Nexobrid

Patient Information Leaflet: Information for the User

NexoBrid 2 g powder and gel for gel

proteolytic enzyme concentrate enriched with bromelain
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you or the child experience any side effects, including any not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet:

1. What NexoBrid is and what it is used for
2. What you need to know before NexoBrid is used
3. How to use NexoBrid
4. Possible side effects
5. How to store NexoBrid
6. Contents of the pack and other information

1. What NexoBrid is and what it is used for

What NexoBrid is
NexoBrid contains a mixture of enzymes called "proteolytic enzyme concentrate enriched with
bromelain", which is derived from an extract of the pineapple stem.
What NexoBrid is used for
NexoBrid is used in adults, adolescents, and children of all ages to remove burned tissue from
deep or partially deep skin burns.
The use of NexoBrid may reduce the need for, or extent of, surgical removal of burned tissue and/or skin grafting.

2. What you should know before NexoBrid is used

NexoBrid must not be used:

• if you or the child are allergic to bromelain
• if you or the child are allergic to pineapple
• if you or the child are allergic to papaya/papain
• if you or the child are allergic to any of the other components of the powder or gel (listed in section 6).

Warnings and precautions
Talk to your doctor or nurse before using NexoBrid if:

• you or the child has a heart disease;
• you or the child has diabetes;
• you or the child has an active stomach ulcer (peptic ulcer);
• you or the child has a vascular disease (with vascular occlusion);
• you or the child has varicose veins in the area near the burn;
• you or the child has implants, pacemakers, or vascular shunts;
• you or the child has bleeding problems or is taking medications to thin the blood;
• your wound(s) or the child’s wound(s) have been exposed to chemicals or other hazardous substances;
• you or the child has a lung disease;
• your lungs or the child’s lungs have been, or may have been, damaged by smoke inhalation;
• you or the child is allergic to latex, bee stings, or olive pollen. In this case, you or the child may develop allergic reactions to NexoBrid. Allergic reactions may cause, for example, difficulty breathing, skin swelling, hives, other skin reactions, skin redness, low blood pressure, rapid heartbeat, abdominal discomfort, or a combination of these effects. If you or the child notice any of these signs or symptoms, inform your doctor or healthcare provider immediately. Allergic reactions can be serious and may require medical treatment. If NexoBrid comes into contact with the skin, wash it off with water. This reduces the likelihood of an allergic reaction to NexoBrid.

The use of NexoBrid to remove burned tissue may cause fever, wound inflammation, or infection, and possibly generalized infection. You or the child may be monitored regularly for these conditions and may receive medications to prevent or treat infections.
NexoBrid may reduce the blood’s ability to clot, increasing the risk of bleeding. NexoBrid should be used with caution if you or the child is taking medications that reduce blood clotting (called anticoagulants), or if you or the child has a general tendency to bleed, a stomach ulcer, blood poisoning, or other conditions that could cause bleeding. After treatment with NexoBrid, your doctor may check your blood clotting levels.
Direct contact of NexoBrid with the eyes must be avoided. If NexoBrid comes into contact with the eyes, rinse them thoroughly with plenty of water for at least 15 minutes.
To prevent problems with wound healing, the treated burn wound will be covered as quickly as possible with temporary or permanent skin substitutes or dressings.
NexoBrid must not be used on chemical burn wounds, electrical burns, foot burns in diabetic patients, or in patients with obstructive vascular disease, on contaminated wounds, or on wounds where NexoBrid could come into contact with foreign materials (e.g., implants, pacemakers, and shunts) or large blood vessels, eyes, or other vital body parts. NexoBrid should be used with caution in areas with varicose veins (dilated and twisted veins) to prevent the risk of bleeding from these veins.

