Nanolipo

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Nanolipo, 40 mg/g, cream

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One gram of cream contains 40 mg of lidocaine.
Excipient with known effect:
One gram of cream contains 75 mg of propylene glycol.
One gram of cream contains 73.2 mg of hydrogenated soybean lecithin.
One gram of cream contains 15 mg of benzyl alcohol.
For the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Cream
White, almost white or yellowish cream.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Topically acting local anaesthetic medicinal product intended for surface anaesthesia of the skin prior to:

• catheterization and venipuncture in adults, adolescents and children from 1 month of age
• painful local procedures on larger areas of intact skin, when use of a topical local anaesthetic medicinal product is considered appropriate only in adults.

4.2 Dosage and Administration

Topical application.
Catheterization or venipuncture:
Dosage:
Adults, including elderly patients, and children from 1 month of age:
Children and adolescents:
The use of Nanolipo medicinal product for this indication is not recommended in infants below 1 month of age.
Administration method:
Apply 1 g to 2.5 g of cream to the skin to cover an area measuring 2.5 cm x 2.5 cm (6.25 cm²), at the site of catheterization or venipuncture. In infants under 1 year of age, no more than 1 g of cream should be applied. One gram of cream corresponds to approximately 5 cm of cream squeezed from a 5 g tube or 3.5 cm of cream squeezed from a 30 g tube.
After squeezing out the cream, do not rub it into the skin. The area where the cream has been applied may be covered with an occlusive dressing to prevent interference with the medicinal product's action by the patient or other external factors. Adequate anesthesia should occur within 30 minutes; however, the Nanolipo medicinal product may remain under an occlusive dressing for up to 5 hours. Before starting the procedure, the Nanolipo medicinal product must be removed using cotton gauze, and the site for catheterization or venipuncture should be prepared in the usual manner. The procedure should begin immediately after removal of the cream.
The maximum application time of the cream in infants aged 1 to 3 months should not exceed 60 minutes. The maximum application time of the cream in infants aged 3 to 12 months should not exceed 4 hours. The maximum application time of the cream in infants aged 12 months and older, children, adolescents, and adults should not exceed 5 hours.

Painful local procedures on larger areas of intact skin:
Dosage:
Adults, including elderly patients
Children and adolescents:
The use of Nanolipo medicinal product for this indication is not recommended in patients under 18 years of age.
Administration method:
Apply the cream at a dosage of approximately 1.5 g to 2 g of Nanolipo medicinal product per 10 cm² of skin surface or multiples thereof, up to a maximum area of 300 cm². The medicinal product should be applied until response is achieved; in clinical studies, response to the medicinal product occurred within 30 to 60 minutes.
Typical larger amounts include 30 g–40 g / 200 cm² (approximately 10 cm x 20 cm, corresponding to facial area), 45 g–60 g / 300 cm² (approximately 10 cm x 30 cm, corresponding to arm area).
Indirect evidence suggests that repeated use of topical anesthetic medicinal products containing lidocaine may lead to systemic accumulation of lidocaine. Therefore, Nanolipo medicinal product should not be re-applied before 12 hours have elapsed since its removal, with a maximum of 2 doses administered within 24 hours.
Nanolipo medicinal product should be applied evenly in the specified dose, forming a uniform layer of consistent thickness over the area undergoing the local procedure. The site of cream application may be protected from disturbance until adequate anesthetic effect is achieved.
Before starting the procedure, the Nanolipo medicinal product must be removed using cotton gauze, and the site for the local procedure should be prepared in the usual manner. The procedure should begin immediately after removal of the cream.

4.3 Contraindications

Hypersensitivity to the active substance or to other locally-acting anaesthetic medicinal products of amide type, or to any excipient listed in section 6.1.
Hypersensitivity to soy or peanuts.

