Nanolipo

CHARACTERISTICS OF THE MEDICINAL PRODUCT

• 1.

NAME OF THE MEDICINAL PRODUCT

Nanolipo, 40 mg/g, cream

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 gram of cream contains 40 mg of lidocaine.
Auxiliary substance with known action:
1 gram of cream contains 75 mg of propylene glycol.
1 gram of cream contains 73.2 mg of hydrogenated soybean lecithin.
1 gram of cream contains 15 mg of benzyl alcohol.
Full list of auxiliary substances, see section 6.1.

3. PHARMACEUTICAL FORM

Cream
White, almost white or yellowish cream.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Topical anesthetic medicinal product intended for the anesthesia of superficial skin layers before:

• venipuncture and venous cannulation in adults and adolescents and children from 1 month of age
• painful local procedure on larger areas of intact skin, in cases where the use of a topical anesthetic medicinal product is appropriate only in adults.

4.2 Posology and method of administration

Application to the skin.

Venipuncture or venous cannulation:

Dosage:
Adults, including the elderly and children from 1 month of age:
Children and adolescents:
The use of Nanolipo medicinal product in this indication is not recommended in infants below 1 month of age.
Method of administration:
Apply 1 g to 2.5 g of cream to the skin, to cover an area of 2.5 cm x 2.5 cm (6.25 cm²), at the site of venipuncture or venous cannulation. In infants under 1 year of age, do not apply more than 1 g of cream. 1 gram of cream, which corresponds to approximately 5 cm of cream line extruded from a 5 g tube or 3.5 cm of cream line extruded from a 30 g tube.
After application of the cream, do not rub it into the skin, and the application site may be covered with an occlusive dressing to prevent interference with the action of the medicinal product by the patient or other external factors. Proper anesthesia should occur after 30 minutes, however, the Nanolipo medicinal product may be used for up to 5 hours under an occlusive dressing. Before starting the procedure, the Nanolipo medicinal product should be removed using a cotton swab, and the site of venipuncture or venous cannulation should be prepared in the usual manner. The procedure should be started immediately after removal of the cream.
The maximum application time of the cream for venipuncture in infants from 1 to 3 months should not exceed 60 minutes. The maximum application time of the cream for venipuncture in infants from 3 to 12 months should not exceed 4 hours. The maximum application time of the cream for venipuncture in infants over 12 months, children, and adolescents, as well as adults, should not exceed 5 hours.

Painful local procedures on larger areas of intact skin:

Dosage:
Adults, including the elderly
Children and adolescents:
The use of Nanolipo medicinal product in this indication is not recommended in patients below 18 years of age.
Method of administration:
Apply a dose of approximately 1.5 g to 2 g of Nanolipo medicinal product per 10 cm² of skin or a multiple thereof up to a maximum area of 300 cm². The medicinal product should be applied until a response is obtained; in clinical trials, the response to the medicinal product occurred within 30 to 60 minutes.
Typical larger quantities are 30 g to 40 g / 200 cm² (approximately 10 cm x 20 cm, corresponding to the area of the face), 45 g to 60 g / 300 cm² (approximately 10 cm x 30 cm, corresponding to the area of the arm).
Indirect evidence suggests that repeated use of topical anesthetic medicinal products containing lidocaine may lead to systemic accumulation of lidocaine. Therefore, the Nanolipo medicinal product should not be reapplied before 12 hours have elapsed from its removal, with a maximum of 2 doses in 24 hours.
The Nanolipo medicinal product should be applied evenly in the specified dose, in a uniform layer on the area to be treated. The application site of the cream can be secured against interference until the desired anesthetic effect is achieved.
Before starting the procedure, the Nanolipo medicinal product should be removed using a cotton swab, and the site of the local procedure should be prepared in the usual manner. The procedure should be started immediately after removal of the cream.

4.3 Contraindications

Hypersensitivity to the active substance or to other topical anesthetic medicinal products of the amide type or to any of the auxiliary substances listed in section 6.1.
Hypersensitivity to soy or peanuts.