Other medicines and NexoBrid
Inform your doctor if you or the child are taking, have recently taken, or might take any other medicines.
Your doctor will pay attention and monitor for any signs of reduced blood clotting or bleeding when prescribing other medicines that affect blood clotting, as NexoBrid can reduce blood clotting.
NexoBrid may:

• increase the effects of certain medicines that are inactivated by liver enzymes called CYP2C8 and CYP2C9. This occurs because NexoBrid can be absorbed from the burn wound into the bloodstream. These medicines include:
  • amiodarone (used to treat certain types of irregular heartbeat),
  • amodiaquine and chloroquine (used to treat malaria and certain types of inflammation),
  • fluvastatin (used to treat high cholesterol),
  • pioglitazone, repaglinide, tolbutamide, and glipizide (used to treat diabetes),
  • paclitaxel (used to treat cancer),
  • torasemide (used to increase urine flow),
  • ibuprofen (used to treat fever, pain, and certain types of inflammation),
  • losartan (used to treat high blood pressure),
  • celecoxib (used to treat certain types of inflammation),
  • warfarin (used to reduce blood clotting), and
  • phenytoin (used to treat epilepsy)
• intensify your or the child’s reaction to the anticancer medicines fluorouracil and vincristine
• cause an unwanted drop in blood pressure when you or the child is being treated with medicines called ACE inhibitors, used to treat high blood pressure and other conditions
• increase drowsiness when used together with medicines that cause drowsiness. These medicines include, for example, sleeping pills, so-called tranquillisers, certain painkillers, and antidepressants
• silver sulfadiazine or povidone-iodine applied to the wound may reduce the effectiveness of the medicine.

If you are unsure whether you or the child is taking any of the medicines listed above, consult your doctor before NexoBrid is used.

Pregnancy and breastfeeding
The use of NexoBrid during pregnancy is not recommended.
As a precautionary measure, you must not breastfeed for at least 4 days after application of NexoBrid.
If you are pregnant, breastfeeding, or think you may be pregnant or are planning a pregnancy, talk to your doctor or pharmacist before using this medicine.

3. How to use NexoBrid

NexoBrid must be used exclusively by specialists in burn centers. It will be prepared immediately before use and applied by a physician or another healthcare professional.
2 g of NexoBrid powder mixed with 20 g of gel should be applied in a layer 1.5–3 mm thick to a burn area corresponding to 1 percent of the body surface area of an adult patient.
The gel should be left in place for 4 hours and then removed. A subsequent second application is not recommended.

• NexoBrid must not be applied to more than 15% of total body surface area in adults and children/adolescents aged 4 to 18 years.
• This medicine must not be applied to more than 10% of total body surface area in children aged 0 to 3 years.

Instructions for preparing the NexoBrid gel are provided at the end of this leaflet, in the section intended for medical or healthcare professionals.
Before being applied to a burn wound, NexoBrid powder is mixed into a gel and must be used within 15 minutes after mixing.

• NexoBrid will be applied to a clean, blister-free, moist wound area.
• Other medicinal products (such as silver sulfadiazine or povidone-iodine) will be removed from the wound area prior to application of NexoBrid.
• Prior to application of NexoBrid, a dressing impregnated with antibacterial solution will be applied for 2 hours.
• At least 15 minutes before application of NexoBrid, and prior to removal, you or the child will be given appropriate medications to prevent and treat pain.
• After removal of NexoBrid and dead tissue from the wound, a dressing soaked with antibacterial solution will be applied for an additional 2 hours.
• The vial containing the powder, the gel container, and the prepared gel after mixing are for single use only.

If you use too much NexoBrid
If too much NexoBrid gel is applied to a burn wound, the excess gel can be removed.
If you have any doubts about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
If you or the child notice any of these signs or symptoms, inform your doctor or healthcare professional immediately.
Allergic reactions to NexoBrid may occur and may cause, for example, difficulty breathing, skin swelling, hives, skin redness, low blood pressure, rapid heartbeat, nausea/vomiting/stomach cramps, or a combination of these effects.