4.4 Special warnings and precautions for use

For external use only.
Avoid contact of the medicinal product with the eyes.
Do not apply to irritated skin or in case of excessive irritation.
If symptoms worsen, persist unchanged for more than seven days,
or resolve and recur within a few days, discontinue use
of the medicinal product and consult a physician.
Do not use in large amounts on irritated or burned skin.
The medicinal product Nanolipo contains propylene glycol, which may cause irritation.
The medicinal product Nanolipo should not be applied to wounds, mucous membranes, or used in patients
with atopic dermatitis, due to lack of clinical data on this issue.
The medicinal product Nanolipo contains hydrogenated soy lecithin. Do not use this medicinal product
in patients with hypersensitivity to peanuts or soy.
Application of lidocaine over large areas or for longer than recommended may
lead to systemic absorption of lidocaine, resulting in severe adverse effects.
Animal studies (in guinea pigs) have shown that lidocaine has ototoxic effects when instilled into the middle ear.
In the same studies, no abnormalities were observed after administration of lidocaine into the external auditory canal.
Lidocaine should not be used in any clinical conditions where penetration or migration of the medicinal product
beyond the tympanic membrane into the middle ear is possible.
Application of lidocaine to the skin may cause transient local pallor followed by transient erythema.

PRECAUTIONS
General: Repeated doses of lidocaine may increase blood concentrations of lidocaine. Caution should be exercised when using lidocaine in patients who may be more sensitive to the systemic effects of lidocaine, including critically ill, debilitated, or elderly patients.
Avoid contact of lidocaine with the eyes, as animal studies have shown that this leads to severe eye irritation. Also, loss of protective reflexes may facilitate corneal irritation and potential abrasion. Absorption of lidocaine in conjunctival tissues has not been established.
If the cream comes into contact with the eye, immediately rinse the eye with water or sodium chloride solution and protect the eye until sensation returns.
Cross-sensitivity to lidocaine has not been demonstrated in patients allergic to para-aminobenzoic acid derivatives (e.g. procaine, tetracaine, benzocaine, etc.); however, caution should be exercised when administering lidocaine to patients with a history of hypersensitivity to medicinal products, especially when the etiological factor has not been identified. Due to impaired metabolism of local anesthetic agents, patients with severe liver disease are at increased risk of developing toxic plasma concentrations of lidocaine.
When lidocaine is used, patients should be informed that numbness of the superficial skin layer may be accompanied by loss of sensation to all stimuli in the anesthetized area. Therefore, patients should avoid unintentional injury to the anesthetized skin area by scratching, rubbing, or exposure to extremely high or low temperatures until sensation returns.
Lidocaine at concentrations greater than 0.5% exhibits bactericidal and antiviral activity.
Therefore, monitoring of intradermal injections of live vaccines (e.g. BCG vaccines) is recommended.
Patients receiving class III antiarrhythmic medicinal products (e.g. amiodarone) should be under close observation, and ECG monitoring should be considered, as cardiac effects may be additive.

Children and adolescents
The efficacy of the medicinal product for heel prick anesthesia in neonates has not been studied.

4.5 Interactions with other medicinal products and other forms of interaction

Caution should be exercised when administering lidocaine to patients receiving antiarrhythmic agents of Class I and III (e.g. tocainide and mexiletine), since toxic effects may be additive and are generally synergistic.
Medicinal products that reduce lidocaine clearance (e.g. cimetidine or beta-blocking agents such as propranolol) may lead to potentially toxic plasma concentrations of lidocaine when lidocaine is administered in high repeated doses over a prolonged period. Such interactions are therefore not expected to be clinically relevant when lidocaine is used short-term (e.g. the medicinal product Nanolipo) at recommended doses.
The risk of additional systemic toxicity should be considered when large doses of the medicinal product Nanolipo are used in patients who are already receiving other locally acting anaesthetic agents.

Children and adolescents
Specific interaction studies in children have not been conducted. Interactions in children and adolescents are expected to be similar to those in the adult population.

4.6 Fertility, pregnancy and lactation

Pregnancy
Although lidocaine is absorbed to a minimal extent into the systemic circulation following topical application, Nanolipo should be used with caution during pregnancy due to a lack of data or insufficient data from adequate and well-controlled clinical studies in pregnant women. Animal studies on reproductive toxicity are insufficient, but do not indicate any direct or indirect adverse effects of the medicinal product on pregnancy, embryonic or fetal development, course of parturition, or postnatal development of offspring. Toxic effects on reproductive function have been demonstrated in animals following subcutaneous or intramuscular administration of high doses of lidocaine, significantly exceeding exposure levels achieved with topical skin application (see section 5.3). Lidocaine crosses the placental barrier and may be absorbed by fetal tissues. It is reasonable and justified to assume that lidocaine has been used in many pregnant women and women of reproductive age. To date, no specific reproductive disorders have been reported, such as increased incidence of congenital malformations or developmental abnormalities, or other direct or indirect harmful effects on the fetus.

