricking pain was 15-20 min (individual variations in the range 5-45 min) (ref 66).

Reliable anaesthesia for the cleansing of leg ulcers is achieved after an application time of 30 minutes in most patients (refs 6,7,8). An application time of 60 minutes may improve the anaesthesia further (ref 9). The cleansing procedure should start within 10 minutes of removal of the cream. Clinical data from a longer waiting period are not available. EMLA reduces the postoperative pain for up to 4 hours after debridement (refs 7,67). EMLA reduces the number of cleansing sessions required to achieve a clean ulcer compared to debridement with placebo cream (ref 8). No negative effects on ulcer healing or bacterial flora have been observed (refs 7,8,26).

EMLA produces a biphasic vascular response involving initial vasoconstriction followed by vasodilatation at the application site (see section 4.9 "Undesirable effects") (refs 15,19,42,46). Irrespective of the vascular response, EMLA facilitates the needle procedure compared to placebo cream (refs 68-75).

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 for use") (ref 30).

5.2 Pharmacokinetic properties

The systemic absorption of lidocaine and prilocaine from EMLA is dependent upon the dose, area of application and application time. Other factors are: following application to skin: thickness of the skin, which varies in different areas of the body, and other conditions of the skin; following application to leg ulcers: the characteristics of the leg ulcer. (refs 8,12,29,47 53)

Intact skin. Following application to the thigh in adults (60 g cream/400 cm2 for 3 hours), the extent of absorption was approx 5% of lidocaine and prilocaine. Maximum plasma concentrations (mean 0.12 and 0.07 µg/ml) were reached approx 2-6 hours after application. (ref 53)

The extent of systemic absorption was approx 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 approx 1.5-3 hours. (ref 48)

Plasma levels of lidocaine and prilocaine in both geriatric and non-geriatric patients following application of EMLA to intact skin are very low and well below potentially toxic levels (refs 86,94).

Children. Following the application of 1.0 g EMLA Cream in neonates below 3 months of age, to approx 10 cm2 for one hour, the maximum plasma concentrations of lidocaine and prilocaine were 0.135 µg/ml and 0.107 µg/ml respectively. Following the application of 2.0 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 µg/ml and 0.131 µg/ml respectively. Following the application of 10.0 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 µg/ml and 0.215 µg/ml respectively. Following the application of 10.0-16.0 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 µg/ml and 0.110 µg/ml respectively (ref 20).

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 (ref 51).

Leg ulcer. Following a single application of 5 to 10 g of EMLA Cream to leg ulcers with an area of up to 64 cm2 for 30 minutes, the maximum plasma levels of lidocaine (range 0.05-0.25 µg/ml, one individual value of 0.84 µg/ml) and of prilocaine (0.02-0.08 µg/ml) were reached within 1-2.5 hours (ref 28).

After an application time of 24 hours to leg ulcers with an area of up to 50-100 cm2, the maximum plasma levels of lidocaine (0.19-0.71 µg/ml) and of prilocaine (0.06-0.28 µg/ml) were usually reached within 2-4 hours (ref 29).

Following repeated application of 2-10 g EMLA Cream to leg ulcers with an area of up to 62 cm2 for 30-60 minutes 3-7 times a week for up to 15 doses during a period of one month, there was no apparent accumulation in plasma of lidocaine and its metabolites monoglycinexylidide and 2,6-xylidine or of prilocaine and its metabolite ortho-toluidine. The maximum observed plasma levels for lidocaine, monoglycinexylidide and 2,6-xylidine were 0.41, 0.03 and 0.01 µg/ml respectively. The maximum observed plasma levels for prilocaine and ortho-toluidine were 0.08 µg/ml and 0.01 µg/ml respectively. (ref 27).