Very common (occur in more than 1 person out of 10)

• Fever

Common (occur in less than 1 person out of 10)

• Pain in the area of the treated burn wound (even if medications are used to prevent or reduce pain associated with the removal of burned tissue)
• Burn wound infection, including skin infection around the wound (cellulitis)
• Wound complications, including increased wound depth, wound opening, wound drying and breakdown, inadequate healing of skin grafts
• Skin rash or redness in the area around the burn wound
• Non-severe allergic reactions, such as rash
• Rapid heartbeat
• Itching in the area of the burn wound. Itching in the area of the burn wound is very common as part of the normal burn healing process

Uncommon

• Bruising in the area of the wound

Frequency not known (frequency cannot be estimated from the available data)

• Severe allergic reactions including anaphylaxis

Reporting of side effects
If you or the child experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse.
You can also report side effects directly via the national reporting system in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NexoBrid

Keep this medicine out of the sight and reach of children.
Do not use NexoBrid after the expiry date which is stated on the label of the vial, bottle, and carton after “Exp.”. The expiry date refers to the last day of that month.
Store and transport in a refrigerator at 2 °C – 8 °C.
NexoBrid must be stored in an upright position to keep the gel at the bottom of the vial and in the original packaging to protect the medicine from light.
Do not freeze.
NexoBrid must be used within 15 minutes after mixing the powder with the gel.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What NexoBrid contains

• The active substance (in the powder in the vial) is a proteolytic enzyme concentrate enriched with bromelain: one vial contains 2 g, which corresponds, after reconstitution, to 0.09 g of proteolytic enzyme concentrate enriched with bromelain.
• The other ingredients are:
  – for the powder: ammonium sulfate and acetic acid
  – for the gel: carbomer 980, anhydrous dibasic sodium phosphate, sodium hydroxide and water for injections.

Description of the appearance of NexoBrid and contents of the pack
This medicinal product is supplied as a powder and gel for gel (powder in one vial (2 g) and gel in one tube (20 g)), pack size: 1 (one pack comprises one vial of powder and one tube of gel).
The colour of the powder ranges from ivory white to light brown and the gel is transparent and colourless.
For further information on this medicinal product, please contact the Marketing Authorisation Holder.

Marketing Authorisation Holder
MediWound Germany GmbH
Hans-Sachs-Strasse 100
65428 Rüsselsheim
Germany
e-mail: [email protected]

Manufacturer
Diapharm GmbH & Co. KG
Am Mittelhafen 56
48155 Münster
Germany

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. In addition, links to other websites on rare diseases and related therapeutic treatments are provided.

The following information is intended exclusively for healthcare professionals:

Preparation and Administration
From a microbiological standpoint, and because the enzymatic activity of the product progressively decreases after mixing, the reconstituted product must be used immediately after preparation (within 15 minutes).
NexoBrid should be applied to a moist, clean wound area free of keratin (from which blisters have been removed).
Topically applied wound medications (such as silver sulfadiazine or povidone-iodine) must be removed, and the wound thoroughly cleaned prior to NexoBrid application.

Patient and Wound Area Preparation

• In each treatment session, a total wound area not exceeding 15% of total body surface area (TBSA) may be treated with NexoBrid in adults and children/adolescents aged > 3 years; in children aged 0 to 3 years, a wound area not exceeding 10% of TBSA may be treated.
• Enzymatic debridement is a painful procedure requiring adequate analgesia and/or anesthesia.
• At least 15 minutes prior to NexoBrid application, initiate preventive pain management according to standard practices for large dressing changes.
• Thoroughly clean the wound and remove the superficial keratin layer or blisters, as keratin acts as a barrier preventing direct contact between the eschar and NexoBrid, thereby inhibiting its removal.
• Apply a gauze pad soaked in antibacterial solution to the wound for 2 hours.
• Remove all topically applied antibacterial medications before applying NexoBrid. Residual antibacterial agents may limit the activity of NexoBrid and reduce its efficacy.
• Surround the area from which eschar removal is desired with an adhesive barrier made of sterile paraffin-based ointment, applied several centimeters outside the treatment area (using a dispenser). The paraffin layer must not come into contact with the treatment zone to avoid covering the eschar and isolating it from direct contact with NexoBrid. To prevent irritation of abraded skin through inadvertent contact with NexoBrid and to prevent bleeding, acute lesions such as lacerations or escharotomy incisions can be protected with a layer of sterile greasy ointment (e.g., petrolatum gauze). The medicinal product must be used with caution in areas with varicose veins to prevent erosion of the vascular wall and risk of bleeding.
• Spray an isotonic sterile sodium chloride solution at 9 mg/mL (0.9%) onto the burn wound. The wound must remain moist during the application procedure.