4.4 Special warnings and precautions for use

For external use only.
Should be avoided contact of the medicinal product with the eyes.
Should not be applied on irritated skin or in case of excessive irritation.
In case of worsening symptoms, persistence of unchanged symptoms for more than seven days or disappearance of symptoms and their reappearance within a few days, the use of the medicinal product should be discontinued and a doctor should be consulted.
Should not be applied in large quantities on irritated or burned skin.
The Nanolipo medicinal product contains propylene glycol, which may cause irritation.
The Nanolipo medicinal product should not be used on wounds, mucous membranes, or in patients with atopic dermatitis, due to the lack of clinical data on this matter.
The Nanolipo medicinal product contains hydrogenated soybean lecithin. This medicinal product should not be used in case of allergy to peanuts or soy.
Application of lidocaine to a larger area or for a longer period than recommended may lead to absorption of lidocaine, resulting in serious adverse effects.
Animal studies (guinea pigs) have shown that lidocaine has ototoxic effects when instilled into the middle ear. In the same studies, no abnormalities were found after administration of lidocaine to the external auditory canal of the animals. Lidocaine should not be used in any clinical conditions where penetration or displacement of the medicinal product beyond the eardrum into the middle ear is possible.
Application of lidocaine to the skin may cause transient local skin blanching, followed by transient erythema.
PRECAUTIONS
General: Repeated doses of lidocaine may increase the blood concentration of lidocaine. Caution should be exercised when using lidocaine in patients who may be more susceptible to the systemic effects of lidocaine, including severely ill, debilitated, or elderly patients.
Should be avoided contact of lidocaine with the eyes, as animal studies have shown that it leads to serious eye irritation. Loss of protective reflexes may also facilitate corneal irritation and potential scratching. The absorption of lidocaine into the conjunctival tissues has not been determined. In case of contact of the cream with the eye, the eye should be immediately rinsed with water or sodium chloride solution and protected until the sensation returns.
No cross-sensitivity to lidocaine has been demonstrated in patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.); however, caution should be exercised when using lidocaine in patients with a history of drug allergy, especially if the etiologic factor has not been established. Due to the inability to properly metabolize topical anesthetic medicinal products, patients with severe liver disease are at increased risk of developing toxic blood concentrations of lidocaine.
When using lidocaine, the patient should be informed that the anesthesia of the superficial skin layer may be accompanied by a blockage of the sensation of all stimuli in the anesthetized area. Therefore, the patient should avoid unintentional injury to the anesthetized area of the skin by scratching, rubbing, or exposure to extremely high or low temperatures until the sensation returns.
Lidocaine at a concentration greater than 0.5% has bactericidal and antiviral effects. Therefore, it is recommended to monitor the results of intradermal injections of live vaccines (such as BCG vaccines).
Patients taking antiarrhythmic medicinal products of class III (e.g., amiodarone) should be under close surveillance, and consideration should be given to monitoring their ECG, as the effect on the heart may be additive.
Children and adolescents
Nanolipo medicinal product has not been studied for efficacy in venipuncture in newborns.

4.5 Interaction with other medicinal products and other forms of interaction

Caution should be exercised when using lidocaine in patients taking antiarrhythmic medicinal products of class I and III (e.g., tocainide and mexiletine), as the toxic effects of the medicinal products are additive and generally synergistic.
Medicinal products that reduce the clearance of lidocaine (e.g., cimetidine or beta-adrenergic blocking agents, e.g., propranolol) may lead to potentially toxic blood concentrations of lidocaine when lidocaine is administered in large doses repeatedly over a long period. Such interactions should not, therefore, be of clinical significance in the case of short-term use of lidocaine (e.g., Nanolipo medicinal product) in the recommended doses.
Consideration should be given to the risk of additional systemic toxicity when using large doses of the Nanolipo medicinal product in patients who are already taking other topical anesthetic medicinal products.
Children and adolescents
No specific interaction studies have been conducted in children. It can be expected that interactions in children and adolescents are similar to those in the adult population.

4.6 Fertility, pregnancy and lactation

Pregnancy
Although lidocaine is minimally absorbed after topical application, the use of the Nanolipo medicinal product in pregnant women should be exercised with caution due to the lack of data or limited amount of data from clinical studies in pregnant women. Animal studies on reproductive toxicity are insufficient, but they do not indicate any direct or indirect harmful effects of the medicinal product on pregnancy, embryonic/fetal development, parturition, or postnatal development. Toxic effects on reproductive function have been demonstrated after subcutaneous or intramuscular administration of large doses of lidocaine, significantly exceeding the exposure to the medicinal product during topical application to the skin (see section 5.3).
Lidocaine crosses the placental barrier and may be absorbed by fetal tissues. It is reasonable to assume that lidocaine has been used in many pregnant women and women of childbearing age. So far, no specific reproductive toxicity has been reported, e.g., increased frequency of malformations or other direct or indirect harmful effects on the fetus.
Breast-feeding
Lidocaine is excreted into human milk, but in such small amounts that there is virtually no risk to the child during therapeutic use of the medicinal product. The Nanolipo medicinal product may be used during breast-feeding if clinically justified.
Fertility
There are no data on the effects of lidocaine on fertility. Animal studies have not demonstrated any impairment of fertility in male or female rats (see section 5.3).