5.3 Preclinical safety data

In animal studies the toxicity noted after high doses of either lidocaine or prilocaine, alone or in combination, consisted of effects on the central nervous and cardiovascular systems. When lidocaine and prilocaine were combined, only additive effects were seen, with no indication of synergism or unexpected toxicity. Both compounds were shown to have a low oral acute toxicity, providing a good safety margin in the event that EMLA is inadvertently swallowed. No drug-related adverse effects were seen in the reproduction toxicity studies, using either compound separately or together.

Neither local anaesthetic showed a mutagenic potential in either in vitro or in vivo mutagenicity tests. Cancer studies have not been performed with either lidocaine or prilocaine alone or in combination, due to the indication and duration of therapeutic use of these drugs.

Genotoxicity tests with lidocaine showed no evidence of mutagenic potential A metabolite of lidocaine, 2,6-xylidine, showed weak evidence of activity in some genotoxicity tests. The metabolite 2,6-xylidine has been shown to have carcinogenicity potential in preclinical toxicological studies evaluating chronic exposure. Risk assessments comparing the calculated maximum human exposure from intermittent use of lidocaine, with the exposure used in preclinical studies, indicate a wide margin of safety for clinical use.(ref 96)

Local tolerance studies using a 1:1 (w/w) mixture of lidocaine and prilocaine as an emulsion, cream or gel indicated that these formulations are well tolerated by intact and damaged skin and mucosal membranes. (refs 87,93)

A marked irritative reaction was seen after single ocular administration of a 50 mg/g lidocaine + prilocaine 1:1 (w/w) emulsion, in an animal study (refs 32,93). This is the same concentration of local anaesthetics and a similar formulation as for EMLA cream and patch. This ocular reaction may have been influenced by the high pH of the formulation of the emulsion (approximately 9), but is probably also partly a result of the irritative potential of the local anaesthetics themselves.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Carboxypolymethylene, polyoxyl hydrogenated castor oil, sodium hydroxide to pH 8.7-9.7, purified water.

Contains no preservative.

6.2 Incompatibilities

Not applicable

6.3 Shelf-life

3 years

6.4 Special precautions for storage

Do not store above 30°C. Do not freeze.
EU: Do not freeze. The product is stable at ICH storage conditions of 25°C±2°C/60% RH±5% (long term) and 40°C±2°C/75% RH±5% (short term). Therefore the product does not require any special storage conditions within EU countries (Climatic zone 2). (ref 88)

6 .5 Nature and contents of container
Collapsible tube of aluminium, internally coated with protective lacquer. EMLA Cream is available in tubes of 5 g and 30 g.

6.6 Instructions for use, handling and disposal

The protective membrane of the tube is perforated by applying the cap. The EMLA tube is intended for single use when used on leg ulcers: discard the tube with any remaining contents after each occasion that a patient has been treated. See "EMLA Cream Instructions for use", 19 August 2005 and “EMLA Cream Leg Ulcer Instructions for Use”, 19 August 2005.

Date of text: August 2005

REFERENCES

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2. Minor B, Grafford K. EMLA Cream 5% Summary and evaluation of clinical data.Astra Report N 802-10 AC 073, 1988-02-25.

3. Zilbert A W, Lewandowski K. A double-blind study on the topical analgesia experienced with EMLA Cream as a premedication to infiltration anaeshesia in the genital mucosa of women.Astra Report N 62-18/051-18, 1992-08-05.

4. Eriksson G. Export Report on the clinical documentation for EMLA Cream 5% sterile - topical anaesthetic for the cleansing/debridement of leg ulcers. Supplemented with two multicentre studies.Astra Report N 802-540-LC-0040-01, 1993-02-28.

5. Eriksson G. Clinical Expert Report: Replacement of EMLA® sterile cream 5% by EMLA® cream 5% for cleansing/debridement of leg ulcers and new data on local and systemic tolerability, including repeated-dose pharmacokinetics. Addendum to Clinical Expert Report N 802-540-LC-0040-01.Astra Report N 802-540-LC-0093, 1997-02-19.

6. Holm J, Andrén B, Grafford K. A double-blind clinical study of EMLA Cream used as topical analgesic for debridement of leg ulcers. A comparison with placebo.Astra Report N 802-10 AC 044, 1987-01-09.