Breastfeeding
Lidocaine is excreted into human milk, but in such small amounts that there is essentially no risk of harm to the breastfed infant when the medicinal product is used at therapeutic doses. Nanolipo may be used during breastfeeding if clinically indicated.

Fertility
There are no data available on the effect of lidocaine on human fertility. Animal studies have shown no impairment of fertility in male or female rats (see section 5.3).

4.7 Effects on ability to drive and use machines

The medicinal product Nanolipo has no effect or has negligible effect on the ability to drive
and operate machinery.

4.8 Undesirable effects

Common adverse reactions include irritation, redness, itching or rash.
Rarely, the use of topical local anaesthetic medicinal products has been associated with allergic reactions, including anaphylactic shock.
Corneal irritation following accidental exposure of the eye to the medicinal product.

Children and adolescents
The frequency, type, and severity of adverse reactions are similar in children and adolescents compared to adults.

Reporting suspected adverse reactions
It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions to the Department of Monitoring Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products.

Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +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 responsible entity.

4.9 Overdose

Overdose of the medicinal product Nanolipo is unlikely; however, systemic symptoms of toxicity would 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 drowsiness, breathing difficulties, tremors, chest pain, or irregular heartbeat.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Products containing local anaesthetics, lidocaine, ATC code: N01BB02

Mechanism of action and pharmacodynamic properties
The medicinal product Nanolipo, when applied to intact skin, provides skin anaesthesia by releasing lidocaine from the cream into the epidermis and dermis, and by accumulation of lidocaine around cutaneous pain receptors and nerve endings. Lidocaine is an amide-type local anaesthetic agent that stabilizes neuronal membranes by inhibiting the ionic fluxes required for initiation and conduction of nerve impulses, resulting in local anaesthesia of the area exposed to the medicinal product. The primary action of the medicinal product is blockade of voltage-dependent sodium channels.
The onset, quality, and duration of skin anaesthesia by lidocaine primarily depend on the duration of contact between the cream and the skin. The medicinal product Nanolipo may cause transient constriction of peripheral blood vessels, followed by transient vasodilation at the site of application.

Clinical efficacy and safety
Clinical studies have shown that the medicinal product Nanolipo provides reliable anaesthesia when applied for 30 to 60 minutes. The cream may remain on the skin longer if adequate anaesthesia has not been achieved. Particular caution should be exercised when applying the medicinal product Nanolipo over large skin areas for more than 2 hours.
When used within the recommended dosage range on intact skin, the local toxicity of the medicinal product Nanolipo has been shown to be low. The frequency of systemic adverse reactions is expected to be directly proportional to the surface area and duration of exposure to the medicinal product.

Children and adolescents
In clinical studies involving venous puncture in children, use of the medicinal product Nanolipo was associated with higher success rates of venous cannulation, reduced pain perception, shorter total procedure time, and fewer skin changes in children undergoing cannulation. The frequency of adverse reactions was low. The medicinal product Nanolipo provided satisfactory skin anaesthesia prior to venous puncture after 30 minutes of application without an occlusive dressing in children.
The maximum application time of the cream for venous cannulation should not exceed 60 minutes in infants aged 1 to 3 months, should not exceed 4 hours in infants aged 3 to 12 months, and should not exceed 5 hours in infants older than 12 months, children, adolescents, and adults.

