Patient leaflet - Nexobrid 2 g powder and gel for gel

1. What NexoBrid is and what it is used for

What NexoBrid is

NexoBrid contains a mixture of enzymes called “concentrate of proteolytic enzymes enriched in bromelain”, which is produced from an extract from the stem of the pineapple plant.

What NexoBrid is used for

NexoBrid is used in adult patients to remove burnt tissue from deep or partially deep burn wounds of the skin. Using NexoBrid may reduce the need for, or the extent of, surgical removal of burnt tissue and/or skin transplantation.

2. What you need to know before NexoBrid is used

NexoBrid must not be used:

if you are allergic to bromelain
if you are allergic to pineapples
if you are allergic to papain
if you are allergic to any of the other ingredients of the
powder or gel (listed in section 6).
Warnings and precautions
- Talk to your doctor or nurse before NexoBrid is used if
- you have a heart disease;
- you have diabetes;
- you have an active peptic ulcer in the stomach,
- you have a vascular disease (with vascular occlusion);
- you have implants or a pacemaker or a vascular shunt;
- you have problems with bleeding or if you take blood-
  thinners;
- your wound(s) came into contact with chemicals or other
  hazardous substances;
- you have a lung disease;
- your lung has been, or may have been damaged by
  inhalation of smoke;
- you are allergic to latex, bee stings, or olive tree pollen. If
  so, you may also experience allergic reactions to NexoBrid.

Allergic reactions can cause, for example, breathing difficulties, swelling of the skin, hives, other skin reactions, redness of the skin, low blood pressure, fast heart rate and abdominal discomfort, or a combination of such effects. If you notice any of these signs or symptoms, inform your doctor or caregiver immediately.

Allergic reactions can be severe and require medical treatment.

In case of skin contact, rinse NexoBrid off with water. This is to make it less likely that you develop an allergic reaction to NexoBrid.

The use of NexoBrid to remove burnt tissue may lead to fever, to wound inflammation or wound infection, and possibly to general infection. You may be checked regularly for these conditions. You may receive medicines to prevent or treat infections.

NexoBrid may reduce the ability of your blood to form clots, which increases the risk of bleeding. NexoBrid should be used with caution if you are treated with medicines that reduce your blood’s ability to form clots (so-called blood-thinners) or if you have a general tendency to bleed, a stomach ulcer, blood poisoning, or another condition that could cause you to bleed. After treatment with NexoBrid your doctor may check your blood coagulation levels.

Direct contact of NexoBrid with the eyes should be avoided. If NexoBrid goes into the eyes, wash them with lots of water for at least 15 minutes.

To prevent wound-healing problems, the treated burn wound will be covered as soon as possible by temporary or permanent skin substitutes or dressings.

NexoBrid should not be used in chemical burn wounds, electrical burns, foot burns in diabetic patients and patients with occlusive vascular disease, in contaminated wounds and wounds where NexoBrid could come in contact with foreign materials (for example, implants, pacemakers, and shunts) or large blood vessels, the eyes or other important body parts.

Children and adolescents

NexoBrid is not for use in patients younger than 18 years.

Other medicines and NexoBrid

Tell your doctor if you are taking, have recently taken or might take any other medicines.

Your doctor will be cautious and watch for signs of reduced blood coagulation or bleeding when prescribing other medicines that affect blood coagulation, because NexoBrid may reduce blood coagulation.

NexoBrid may:

increase the effects of certain medicines that are inactivated
by a liver enzyme called CYP2C8 and CYP2C9. This is because NexoBrid can be absorbed from the burn wound into the blood stream . Examples of such medicines are:
- amiodarone (used to treat certain forms
  of irregular heartbeat),
- amodiaquine and chloroquine
  (used to treat malaria and some forms of inflammation),
  - fluvastatin (used to treat high cholesterol),
  - pioglitazone, rosiglitazone, repaglinide, tolbutamide and
    glipizide (used to treat diabetes),
  - paclitaxel and sorafenib (used to treat cancer),
  - torasemide (used to increase urine flow),
  - ibuprofen (used to treat fever, pain and
    some forms of inflammation),
  - losartan (used to treat high blood pressure),
  - celecoxib (used to treat some forms of inflammation),
  - warfarin (used to reduce blood coagulation), and
  - phenytoin (used to treat epilepsy).
  - intensify your reaction to the cancer medicines fluorouracil
    and vincristine.
  - cause an unwanted drop in blood pressure when you are
    treated with medicines called ACE inhibitors, which are used to treat high blood pressure and other conditions.
  - increase drowsiness when used at the same time with
    medicines that can cause drowsiness. These medicines include, for example, sleep medications, so-called tranquil-izers, some pain medications and antidepressants.

If you are not sure whether you are taking any of the medicines mentioned above, ask your doctor before NexoBrid is used.

Pregnancy and breast-feeding

The use of NexoBrid during pregnancy is not recommended.

As a precautionary measure, you should not breast-feed for at least 4 days after NexoBrid application.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, talk to your doctor or pharmacist before this medicine is used.