7. Hansson C, Holm J, Lillieborg S, Syrén A. Repeated treatment with EMLA Cream 5% as a topical analgesic for the cleansing of venous leg ulcers. A controlled study.Astra Report N 802-40 AC 098, 1990-11-30.

8. Kalis B, Trinquet F, Benes G, Jaquemet N. A randomized, double-blind multicentre study of EMLA® sterile cream 5% as a topical anaesthetic for the repeated mechanical debridement of venous leg ulcers.Astra Report N 802-540-LC-0095-01, 1996-12-19.

9. Holst R, Kristofferson A, Syrén A. EMLA 5% cream as a topical analgesic for the cleansing of leg ulcers. A single-blind comparison of analgesic effect after treatment for 10, 20 or 60 minutes.Astra Report N 802-10 AC 095, 1990-11-09.

10. Evers H, Danielson K, Vinnars E. Dermal analgesia and local circulatory effects in volunteers after epicutaneous application of EMLA Cream. Influence of applied dose and size of test area.Astra Report N 802-10 AC 050-1, 1987-07-29.

11. Ohlsén L, Lähteenmäki T, Olenius M, Strömbeck J-O, Lillieborg S. Comparison of two doses of EMLA Cream as local analgesia for cutting split skin grafts. A multicentre study.Astra Report N 802-10 AC 046, 1986-11-28.

12. Haugstvedt S, Friman A-M, Danielson K. EMLA Cream 5% for removal of mollusca. A clinical study of plasma concentrations of lidocaine and prilocaine and analgesic effect in children.Astra Report N 802-10 AC 070-1, 1988-02-26.

13. Oranje AP, de Waard-van der Spek FB, Stolz E, Lillieborg S. Analgesia for the surgical removal of mollusca contagiosa in children: A double-blind, placebo-controlled, time-response study of EMLA® (lidocaine/prilocaine) creamAstra Report N 802-10 AC 082-1, 1990-02-05.

14. Rosdahl I, Edmar B, Gisslén H, Nordin P, Lillieborg S. Topical analgesia with EMLA Cream for curettage of mollusca contagiosa in children.Astra Report N 802-10 AC 054-2, 1986-12-18.

15. Evers H, Danielson K, Vinnars E. Dermal analgesia and local circulatory effects in volunteers after epicutaneous application of EMLA Cream. Influence of application time.Astra Report N 802-10 AC 052-1, 1987-07-29.

16. Ehrenström-Reiz G, Reiz S, Stockman O. Topical anaesthesia with EMLA, a new lidocaine-prilocaine cream and the cusum technique for detection of minimal application time.Acta Anaesth Scand 1983;27:510-2.

17. Hallen B, Olsson G, Uppfeldt A. Determination of a minimum application time for efficacy of a 5% lidocaine-prilocaine cream, EMLA (Eutectic Mixture of Local Anaesthetics), used for relief of venipuncture pain in children.Astra Report N 802-10 AC 015-2, 1983-03-31.

18. Sanders R, Goodacre TEE, Watts DA. The use of the topical local anaesthetic EMLA in split skin grafting: A comparison with infiltration anaesthesia.Astra Report N 802-10 AC 060-1, April 1987.

19. Evers H, Danielson K, Vinnars E. Dermal analgesia and local circulatory effects in volunteers after epicutaneous application of EMLA Cream. Influence of application time.Astra Report N 802-10 AC 051-1, 1987-07-29.

20. Larsson L. EMLA in children; use in neonates and recommended doses for children of all age groups.Clinical Expert Report N 802-540-LC-0105-01, 1997-04-28.

21. Engberg G, Henneberg S, Nilsson A, Danielson K. Plasma concentrations of prilocaine and lidocaine and Methemoglobin formation in infants after dermal application of a 5% lidocaine-prilocaine cream (EMLA).Astra Report N 802-10 AC 026-5, 1986-01-31.