Preparation of NexoBrid Gel (mixing powder with gel)

• NexoBrid powder and gel are sterile. Use aseptic technique when mixing NexoBrid powder with the gel. Inhalation of the powder must be avoided. Gloves, protective clothing, safety goggles, and a surgical mask must be worn.
• Open the vial containing NexoBrid powder by carefully tearing off the aluminum seal and removing the rubber stopper.
• When opening the gel vial, verify that the tamper-evident ring separates from the cap. If the tamper-evident ring has already separated from the cap before opening, discard the gel vial and use a new one.
• Transfer the NexoBrid powder into the corresponding gel vial.
• Mix the NexoBrid powder and gel thoroughly until a uniform mixture of light brown to pale brown color is obtained. This usually requires mixing for 1–2 minutes.
• Prepare the NexoBrid gel near the patient’s bedside.

Application of NexoBrid

• Moisten the treatment area by applying sterile physiological saline solution to the area delineated by the adhesive barrier created with greasy ointment.
• Within 15 minutes of mixing, apply NexoBrid topically to the burn wound in a layer 1.5–3 millimeters thick.
• The wound should then be covered with a sterile occlusive film dressing that adheres to the sterile adhesive barrier applied as described previously (see Patient and Wound Area Preparation). The NexoBrid gel must completely fill the occlusive dressing, with no air pockets underneath. Gently press the occlusive dressing at the point of contact with the adhesive barrier to ensure adhesion between the film and the barrier, thus fully enclosing NexoBrid within the treatment area.
• The dressed wound should be covered with a soft, thick, non-constrictive secondary dressing secured with a bandage.
• The dressing must remain in place for 4 hours.

Removal of NexoBrid

• Removal of NexoBrid is a painful procedure requiring adequate analgesia and/or anesthesia. Appropriate preventive analgesics should be administered at least 15 minutes before NexoBrid application.
• After 4 hours of NexoBrid treatment, remove the occlusive dressing using aseptic techniques.
• Remove the adhesive barrier using a sterile instrument with rounded edges (e.g., a tongue depressor).
• Remove the dissolved eschar from the wound using a sterile instrument with rounded edges.
• Thoroughly clean the wound first with a large, dry, sterile gauze or cloth, followed by a sterile gauze or cloth moistened with sterile isotonic sodium chloride solution (9 mg/mL, 0.9%). Rub the treated area until a pink surface with pinpoint bleeding or whitish tissue appears. Rubbing does not remove eschar adherent to areas where dissolution has not occurred.
• Apply a gauze pad soaked in antibacterial solution for an additional 2 hours.

Wound Care After Debridement

• Immediately cover the debrided area with skin substitutes or temporary or permanent dressings to prevent drying and/or formation of pseudoeschar and/or infection.
• Before applying a permanent skin cover or temporary skin substitute to a recently enzymatically debrided area, apply a wet-to-dry dressing.
• Before applying grafts or primary dressings, clean and refresh the debrided bed, e.g., by brushing or curettage, to allow proper adhesion of the dressing.
• Wounds with deep and full-thickness burns should undergo autografting as soon as possible after debridement with NexoBrid. Consideration should also be given to placing permanent skin coverings (e.g., autografts) on deep partial-thickness wounds immediately after debridement with NexoBrid.

Safe Handling Recommendations
Each vial, gel, or reconstituted gel of NexoBrid must be used for a single patient only.
Cases of occupational exposure to bromelain resulting in sensitization have been reported. Sensitization may have occurred due to inhalation of bromelain powder. Allergic reactions to bromelain include anaphylactic reactions and other immediate-type reactions with manifestations such as bronchospasm, angioedema, urticaria, and mucosal and gastrointestinal reactions. Appropriate precautions must be taken when mixing NexoBrid powder with gel, including wearing gloves, protective clothing, safety goggles, and a surgical mask. The powder must not be inhaled.
Avoid accidental eye exposure. In case of eye exposure, irrigate eyes with copious amounts of water for at least 15 minutes. In case of skin exposure, wash NexoBrid off with water.

Disposal
Unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations.