4.7 Effects on ability to drive and use machines

The Nanolipo medicinal product has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Frequent undesirable effects include irritation, redness, itching, or rash.
In rare cases, the use of topical anesthetic medicinal products has been associated with allergic reactions, including anaphylactic shock.
Corneal irritation after accidental exposure of the eye to the medicinal product.

Children and adolescents
The frequency, type, and severity of undesirable effects are similar in the pediatric population and adults.
Reporting of suspected adverse reactions
After the medicinal product has been placed on the market, it is important to report any suspected adverse reactions. This allows for continued monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Adverse Reaction Reporting Scheme of the Medicinal Products Agency.
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.

4.9 Overdose

Overdose of the Nanolipo medicinal product is unlikely, however, systemic symptoms of toxicity should be of a similar nature to those observed after administration of lidocaine by other routes.
Systemic symptoms of toxicity may include blurred vision, dizziness or somnolence, breathing difficulties, tremors, chest pain, or irregular heartbeat.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Therapeutic category: Medicinal products containing local anesthetics, lidocaine, ATC code: N01BB02
Mechanism of action and pharmacodynamic properties
The Nanolipo medicinal product applied to intact skin provides skin anesthesia by releasing lidocaine from the cream into the stratum corneum and dermis and accumulating lidocaine in the area of skin pain receptors and nerve endings. Lidocaine is an amide-type local anesthetic medicinal product, causing stabilization of neuronal membranes by inhibiting the flow of ions necessary to initiate and conduct nerve impulses, resulting in local anesthesia of the area exposed to the medicinal product. The main action of the medicinal product is to block voltage-dependent sodium channels.
Onset, quality, and duration of skin anesthesia by lidocaine depend mainly on the contact time of the cream with the skin. The Nanolipo medicinal product may cause transient vasoconstriction of peripheral blood vessels, followed by transient vasodilation at the site of application of the medicinal product.
Clinical efficacy and safety
Clinical trials have demonstrated that the Nanolipo medicinal product provides reliable anesthesia when applied for 30 to 60 minutes. The cream may remain on the skin for longer if adequate anesthesia is not achieved. Particular caution should be exercised when using the Nanolipo medicinal product on large areas of skin for more than 2 hours.
It has been shown that when the Nanolipo medicinal product is used within the recommended dose range on intact skin, the local toxicity of the medicinal product is minimal. The frequency of systemic undesirable effects should be directly proportional to the area and duration of exposure to the medicinal product.
Children and adolescents
In clinical trials of venipuncture in children of different ages, the use of the Nanolipo medicinal product was associated with a higher success rate of venipuncture, less pain, shorter total procedure time, and fewer skin changes in children undergoing venipuncture. The frequency of undesirable effects was low. The Nanolipo medicinal product provided satisfactory skin anesthesia before venipuncture after 30 minutes of application without an occlusive dressing in children.
The maximum application time of the cream for venipuncture in infants from 1 to 3 months should not exceed 60 minutes, in infants from 3 to 12 months should not exceed 4 hours, and in infants over 12 months, children, and adolescents, as well as adults, should not exceed 5 hours.