3. How NexoBrid is used

NexoBrid is for use by specialists in burn clinics only. It will be prepared directly before use and applied by a doctor or another healthcare professional.

2 g NexoBrid powder mixed in 20 g gel is applied 1.5 to 3 millimetres thick to a burn wound area of 1 percent of an adult patient’s body surface

It should be left for 4 hours, and then be removed. A second and subsequent application is not recommended.

NexoBrid should not be applied to more than 15% (one eighth) of the total body surface.

Instructions for the preparation of the NexoBrid gel are given at the end of this leaflet in the section intended for medical or healthcare professionals.

Before it is applied to a burn wound, NexoBrid powder is mixed into a gel. It should be used within 15 minutes after mixing.

NexoBrid will be applied to a wound area that is clean, blister free, and moist.

Other medicines (such as silver sulfadiazine or povidone-iodine) will be removed from the wound area before NexoBrid is applied.
Before NexoBrid application, a dressing soaked with an antibacterial solution will be applied for 2 hours.
You will be given appropriate medicine to prevent and treat pain at least 15 minutes before NexoBrid is applied and before removal.
After NexoBrid and the dead tissue have been removed from the wound, a dressing soaked with an antibacterial solution will be applied for an additional 2 hours.
The vial containing NexoBrid powder, gel bottle, and the prepared NexoBrid gel should only be used for one patient.

If too much NexoBrid is used

If too much NexoBrid gel is applied on a burn wound, excess gel may be wiped off.

If you have any further questions on the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions to NexoBrid can occur and can cause, for example, breathing difficulties, swelling of the skin, hives, redness of the skin, low blood pressure, fast heart rate and sickness/vomiting/stomach cramp, or a combination of such effects. If you notice any of these symptoms or signs, inform your doctor or caregiver immediately.

Very common side effects (may affect more than 1 in 10 people)

Fever
Common side effects (may affect up to 1 in 10 people) Pain (even if medicines are used to prevent or lessen pain caused by the removal of burnt tissue)
- Infection of the burn wound
- Complications of the wound including wound opening, wounds drying out and breaking down, failure of skin grafts to heal properly, and Non serious allergic reactions such as rash.
- Rapid heartbeat

Side effects with unknown frequency (cannot be estimated from the available data)

Serious allergic reactions including anaphylaxis

Reporting of side effects:

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via:

Ireland:

HPRA Pharmacovigilance

Website: www.hpra.ie

UK:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Malta:

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

By reporting side effects you can help provide more information on the safety of this medicine.

5. How NexoBrid is stored

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 box after “EXP”. The expiry date refers to the last day of that month. Eng Package leaflet: Information for the user

NexoBrid 2 g powder and gel for gel

Concentrate of proteolytic enzymes enriched in bromelain

The following information is intended for healthcare professionals only:

Preparation and administration

From a microbiological point of view and as the enzymatic activity of the product decreases progressively following mixing, the reconstituted product should be used immediately after preparation (within 15 minutes).

NexoBrid should be applied to a clean, keratin-free (blisters removed), and moist wound area.

Topically applied medicinal products (such as silver sulfadiazine or povidone-iodine) at the wound site must be removed and the wound must be cleansed prior to NexoBrid application.

Preparation of patient and wound area

A total wound area of not more than 15% TBSA can be
treated by NexoBrid.
Enzymatic debridement is a painful procedure and
requires adequate analgesia and/or anaesthesia.
Pain management must be used as commonly practiced
for an extensive dressing change; it should be initiated at least 15 minutes prior to NexoBrid application.
The wound must be cleaned thoroughly and the
superficial keratin layer or blisters removed from the wound area, as the keratin will isolate the eschar from direct contact with NexoBrid and prevent eschar removal by NexoBrid.
Dressing soaked with an antibacterial solution must be
applied for 2 hours.
All topically applied antibacterial medicinal products
must be removed before applying NexoBrid. Remaining antibacterial medicinal products may reduce the activity of NexoBrid by decreasing its efficacy.
The area from which you wish to remove the eschar
must be surrounded with a sterile paraffin ointment adhesive barrier by applying it a few centimetres outside of the treatment area (using a dispenser). The paraffin layer must not come into contact with the area to be
treated in order to avoid covering the eschar, thus isolating the eschar from direct contact with NexoBrid.
- To prevent possible irritation of abraded skin by
  inadvertent contact with NexoBrid, and possible bleeding from the wound bed, acute wound areas such as lacerations or escharotomy incisions should be protected by a layer of a sterile fatty ointment or fatty dressing (e.g. petrolatum gauze).
- Sterile isotonic sodium chloride 9 mg/ml (0.9%) solution
  must be sprinkled on the burn wound. The wound must be kept moist during the application procedure.