Package leaflet: Information for the user

NexoBrid 5 g powder and gel for gel

proteolytic enzymes concentrate enriched with bromelain
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you or the child experience any side effects, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet:

1. What NexoBrid is and what it is used for
2. What you need to know before NexoBrid is used
3. How to use NexoBrid
4. Possible side effects
5. How to store NexoBrid
6. Contents of the pack and other information

1. What NexoBrid is and what it is used for

What NexoBrid is
NexoBrid contains a mixture of enzymes called "proteolytic enzyme concentrate enriched with
bromelain", which is derived from an extract of the pineapple stem.
What NexoBrid is used for
NexoBrid is used in adults, adolescents, and children of all ages to remove burned tissue from
deep or partially deep skin burns.
The use of NexoBrid may reduce the need for, or extent of, surgical removal of burned tissue and/or
skin grafting.

2. What you must know before NexoBrid is used

NexoBrid must not be used:

• if you or the child are allergic to bromelain
• if you or the child are allergic to pineapple
• if you or the child are allergic to papaya/papain
• if you or the child are allergic to any of the other components of the powder or gel (listed in section 6).

Warnings and precautions
Speak to your doctor or nurse before using NexoBrid if:

• you or the child has heart disease;
• you or the child has diabetes;
• you or the child has an active stomach ulcer (peptic ulcer);
• you or the child has vascular disease (with vascular occlusion);
• you or the child has varicose veins in the area near the burn;
• you or the child has implants, pacemakers, or vascular shunts;
• you or the child has bleeding disorders or is taking medications to thin the blood;
• your wound(s) or the child’s wound(s) have been exposed to chemicals or other hazardous substances;
• you or the child has lung disease;
• your lungs or the child’s lungs have been, or may have been, damaged by smoke inhalation;
• you or the child is allergic to latex, bee stings, or olive pollen. In this case, you or the child may develop allergic reactions to NexoBrid. Allergic reactions may cause, for example, difficulty breathing, skin swelling, hives, other skin reactions, skin redness, low blood pressure, rapid heartbeat, abdominal discomfort, or a combination of these effects. If you or the child notice any of these signs or symptoms, inform the doctor or healthcare professional immediately. Allergic reactions can be serious and may require medical treatment. If NexoBrid comes into contact with the skin, wash it off with water. This reduces the likelihood of an allergic reaction to NexoBrid.

The use of NexoBrid to remove burned tissue may cause fever, wound inflammation, or infection, and possibly systemic infection. You or the child may undergo regular checks for these conditions and may receive medications to prevent or treat infections.
NexoBrid may reduce blood clotting ability, increasing the risk of bleeding. NexoBrid should be used with caution if you or the child are being treated with medicines that reduce blood clotting (called anticoagulants), or if you or the child have a general tendency to bleed, stomach ulcer, blood poisoning, or other conditions that could cause bleeding. After treatment with NexoBrid, the doctor may check blood clotting levels.
Direct contact of NexoBrid with the eyes must be avoided. If NexoBrid comes into contact with the eyes, rinse them thoroughly with plenty of water for at least 15 minutes.
To prevent wound healing problems, the treated burn wound will be covered as quickly as possible with temporary or permanent skin substitutes or dressings.
NexoBrid must not be used on chemical burn wounds, electrical burns, foot burns in diabetic patients, or patients with obstructive vascular disease, on contaminated wounds, or on wounds where NexoBrid may come into contact with foreign materials (e.g., implants, pacemakers, and shunts) or large blood vessels, eyes, or other vital body parts. NexoBrid should be used with caution in areas with varicose veins (dilated and twisted veins) to prevent the risk of bleeding from these veins.