5.2 Pharmacokinetic properties

Absorption, distribution, metabolism, and excretion
No pharmacokinetic studies of the Nanolipo medicinal product have been conducted in animals. However, significant amounts of data on the pharmacokinetic properties of lidocaine are available from its long-term use worldwide as a topical anesthetic medicinal product. The amount of systemically absorbed lidocaine is directly dependent on both the contact time of the cream with the skin and the skin area to which the medicinal product is applied. It is not known whether lidocaine is metabolized in the skin. Lidocaine is rapidly metabolized in the liver to several metabolites, including monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which have pharmacological activity similar to that of lidocaine but less potent. The 2,6-xylidine metabolite has unknown pharmacological activity but has been shown to have carcinogenic effects in rats.
After intravenous administration, the plasma concentrations of MEGX and GX range from 11% to 36% and from 5% to 11%, respectively. The elimination half-life of lidocaine from plasma after intravenous administration is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13). The elimination half-life of lidocaine from plasma after intravenous administration may be prolonged in patients with cardiac or hepatic dysfunction. More than 98% of the absorbed dose of lidocaine can be recovered in the urine as metabolites or the original medicinal product. The systemic clearance is 10 to 20 ml/min/kg body weight (mean 13, ±3 SD, n=13).
After topical application to intact skin, the absorption of lidocaine is very slow. Increased absorption should therefore occur when the medicinal product is applied to mucous membranes or previously damaged skin. Pharmacokinetic data confirm that systemic concentrations of lidocaine are below the systemic therapeutic concentration of 1 µg/ml when the Nanolipo medicinal product is used in the recommended dose at various sites on the skin.
Children and adolescents
During a study of the use of the Nanolipo medicinal product for venipuncture in children of different ages, the maximum concentration of the active substance in plasma was very low (0.3 µg/ml or less). This was significantly below the potentially toxic concentration of the medicinal product in plasma.

5.3 Preclinical safety data

No detailed toxicological study of lidocaine or the Nanolipo medicinal product has been conducted, but relevant preclinical data are available from numerous individual animal studies.
Large amounts of lidocaine introduced into the circulation may cause objective and subjective symptoms of toxicity, largely resulting from effects on the central nervous system and cardiovascular system. Since lidocaine crosses the placental barrier, there is also a risk of toxic effects on the fetus. The likelihood of adverse effects on the fetus is increased in the event of acidosis, leading to accumulation of the medicinal product in the fetus.
Lidocaine may cause methemoglobinemia, but its frequency is significantly lower than that of methemoglobinemia caused by the use of prilocaine, so this risk is considered extremely low, especially with topical use.
The mutagenic potential of lidocaine has been tested in the Ames test and by analysis of structural chromosome aberrations in human lymphocytes in vitro and in the micronucleus test in mice in vivo. No mutagenic effects were found in these studies. A metabolite of lidocaine, 2,6-dimethylaniline, has shown signs of genotoxic effects. In preclinical toxicological studies for the assessment of chronic exposure, it has been shown that these metabolites have carcinogenic properties. After topical application to intact skin, the absorption of lidocaine is very slow, so the formation of significant amounts of systemic 2,6-dimethylaniline is unlikely.
Animal studies on the potential reproductive and developmental toxicity of lidocaine have not provided any evidence of significant teratogenic effects of lidocaine, but some behavioral effects have been demonstrated at high concentrations of the medicinal product.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl alcohol
Carbomer 940
Cholesterol
Hydrogenated soybean lecithin
Polysorbate 80
Propylene glycol
Tromethamine
all-rac-α-Tocopheryl acetate
Purified water

6.2 Incompatibilities

None.

6.3 Shelf life

3 years
Shelf life after first opening of the tube: 6 months

6.4 Special precautions for storage

No special precautions for storage of the medicinal product.
Storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

The containers contain 5 g or 30 g of the medicinal product. Both sizes of containers consist of:

• an aluminum tube with an inner coating of epoxy-phenolic resin with a PP cap or
• an aluminum tube with an inner coating of polyamide-imide resin with an HDPE cap.

The following types of containers have been approved for marketing, but not all pack sizes must be marketed:

• 1) a cardboard box containing one 5 g tube.
• 2) a cardboard box containing five 5 g tubes.
• 3) a cardboard box containing one 5 g tube and two Tegaderm occlusive dressings.
• 4) a cardboard box containing five 5 g tubes and ten Tegaderm occlusive dressings.
• 5) a cardboard box containing one 30 g tube.

Not all pack sizes must be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORIZATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

Adamed Pharma S.A.
Pieńków, ul. M. Adamkiewicza 6A
05-152 Czosnów
Poland

8. MARKETING AUTHORIZATION NUMBER

23052

9. DATE OF FIRST AUTHORIZATION

DATE OF LAST RENEWAL

Date of first authorization: 15 March 2016
Date of last renewal: 1 July 2021

10. DATE OF REVISION OF THE TEXT

OF THE SUMMARY OF PRODUCT CHARACTERISTICS

• 21.07.2022