NexoBrid gel preparation (mixing powder with gel)

The NexoBrid powder and gel are sterile. Aseptic technique
must be used when mixing NexoBrid powder with the gel. The powder should not be inhaled. Wearing of gloves and protective clothing as well as eye shielding glasses and surgical mask, is required.
The NexoBrid powder vial must be opened by carefully
tearing off the aluminium cap and removing the rubber stopper.
When opening the gel bottle, it must be confirmed that the
tamper-evident ring is separating from the bottle’s cap. If the tamper-evident ring was already separated from the cap before opening, the gel bottle must be discarded and another, new gel bottle used.
NexoBrid powder is then transferred into the corresponding
gel bottle.
NexoBrid powder and gel must be mixed thoroughly until
a uniform, slightly tan to slightly brown mixture is obtained. This usually requires mixing the NexoBrid powder and the gel for 1 to 2 minutes.
NexoBrid gel should be prepared at the patient’s bedside.

NexoBrid application

Moisten the area to be treated by sprinkling sterile saline
onto the area bordered by the fatty ointment adhesive barrier.
Within 15 minutes of mixing, NexoBrid must be applied
topically to the burn wound, at a thickness of 1.5 to 3 millimetres.
- The wound must then be covered with a sterile occlusive film
  dressing that adheres to the sterile adhesive barrier material applied as per the instruction above (see Preparation of patient and wound area). The NexoBrid gel should fill the entire occlusive dressing, and special care should be taken not to leave air under this occlusive dressing. Gentle pressing of the occlusive dressing at the area of contact with the adhesive barrier will ensure adherence between the occlusive film and the barrier and achieve complete containment of NexoBrid on the treatment area.
- The dressed wound must be covered with a loose, thick
  fluffy dressing, held in place with a bandage.
- The dressing must remain in place for 4 hours.

Removal of NexoBrid

Removal of NexoBrid is a painful procedure and requires
adequate analgesia and/or anaesthesia. Appropriate preventive analgesia medicinal products must be administered at least 15 minutes prior to NexoBrid application.
After 4 hours of NexoBrid treatment, the occlusive dressing
must be removed using aseptic techniques.
The adhesive barrier must be removed using a sterile blunt-
edged instrument (e.g., tongue depressor).
The dissolved eschar must be removed from the wound by
wiping it away with a sterile blunt-edged instrument.
The wound must be wiped thoroughly first with a large sterile
dry gauze or napkin, followed by a sterile gauze or napkin that has been soaked with sterile isotonic sodium chloride 9 mg/ml (0.9%) solution. The treated area must be rubbed until the appearance of a pinkish surface with bleeding points or a whitish tissue. Rubbing will not remove adhering undissolved eschar in areas where the eschar still remains.
A dressing soaked with an antibacterial solution must be
applied for an additional 2 hours.

Wound care after debridement

The debrided area must be covered immediately by
temporary or permanent skin substitutes or dressings to prevent desiccation and/or formation of pseudoeschar and/or infection.
- Before a permanent skin cover or temporary skin substitute is applied to a freshly enzymatically debrided area, a soaking wet-to-dry dressing should be applied.
- Before application of the grafts and primary dressing, the debrided bed must be cleaned and refreshed by, e.g., brushing or scraping to allow dressing adherence.
- Wounds with areas of full thickness and deep burn should be autografted as soon as possible after NexoBrid debridement. Careful consideration should also be given to placing permanent skin covers (e.g. autografts) on deep partial thickness wounds soon after NexoBrid debridement.

Recommendations for safe handling

Each NexoBrid vial, gel, or reconstituted gel should be used for a single patient only.

There are reports of occupational exposure to bromelain leading to sensitisation. 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, angiooedema, urticaria, and mucosal and gastrointestinal reactions. When mixing NexoBrid powder with the gel, appropriate handling, including wearing of gloves and protective clothing as well as eye shielding glasses and surgical mask, is required. The powder should not be inhaled.

Avoid accidental eye exposure. In case of eye exposure, irrigate exposed eyes with copious amounts of water for at least 15 minutes. In case of skin exposure, rinse NexoBrid off with water.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

Store and transport refrigerated (2°C-8°C).

NexoBrid must be stored upright to keep the gel at the bottom of the bottle and in the original package to protect from light.

Do not freeze.

NexoBrid should be used within 15 minutes after mixing the powder with the gel.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What NexoBrid contains

The active substance (in the powder in the vial) is a concentrate of proteolytic enzymes enriched in bromelain: 2 g, corresponding to 0.09 g/g concentrate of proteolytic enzymes enriched in bromelain after mixing. The other ingredients are: for the powder: ammonium sulphate and acetic acid and for the gel carbomer 980, disodium phosphate anhydrous, sodium hydroxide, and water for injections.

What NexoBrid looks like and contents of the pack

NexoBrid is provided as a powder and gel for gel (powder in a vial (2 g) and gel in a bottle (20 g)), pack size of 1 (a pack contains one vial of powder and one bottle of gel)

The powder is off-white to light tan and the gel is clear and colourless.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

MediWound Germany GmbH

Hans-Sachs-Strasse 100

65428 Rüsselsheim

Germany

e-mail: info@mediwound.com

Manufacturer:

HÄLSA Pharma GmbH

Hafenweg 18-20

48155 Münster