Other medicines and NexoBrid
Inform your doctor if you or the child are taking, have recently taken, or might take any other medicines.
Your doctor will pay attention and monitor for any signs of reduced blood clotting or bleeding when prescribing other medicines that affect blood clotting, as NexoBrid can reduce blood clotting.
NexoBrid may:

• increase the effects of certain medicines that are inactivated by liver enzymes called CYP2C8 and CYP2C9. This occurs because NexoBrid may be absorbed from the burn wound into the bloodstream. These medicines include:
• amiodarone (used to treat certain types of irregular heartbeat),
• amodiaquine and chloroquine (used to treat malaria and certain types of inflammation),
• fluvastatin (used to treat high cholesterol),
• pioglitazone, repaglinide, tolbutamide, and glipizide (used to treat diabetes),
• paclitaxel (used to treat cancer),
• torasemide (used to increase urine flow),
• ibuprofen (used to treat fever, pain, and certain types of inflammation),
• losartan (used to treat high blood pressure),
• celecoxib (used to treat certain types of inflammation),
• warfarin (used to reduce blood clotting), and
• phenytoin (used to treat epilepsy)
• intensify your or the child’s reaction to the anticancer medicines fluorouracil and vincristine
• cause an unwanted drop in blood pressure when you or the child are being treated with medicines called ACE inhibitors, used to treat high blood pressure and other conditions
• increase drowsiness when used together with medicines that cause drowsiness. These medicines include, for example, sleeping pills, so-called tranquilizers, certain painkillers, and antidepressants
• silver sulfadiazine or povidone-iodine applied to the wound may reduce the effectiveness of the medicine.

If you are unsure whether you or the child are taking any of the medicines listed above, consult your doctor before NexoBrid is used.
Pregnancy and breastfeeding
The use of NexoBrid during pregnancy is not recommended.
As a precautionary measure, you must not breastfeed for at least 4 days after application of NexoBrid.
If you are pregnant, breastfeeding, suspect you may be pregnant, or are planning a pregnancy, talk to your doctor or pharmacist before using this medicine.

3. How to use NexoBrid

NexoBrid must only be used by specialists in burn centres. It will be prepared immediately before use and applied by a doctor or other healthcare professional.
5 g of NexoBrid powder mixed with 50 g of gel should be applied in a thickness of 1.5–3 mm to a burned area corresponding to 2.5 percent of the body surface area of an adult patient.
The gel should be left in place for 4 hours and then removed. A subsequent second application is not recommended.

• NexoBrid must not be applied to more than 15% of total body surface area in adults and children/adolescents aged 4 to 18 years.
• This medicine must not be applied to more than 10% of total body surface area in children aged 0 to 3 years.

Instructions for preparing NexoBrid gel are provided at the end of this leaflet, in the section intended for medical or healthcare professionals.
Before being applied to a burn wound, NexoBrid powder is mixed into a gel and must be used within 15 minutes after mixing.

• NexoBrid will be applied to a clean wound area, free of blisters and moist.
• Other medicinal products (such as silver sulfadiazine or povidone-iodine) will be removed from the wound area before application of NexoBrid.
• Prior to application of NexoBrid, a dressing soaked in antibacterial solution will be applied for 2 hours.
• At least 15 minutes before application of NexoBrid, and prior to its removal, appropriate pain-relieving medication will be administered to you or the child to prevent and treat pain.
• After removal of NexoBrid and dead tissue from the wound, a dressing soaked in antibacterial solution will be applied for another 2 hours.
• The vial containing the powder, the gel container, and the prepared gel after mixing are for single use only.

If you use too much NexoBrid
If too much NexoBrid gel is applied to a burn wound, excess gel may be removed.
If you have any doubts about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them. If you or the child notice any of these signs or symptoms, inform the doctor or healthcare professional immediately.

Allergic reactions to NexoBrid may occur and may cause, for example, breathing difficulties, skin swelling, hives, skin redness, low blood pressure, rapid heartbeat, nausea/vomiting/stomach cramps, or a combination of these effects.

Very common (occur in more than 1 in 10 people)

• Fever

Common (occur in less than 1 in 10 people)

• Pain in the area of the treated burn wound (even when medications are used to prevent or reduce pain caused by removal of burned tissue)
• Infection of the burn wound, including infection of the skin around the wound (cellulitis)
• Wound complications, including increased wound depth, wound opening, wound drying and wound breakdown, inadequate healing of skin grafts
• Skin rash or redness in the area around the burn wound
• Non-severe allergic reactions, such as skin rash
• Rapid heartbeat
• Itching in the area of the burn wound. Itching in the area of the burn wound is very common as part of the normal burn healing process

