NexoBrid

1 

   

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

 

  



2 

 This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

NexoBrid 2 g powder and gel for gel 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

One vial contains 2 g of concentrate of proteolytic enzymes enriched in bromelain, corresponding to 

0.09 g/g concentrate of proteolytic enzymes enriched in bromelain after mixing (or 2 g/22 g gel). 

 

The proteolytic enzymes are a mixture of enzymes from the stem of Ananas comosus (pineapple 

plant). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Powder and gel for gel. 

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

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

NexoBrid is indicated for removal of eschar in adults with deep partial- and full-thickness thermal 

burns. 

 

4.2 Posology and method of administration 
 

NexoBrid should only be applied by trained healthcare professionals in specialist burn centres. 

 

Posology 

2 g NexoBrid powder in 20 g gel is applied to a burn wound area of 100 cm2. 

 

NexoBrid should not be applied to more than 15% Total Body Surface Area (TBSA) (see also section 

4.4, Coagulopathy). 

 

NexoBrid should be left in contact with the burn for a duration of 4 hours. There is very limited 

information on the use of NexoBrid on areas where eschar remained after the first application. 

A second and subsequent application is not recommended. 

 

Special populations 

 

Renal impairment 

There is no information on the use of NexoBrid in patients with renal impairment. These patients 

should be carefully monitored. 

 

Hepatic impairment 

There is no information on the use of NexoBrid in patients with hepatic impairment.  These patients 

should be carefully monitored. 

 



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Elderly patients 

Experience with NexoBrid in elderly patients (>65 years) is limited. Benefit/risk assessment should 

include consideration of the greater frequency of concomitant disease or other medicinal product 

therapy in the elderly. No dose adjustment is required. 

 

Paediatric population 

The safety and efficacy of NexoBrid in children and adolescents younger than 18 years have not yet 

been established. Currently available data are described in section 4.8 and 5.1 but no recommendation 

on a posology can be made. 

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

 

Method of administration 

 

Cutaneous use. 

 

Before use, the powder must be mixed with the gel producing a uniform gel. 

 

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. 

See section 6.6 for instructions on NexoBrid gel preparation. 

 

Preparation of patient and wound area 

A total wound area of not more than 15% TBSA can be treated with NexoBrid (see also section 4.4, 

Coagulopathy). 

 

 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 interfere with 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 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 application 

 Within 15 minutes of mixing, NexoBrid must be applied topically to the moistened 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 must 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 sterile adhesive barrier and achieve complete containment of NexoBrid on the treatment 

area. 



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 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 

 Appropriate preventive analgesia medicinal products must be administered. 

 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 must be applied.  

 Before application of the grafts or 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. 

 See section 4.4. 

 

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

 

4.3 Contraindications 
 

Hypersensitivity to the active substance, to pineapples or papain (see also section 4.4), or to any of the 

excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

Concentrate of proteolytic enzymes enriched in bromelain is systemically absorbed from burn wound 

areas (see section 5.2). 

 

NexoBrid is not recommended for use on: 

- penetrating burn wounds where foreign materials (e.g. implants, pacemakers, and shunts) and/ 
or vital structures (e.g. larger vessels, eyes) are or could become exposed during debridement. 

- chemical burn wounds. 
- wounds contaminated with radioactive and other hazardous substances to avoid unforeseeable 

reactions with the product and an increased risk of spreading the noxious substance. 

 

Use in patients with cardiopulmonary and pulmonary disease 

NexoBrid should be used with caution in patients with cardiopulmonary and pulmonary disease, 

including pulmonary burn trauma and suspected pulmonary burn trauma. 

 

General principles of proper burn wound care must be adhered to when using NexoBrid. This includes 

proper wound cover for the exposed tissue. 



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Burns for which there is limited or no experience 

 

There is no experience of the use of NexoBrid on: 

- perineal and genital burns. 
- electrical burns. 
 

There is limited information on the use of NexoBrid on facial burn wounds. 

 

NexoBrid must be used with caution in such patients. Eyes should be carefully protected during 

treatment of facial burns using adhesive barrier petroleum ointment.  

 

There is limited pharmacokinetic data in patients with TBSA of more than 15%. Due to safety 

considerations (see also section 4.4, Coagulopathy) NexoBrid should not be applied to more than 

15%Total Body Surface Area (TBSA). 

 

Prevention of wound complications 

 

In NexoBrid studies wounds with visible dermal remnants were allowed to heal by spontaneous 

epithelialisation. In several cases adequate healing did not occur and autografting was required at a 

later date, leading to significant delays in wound closure which is associated with increased risk of 

wound-related complications. Therefore, wounds with areas of full-thickness and deep burn should be 

autografted as soon as possible after NexoBrid debridement (see section 5.1 for study results). Careful 

consideration should also be given to placing permanent skin covers (e.g. autografts) on deep partial 

thickness wounds soon after NexoBrid debridement. See also section 4.2 and 4.8. 