22. Ljunghall K, Lillieborg S. Local anaesthesia with EMLA Cream for cautery of condylomata acuminata of the genital mucosa in women - effect of application time.Astra Report N 802-10 AC 064-1, 1988-02-04.

23. Rylander E, Sjöberg I, Lillieborg S. Local anaesthesia with EMLA Cream for laser treatment of condylomata acuminata in women. A double-blind comparison with placebo to evaluate the time of onset and duration of anaesthesia of the genital mucosa.Astra Report N 802-10 AC 062-1, 1987-12-10.

24. Lähteenmäki T, Lillieborg S, Ohlsén L et al Topical analgesia for the cutting of split skin grafts. A multicentre comparison of two doses of a lidocaine-prilocaine cream.Plastic Reconstr Surg 1988;82:458-62.

25. Nilsson A, Danielson K, Enberg G, Henneberg S. A clinical study of plasma concentrations of lidocaine and prilocaine and methaemoglobin formation after dermal application of EMLA in infants. (part B).Astra Report N 802-10 AC 071-1, 1988-02-26.

26. Eriksson G, Wanger L, Syrén A, Karlsson A. A clinical study on the repeated use of EMLA Cream 5% used as a topical analgesic for the mechanical cleansing of leg ulcers and decubitus ulcers.Astra Report N 802-10 AC 087, 1989-08-15.

27. Huledal G, Nilsson M, Kalis B, Trinquet F. Pharmacokinetic report of a randomized, double-blind multicentre study of EMLA® sterile cream 5% as a topical anaesthetic for the repeated mechanical debridement of venous leg ulcers. Plasma levels of lidocaine, prilocaine and their main metabolites.Astra Report N 802-540-LC-0090-01, 1997-02-17.

28. Holm J, Andrén B, Grafford K. A topical lidocaine-prilocaine cream, EMLA, used as local anaesthetic for debridement of leg ulcers.Astra Report N 802-10 AC 034, 1985-12-17.

29. Larsson-Stymne B, Björk M, Rotstein A, Widman M. Plasma concentrations of lidocaine and prilocaine after the application of EMLA® 5% cream to leg ulcers.Astra Report N 802-10 AC 092, 1990-09-14.

30. Juhlin L, Rollman O. Vascular effects of a local anaesthetic mixture in atopic dermatitis.Acta Derm Venereol (Stockh) 1984;64:439-40.

31. Rönnerfält L, Fransson J, Minor BG. EMLA Cream for the removal of mollusca contagiosa on patients with atopic dermatitis.Astra Report N 802-10 AC 080-1, 1990-05-05.

32. Astra Toxicology Laboratories, Södertälje, Sweden. Eye irritation in rabbits after single administration of Xylocain®/Citanest® emulsion.Astra Report N 802-10 T1018, 1980-01-15.

33. Schmidt S-H, Hellström S, Anniko M. Structural effects of the lidocaine-prilocaine anesthetic EMLA on the tympanic membrane.Arch Otorhinolaryngol 1988;245:136-41.

34. Schmidt S-H, Anniko M, Hellström S. Electrophysiological effects of the clinically used local anesthetics lidocaine, lidocaine-prilocaine and phenol on the rat´s inner ear.Eur Arch Otorhinolaryngol 1990;248:87-94.

35. Anniko M, Schmidt S-H. The ototoxic potential of EMLA.Acta Otolaryngol (Stockh) 1988;105:255-265.

36. Böttiger M. Statement; Evaluation of possible negative effects of the application of an anaesthetic cream (EMLA ™) on the immunogenicity of vaccinations. Jan 22, 1996.

37. Jakobson, Nilsson. Methemoglobinemia associated with a prilocaine-lidocaine cream and trimethoprim-sulphamethoxazole. A case report. Acta Anaesthesiol Scand 1985;29:453-5.