Uncommon

• Bruising in the area of the burn wound

Frequency not known (frequency cannot be estimated from the available data)

• Severe allergic reactions including anaphylaxis

Reporting of side effects
If you or the child experience any side effect, including those not listed in this leaflet, consult your doctor or nurse. You may also report side effects directly through the national reporting system detailed in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NexoBrid

Keep this medicine out of the sight and reach of children.
Do not use NexoBrid after the expiry date stated on the vial, bottle, and carton after “Exp.”. The expiry date refers to the last day of that month.
Store and transport in a refrigerator at 2 °C – 8 °C.
NexoBrid must be stored in an upright position to keep the gel at the bottom of the vial and in the original packaging to protect the medicine from light.
Do not freeze.
NexoBrid must be used within 15 minutes after mixing the powder with the gel.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What NexoBrid contains

• The active substance (in the powder vial) is a proteolytic enzyme concentrate enriched with bromelain: one vial contains 5 g, corresponding, after mixing, to 0.09 g of proteolytic enzyme concentrate enriched with bromelain.
• The other ingredients are:
  o for the powder: ammonium sulfate and acetic acid
  o for the gel: carbomer 980, anhydrous disodium phosphate, sodium hydroxide and water for injections.

Description of the appearance of NexoBrid and contents of the pack
NexoBrid is supplied as a powder and gel for gel (powder in a vial (5 g) and gel in a tube (50 g)), pack size 1 (one pack comprises one vial of powder and one tube of gel).
The colour of the powder ranges from ivory white to light brown and the gel is clear and colourless.
For further information on this medicinal product, please contact the Marketing Authorisation Holder.

Marketing Authorisation Holder
MediWound Germany GmbH
Hans-Sachs-Strasse 100
65428 Rüsselsheim
Germany
e-mail: [email protected]

Manufacturer
Diapharm GmbH & Co. KG
Am Mittelhafen 56
48155 Münster
Germany

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. In addition, links to other websites on rare diseases and related therapeutic treatments are provided.

---

The following information is intended for healthcare professionals only:

Preparation and administration
From a microbiological standpoint and because the enzymatic activity of the product progressively decreases after mixing, the reconstituted product must be used immediately after preparation (within 15 minutes).
NexoBrid should be applied to a moist, clean, keratin-free wound area (from which blisters have been removed).
Topically applied medicinal products (such as silver sulfadiazine or povidone-iodine) on the wound must be removed and the wound cleaned before application of NexoBrid.

Preparation of the patient and wound area

• In each treatment session, a total wound area not exceeding 15% of total body surface area (TBSA) may be treated with NexoBrid in adults and children/adolescents aged > 3 years; in children aged between 0 and 3 years, a wound area not exceeding 10% of TBSA may be treated.
• Enzymatic debridement is a painful procedure requiring adequate analgesia and/or anaesthesia.
• At least 15 minutes before application of NexoBrid, preventive pain treatment should be initiated according to standard practices for changing large wound dressings.
• Thoroughly clean the wound and remove the superficial keratin layer or blisters from the wound area, as keratin isolates the eschar from direct contact with NexoBrid and prevents its removal.
• Apply a gauze soaked in antibacterial solution for 2 hours.
• Remove all topically applied antibacterial medicinal products before applying NexoBrid. Residual antibacterial agents may limit the activity of NexoBrid, reducing its effectiveness.
• Surround the area from which eschar removal is desired with an adhesive barrier made of sterile paraffin-based ointment, applied several centimetres outside the treatment area (using a dispenser). The paraffin layer must not come into contact with the area to be treated to avoid covering the eschar and isolating it from direct contact with NexoBrid. To prevent irritation of abraded skin through inadvertent contact with NexoBrid, and to prevent bleeding, acute lesions such as lacerations or escharotic incisions may be protected with a layer of sterile greasy ointment (e.g., petrolatum gauze). The medicinal product must be used with caution in areas with varicose veins to prevent erosion of the vascular wall and the risk of bleeding.
• Spray a sterile isotonic sodium chloride solution 9 mg/mL (0.9%) onto the burn wound. The wound must remain moist during the application procedure.