5.2 Pharmacokinetic properties

Absorption, distribution, metabolism and elimination
Pharmacokinetic studies of the medicinal product Nanolipo have not been conducted in animals. However, substantial data are available on the pharmacokinetic properties of lidocaine from its long-term worldwide use as a locally acting anaesthetic medicinal product. The amount of systemically absorbed lidocaine depends directly on both the duration of contact of the cream with the skin and the surface area of skin 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 into several metabolites, including monoethylglycinylxylidide (MEGX) and glycinylxylidide (GX), both of which have pharmacological activity comparable to lidocaine, although less potent. The metabolite 2,6-xylidine has unknown pharmacological activity but shows carcinogenic effects in rats.
After intravenous administration, plasma concentrations of MEGX and GX range from 11% to 36% and from 5% to 11%, respectively. The plasma half-life of lidocaine after intravenous administration is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13). The plasma half-life of lidocaine after intravenous administration may be prolonged in patients with impaired cardiac or hepatic function. Over 98% of the absorbed dose of lidocaine can be recovered in urine as metabolites or unchanged medicinal product. Systemic clearance ranges from 10 to 20 ml/min/kg body weight (mean 13, ±3 SD, n=13).
After topical application to intact skin, absorption of lidocaine is very slow. Increased absorption is therefore expected when the medicinal product is applied to mucous membranes or previously damaged skin. Pharmacokinetic data confirm that systemic concentrations of lidocaine remain below the systemic therapeutic concentration of 1 µg/ml when the medicinal product Nanolipo is used at the recommended dose applied to various skin sites.

Children and adolescents
In a study evaluating the use of the medicinal product Nanolipo for cannulation in children of various ages, the maximum plasma concentration of the active substance was very low (0.3 µg/ml or less). This was well below the potentially toxic plasma concentrations of the medicinal product's components.

5.3 Preclinical safety data

To date, no detailed toxicological study of lidocaine or the medicinal product Nanolipo has been conducted; however, appropriate 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 due to effects on the central nervous system and the cardiovascular system. Since lidocaine crosses the placental barrier, there is also a risk of toxic effects on the fetus. The likelihood of adverse effects in the fetus is increased in the presence of acidosis, which leads to accumulation of the medicinal product in the fetus.
Lidocaine may cause methemoglobinemia, but its incidence is significantly lower than that associated with prilocaine; therefore, this risk is considered extremely low, especially following topical application.
The mutagenic potential of lidocaine was evaluated in the Ames test, in an analysis of structural chromosomal aberrations in human lymphocytes in vitro, and in the micronucleus test in mice in vivo. No mutagenic effects were observed in these studies. However, a metabolite of lidocaine, 2,6-dimethylaniline, showed signs of genotoxic activity. In preclinical toxicological studies assessing chronic exposure, these metabolites have been shown to have carcinogenic properties. Following topical application to intact skin, absorption of lidocaine is very slow, making significant systemic formation of 2,6-dimethylaniline unlikely.
Animal studies investigating the potential reproductive and developmental toxicity of lidocaine have not provided evidence of significant teratogenic effects of lidocaine, but some behavioral effects were observed at high concentrations of the local anaesthetic product.
6. PHARMACEUTICAL DATA
6.1 List of excipients
Benzyl alcohol
Carbomer 940
Cholesterol
Hydrogenated soybean lecithin
Polysorbate 80
Propylene glycol
Triethanolamine
all-rac-α-Tocopheryl acetate
Water for injections

6.2 Pharmaceutical incompatibilities

Not applicable.

6.3 Shelf life

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

6.4 Special precautions during storage

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

6.5 Type and content of container

Containers hold 5 g or 30 g of medicinal product. Both container sizes consist of:

• an aluminium tube internally coated with epoxy-phenolic lacquer, with a PP cap, or
• an aluminium tube internally coated with polyamide-imide lacquer, with an HDPE cap.

The following types of packaging have been authorised for marketing, but not all pack sizes may be available:

1. cardboard pack containing one 5 g tube.
2. cardboard pack containing five 5 g tubes.
3. cardboard pack containing one 5 g tube and two Tegaderm® occlusive dressings.
4. cardboard pack containing five 5 g tubes and ten Tegaderm® occlusive dressings.
5. cardboard pack containing one 30 g tube.
   Not all pack sizes may be available.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION HOLDER
Adamed Pharma S.A.
Pieńków, ul. M. Adamkiewicz 6A
05-152 Czosnów
Poland

8. MARKETING AUTHORISATION NUMBER

9. DATE OF FIRST AUTHORISATION AND DATE OF RENEWAL

AND DATE OF RENEWAL
Date of first authorisation: 15 March 2016
Date of latest renewal: 1 July 2021

10. DATE OF ADOPTION OR PARTIAL CHANGE OF THE

SUMMARY OF PRODUCT CHARACTERISTICS
21.07.2022