38. Astra Safety Assessment, Södertälje, Sweden. Effects upon pregnancy in rats of a lidocaine HCl (LEA151): prilocaine HCl (LEA154) (1:1 w/w) mixture given subcutaneously - a dose finding study.Astra Report N 802-40 T2412, 1991-06-24.

39. Astra Safety Assessment, Södertälje, Sweden. Effects upon pregnancy in rats of a lidocaine HCl (LEA151): prilocaine HCl (LEA154) (1:1 w/w) mixture given subcutaneously.Astra Report N 802-40 T2413, 1991-06-24.

40. Zeisler, Gaarder, De Mesquita. Lidocaine excretion in breast milk.Drug Intelligence and Clinical Pharmacy 1986;20:691-3.

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42. Minor B. EMLA Cream 5% summary and evaluation of human pharmacological data.Astra Report N 802-10 AC 072, 1988-02-25.

43. Norrbrink L, Waldenlind L. Periodic drug-safety update lidocaine 25 mg/g and prilocaine 25 mg/g. EMLA Cream.Astra Report N 802-540-LC-0074-01, 1995-09-05. Addendum no 1 1997-06-01, Addendum no 2 1998-10-29

44. Eriksson G, Lillieborg S. EMLA sterile cream 5% for the treatment of leg ulcers: Adverse events in clinical trials presented in CIOMS format.Astra Report N 802-540-LC-0094-01, 1997-02-18.

45. Floderus E, Waldenlind L. Periodic Drug-Safety Update lidocaine 25 mg/g and prilocaine 25 mg/g.EMLA® Sterile Cream.Astra Report N 802-540-LC-0082-01, 1996-04-15.

46. Covino BG, Vassallo HG. Local anesthetics. Mechanisms of action and clinical use. Ed. Grune & Stratton, New York 1976, 134-6.

47. Evers H, Vinnars E. Experimental study of local analgesic effect and plasma concentrations of lidocaine and prilocaine after epicutaneous application of EMLA Cream 5%.Astra Report N 802-10 AC 007-3, 1984-10-17.

48. Evers H, Vinnars E. Plasma concentrations of lidocaine and prilocaine after epicutaneous application of EMLA 5% cream to the facial skin and to the lower arms, in volunteers.Astra Report N 802-10 AC 061-1, 1988-02-29.

49. Haugstvedt S, Friman A-M, Danielson K. Open clinical investigation of plasma levels of prilocaine and lidocaine after the dermal application of EMLA to children aged between 2 and 3 years.Astra Report N 802-10 AC 069-1, 1988-02-26.

50. Kull B, Danielson K. An open study on a 5% lidocaine-prilocaine cream, EMLA, used as topical anaesthesia for cervical curettage.Astra Report N 802-10 AC 025-3, 1985-04-02.

51. Nilsson BA, Holmgren K, Danielson K. An open study of EMLA, a lidocaine-prilocaine cream, used as a topical anaesthetic for the prevention of pain during vacuum abortion.Astra Report N 802-10 AC 024-2, 1985-07-31.

52. Ohlsén L, Englesson S, Evers H. An anaesthetic lidocaine/prilocaine cream (EMLA) for epicutaneous application tested for cutting split skin grafts.Scand J Plast Reconstr Surg 1985;19:201-209.

53. Wahlén A, Evers H, Vinnars E. Systemic absorption of lidocaine and prilocaine after topical administration of EMLA 5% cream.Astra Report N 802-10 AC 035-3, 1986-03-20.

54. Rönnerfält L, Fransson J, Wahlgren C-F. EMLA Cream provides rapid pain relief for the curettage of mollusca contagiosa in children with atopic dermatitis without causing serious application-site reactions.Pediatric Dermatology 1998;15(4):309-312.

55. Menter MA. A randomized, open label, comparative parallel group study to evaluate the efficacy and safety of EMLA® Cream and 1% Xylocaine® infiltration in males for relief of pain associated with the removal of genital warts by cryotherapy.Astra Report 93-EML-18, 1994-02-14.