Preparation of NexoBrid gel (by mixing the powder with the gel)

• NexoBrid powder and gel are sterile. Use aseptic technique when mixing NexoBrid powder with the gel. The powder must not be inhaled. Gloves, protective clothing, safety goggles, and a surgical mask must be worn.
• Open the vial containing NexoBrid powder by carefully peeling off the aluminium seal and removing the rubber stopper.
• When opening the gel tube, check that the tamper-evident ring separates from the cap. If the tamper-evident ring has already separated from the cap before opening, discard the gel tube and use a new one.
• Transfer NexoBrid powder into the corresponding gel tube.
• Mix NexoBrid powder and gel thoroughly until a uniform mixture of light brown to pale brown colour is obtained. This usually requires mixing the powder and gel for 1–2 minutes.
• Prepare the NexoBrid gel close to the patient’s bedside.

Application of NexoBrid

• Moisten the treatment area by applying sterile physiological saline solution to the area delineated by an adhesive barrier made of greasy ointment.
• Within 15 minutes of mixing, NexoBrid must be applied topically to the burn wound in a thickness of 1.5–3 millimetres.
• The wound should then be covered with a sterile occlusive film dressing adhering to the sterile adhesive barrier applied as described previously (see Preparation of patient and wound area). The NexoBrid gel must fill the entire occlusive dressing, with no air present underneath. Gently pressing the occlusive dressing at the point of contact with the adhesive barrier ensures adherence between the occlusive film and the barrier, thereby completely enclosing NexoBrid within the treatment area.
• The dressed wound should be covered with a soft, thick, non-constrictive secondary dressing secured with a bandage.
• The dressing should remain in place for 4 hours.

Removal of NexoBrid

• Removal of NexoBrid is a painful procedure requiring adequate analgesia and/or anaesthesia. Appropriate preventive analgesic medication should be administered at least 15 minutes before NexoBrid application.
• After 4 hours of treatment with NexoBrid, remove the occlusive dressing using aseptic techniques.
• The adhesive barrier should be removed using a sterile instrument with rounded edges (e.g., a tongue depressor).
• Remove dissolved eschar from the wound, eliminating it with a sterile instrument with rounded edges.
• Thoroughly clean the wound first with a large, dry, sterile gauze or cloth, followed by a sterile gauze or cloth soaked in sterile isotonic sodium chloride solution 9 mg/mL (0.9%). Rub the treated area until a pink surface with pinpoint bleeding or a whitish tissue appears. Rubbing does not remove eschar adherent to areas where it has not dissolved.
• Apply a gauze soaked in antibacterial solution for an additional 2 hours.

Wound care after debridement

• Immediately cover the debrided area with skin substitutes or temporary or permanent dressings to prevent drying and/or formation of pseudoeschar and/or infections.
• Before applying a permanent skin cover or temporary skin substitute to a recently enzymatically debrided area, a wet-to-dry dressing should be applied.
• Before applying grafts or primary dressings, clean and refresh the debrided bed, e.g., by brushing or scraping, to allow dressing adhesion.
• Wounds presenting areas of deep and full-thickness burns should undergo autografting as rapidly as possible after debridement with NexoBrid. Consideration should also be given to placing permanent skin coverings (e.g., an autograft) on deep partial-thickness wounds immediately after debridement with NexoBrid.

Recommendations for safe handling
Each vial, gel, or reconstituted gel of NexoBrid must be used for one patient only.
Cases of occupational exposure to bromelain resulting in sensitisation have been reported. Sensitisation may have occurred due to inhalation of bromelain powder. Allergic reactions to bromelain include anaphylactic reactions and other immediate-type reactions with manifestations such as bronchospasm, angioedema, urticaria, and mucosal and gastrointestinal reactions. Appropriate precautions must be taken when mixing NexoBrid powder with the gel, including wearing gloves, protective clothing, safety goggles, and a surgical mask. The powder must not be inhaled.
Avoid accidental eye exposure. In case of eye exposure, irrigate eyes with copious amounts of water for at least 15 minutes. In case of skin exposure, wash off NexoBrid with water.

Disposal
Unused medicinal product and waste materials derived from such medicinal product must be disposed of in accordance with local regulations.