56. Hallén A, Ljunghall K, Wallin J. Topical anaesthesia with local anaesthetic (lidocaine and prilocaine, EMLA) cream for cautery of genital warts.Genitourin Med 1987;63:316-319.

57. Lillieborg S, Nörgård J. A discontinued clinical study of thermocautery of condylomata located on genital skin in women under local anaesthesia with EMLA Cream 5%.Astra Report 802-540-LC-0009, May 20, 1998.

58. Tronstad S-E, Mertel A. Diathermy treatment of condylomata in females with EMLA 5% cream.Astra Report 802-540-LC-0008, October 28, 1991, (revised Jan. 27, 1999).

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60. Ramaioli F, Amici De D, Guzinska K et al EMLA Cream and the premature infant. Int Monitor(European Society of Regional Anaesthesia) 1993;59. Abstract..

61. Stevens B, Johnston C, Taddio A et al The safety and efficacy of EMLA for heel lance in preterm neonates. Vancouver, Canada: International Association for the study of pain, 8thWorld Congress on Pain;1996:181-182. Abstract 239.

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63. Rosdahl, Edmar, Gisslen, Nordin, Lillieborg. Curettage of mollusca contagiosa in children: analgesia by topical application of a lidocaine/prilocaine cream (EMLA).Acta Derm Venereol 1988;68:149-153.

64. de Waard-van der Spek FB, Oranje AP. Purpura caused by EMLA is of toxic origin.Contact Dermatitis 1997;36:11-13.

65. Wahlgren C-F, Quiding H, Nilsson M. Standardised dermal sensitivity measures in subjects treated with EMLA for 60 and 120 minutes - An exploratory study.Astra Report 802-540-LC-0128-01.

66. Van Der Burght et al Duration of analgesia following application of eutectic mixture of local anaesthetics (EMLA) on genital mucosa.Acta Derm Venereol 1993:73(6):456-8.

67. Hansson C, Holm J. Lillieborg S, Syrén A. Repeated treatment with lidocaine/prilocaine cream (EMLA®) as a topical anaesthetic for the cleansing of venous leg ulcers.Acta Derm Venereol (Stockh) 1993;73:231-233.

68. Möller C. A lignocaine-prilocaine cream reduces venipuncture pain.Ups J Med Sci 1985;90:239-98.

69. Cooper CM, Gerrish SP, Hardwick M, Kay R. EMLA Cream reduces the pain of venepuncture in children.Eur J Anaesthesiol 1987;4:441-8.

70. Watson AR, Szymkiw P, Morgan AG. Topical anaesthesia for fistula cannulation in heamodialysis patients.Nephrol Dial Transplant 1988;3:800-2.

71. Young SS, Schwartz R, Sheridan MJ. EMLA Cream as a topical anesthetic before office phlebotomy in children.Southern Med J 1996;89(12):1184-7.

72. Halperin DL, Koren G, Attias D, Pellegrini E, Greenberg ML, Wyss M. Topical skin anesthesia for venous subcutaneous drug reservoir and lumbar punctures in children.Pediatrics;84(2):281-4.

73. Rice LJ, Cravero J. Relieveing the pain and anxiety of needle injections - experience with EMLAâ Cream (lidocaine 2.5% and prilocaine 2.5%) dermal anesthetic.Today´s Therapeutic Trends 1994;11(4):175-185

74. Miser A, Goh TS, Dose AM et al Trial of a topically administered local anesthtic (EMLA Cream) for pain relief during central venous port accesses in children with cancer.J Pain and Symptom Management 1994;9(4):259-264.

75. Koren G. Use of the eutectic mixture of local anesthetics in young children for procedure-related pain.J Pediatrics 1993;122:30-5.

76. Floderus E, Parmentier JL. Integrated Summary of Safety: EMLA Cream for anesthesia for superficial minor surgery in genital mucous membranes and as an adjunct for local infiltration anesthesia in genital mucous membranes.Astra Report N 802-540-LC-0131, January 28, 1999.

77. Lillieborg S, Parmentier JL. Integrated Summary of EfficacyEMLA® Cream for Anesthesia for Superficial Minor Surgery in Genital Mucous Membranes and as an Adjunct for Local Infiltration Anesthesia in Genital Mucous Membranes.Astra Report 802-540-LC-0125, January 28, 1999.

78. Dohlwitz A, Hellenberg L, Svedmyr J, Tober L, Wigertz A. No negative influence of EMLA applicatopn prior to B.C.G. vaccination.Acta Paedriatr 1998;87:480-481.

79. Halperin et al A randomized, double-blind, placebo-controlled trial to measure the antibody response to immunization with Measles-Mups-Rubella vaccines using EMLA® Patch for the reduction of pain associated with subcutaneous injection in tweve months old infants.Astra Report 802-540-LC-0122-01, December 18, 1998.

80. Riendeau L, Scavone J, Black Noller G, Ondrasik J. A randomized double-blind study to evaluate the efficacy of EMLA(R) cream in skin types IV-V and VI undergoing the venipuncture procedure.Astra Report 93-EML-16, Nov. 17, 1994.

81. Coleman MD, Coleman NA. Drug-induced methaemoglobinaemia. Treatment issues.Drug Safety 1996; 14:394-405

82. Lillieborg S. Integrated Summary of Effectiveness Data. EMLA® Cream as a Topical Anesthetic of Intact Skin in Geriatric Patients.Astra Report 802-540-LC-0141, August 20, 1999.

83. Lillieborg S, Floderus E. Integrated Summary of Safety. EMLA® Cream and EMLA® Anesthetic Disc as Topical Anesthetics of Intact Skin in Geriatric Patients.Astra Report 802-540-LC-0142, August 19, 1999.

84. Wahlgren C-F. Expert Report. Clinical documentation for reclassification of EMLA® cream 5% and EMLA® patch from medical prescription products to non-prescription products.Astra Report N 802-540-LC-0137, June 16, 1999.

85. Halperin SA. A randomised, double-blind, placebo-controlled trial to evaluate the antibody response to immunisation with diphteria-tetanus-pertussis-inactivated poliovirus-Haemophilus influenzae b and hepatitis B vaccines using EMLA® patch for the reduction of pain associated with intramuscular injection in infants from birth to six months of age.Astra Report N 802-540-LC-0145-01, November 11, 1999.

86. Huledal G. Summary on pharmacokinetics of lidocaine and prilocaine following topical application of EMLA® to intact skin in geriatric patients.Astra Report N 802-540-LC-0140-01, August 20, 1999.

87. Björkheden CA. Nonclinical safety data on local anaesthetics (bupivacaine, ropivacaine, mepivacaine, lidocaine, prilocaine, lidocaine and prilocaine combination).Astra Report N 98373-01, December 4, 1998

88. Barret M, Major M, Gasslander U. Stability Report for EMLA® Cream 5% with Carbopol 974P. Up to 18 months data.Document No. A004337, December 10, 2001

89. Floderus, E. Justification Document EMLA Pregnancy, 2002-06-18 [PAIN.000-034-886]

90. Floderus, E. Justification Document EMLA Precaution - eyes, 2002-06-18 [PAIN.000-034-880]

91. Floderus, E. Justification Document EMLA Methaemoglobinaemia, 2002-06-18 [PAIN.000-034-884]

92. Floderus, E. Justification Document EMLA Vaccination, 2002-06-18 [PAIN.000-034-890]

93. Floderus, E. Justification Document EMLA Preclinical Information, 2002-06-18 [PAIN.000-034-885]

94. Lillieborg, S. Justification Document EMLA™ Cream and EMLA™ Patch Geriatric labeling 2002-06-18[PAIN.000-034-883]

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97. Ahlén K. Clinical Expert Statement EMLA Cream – Dose Administration from the 30 g Aluminium Tube by Measurement of the length of the Cream String. April 22, 2005 [PAIN.000-081-253]