As in the case of surgically debrided bed, in order to prevent desiccation and/or formation of 

pseudoeschar and/or infection, the debrided area should be covered immediately by temporary or 

permanent skin substitutes or dressings. When applying a permanent skin cover (e.g., autograft) or 

temporary skin substitute (e.g., allograft) to a freshly enzymatically debrided area, care should be 

taken to clean and refresh the debrided bed by, e.g., brushing or scraping to allow dressing adherence. 

 

Eye protection 

 

Direct contact with the eyes should be avoided. If there is a risk of eye contact, the patient’s eyes 

should be protected with fatty ophthalmic ointment. 

In case of eye exposure, irrigate exposed eyes with copious amounts of water for at least 15 minutes.  

 

Hypersensitivity reactions, skin exposure 

 

There have been reports of serious allergic reactions including anaphylaxis (with manifestations such 

as rash, erythema, hypotension, tachycardia) in patients undergoing debridement with NexoBrid.  

Allergic reactions to bromelain have been reported in the literature (including anaphylactic reactions 

and other immediate-type reactions with manifestations such as bronchospasm, angiooedema, urticaria, 

and mucosal and gastrointestinal reactions). In addition, a delayed-type allergic skin reaction (cheilitis) 

after longer-term dermal exposure (mouthwash) as well as suspected sensitisation following oral 

exposure and following repeated occupational airway exposure have been reported.  

  

The potential of NexoBrid (a protein product) to cause sensitisation should be taken into account when 

re-exposing patients to bromelain-containing products at a later point in time. The use of NexoBrid in 

subsequent burn injury is not recommended. 

 

In case of skin exposure, NexoBrid should be rinsed off with water to reduce the likelihood of skin 

sensitisation (see section 6.6). 

 

Cross-sensitivity 

 



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Cross-sensitivity between bromelain and papain as well as latex proteins (known as latex-fruit 

syndrome), bee venom, and olive tree pollen has been reported in the literature. 

 

Coagulopathy 

 

It is not known if NexoBrid application has any clinically relevant effect on haemostasis. 

An increase in heart rate (including tachycardia), reduction of platelet aggregation and plasma 

fibrinogen levels and a moderate increase in partial thromboplastin and prothrombin times have been 

reported in the literature as possible effects following oral administration of bromelain. In vitro and 

animal data suggest that bromelain can also promote fibrinolysis. During the clinical development of 

NexoBrid, there was no indication of an increased bleeding tendency or bleeding at the site of 

debridement.  

 

NexoBrid should be used with caution in patients with disorders of coagulation, low platelet counts 

and increased risk of bleeding from other causes e.g. peptic ulcers and sepsis. 

Patients should be monitored for possible signs of coagulation abnormalities. 

 

Monitoring 

 

In addition to routine monitoring for burn patients (e.g., vital signs, volume/water/electrolyte status, 

complete blood count, serum albumin and hepatic enzyme levels), patients treated with NexoBrid 

should be monitored for: 

- Rise in body temperature.  
- Signs of local and systemic inflammatory and infectious processes.  
- Conditions that could be precipitated or worsened by analgesic premedication (e.g., gastric 

dilatation, nausea and risk of sudden vomiting, constipation) or antibiotic prophylaxis (e.g., 

diarrhoea).  

- Signs of local or systemic allergic reactions. 
- Potential effects on haemostasis (see above). 
 

Removal of topically applied antibacterial medicinal products before NexoBrid application 

 

All topically applied antibacterial medicinal products must be removed before applying NexoBrid. 

Remaining antibacterial medicinal products may interfere with the activity of NexoBrid by decreasing 

its efficacy. 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

No interaction studies with NexoBrid have been performed.  

 

Reduction of platelet aggregation and plasma fibrinogen levels and a moderate increase in partial 

thromboplastin and prothrombin times have been reported as possible effects following oral 

administration of bromelain. In vitro and animal data suggest that bromelain can also promote 

fibrinolysis. Caution and monitoring is therefore needed when prescribing concomitant medicinal 

products that affect coagulation. See also section 4.4. 

 

NexoBrid, when absorbed, is an inhibitor of cytochrome P 450 2C8 (CYP2C8) and P450 2C9 

(CYP2C9). This should be taken into account if NexoBrid is used in patients receiving CYP2C8 

substrates (including amiodarone, amodiaquine, chloroquine, fluvastatin, paclitaxel, pioglitazone, 

repaglinide, rosiglitazone, sorafenib and torasemide) and CYP2C9 substrates (including ibuprofen, 

tolbutamide, glipizide, losartan, celecoxib, warfarin, and phenytoin).  

 

Topically applied antibacterial medicinal products (e.g. silver sulfadiazine or povidone iodine) may 

decrease the efficacy of NexoBrid (see section 4.4). 

 

Bromelain may enhance the actions of fluorouracil and vincristine. Patients should be monitored for 

increased toxicity. 



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Bromelain may enhance the hypotensive effect of ACE inhibitors, causing larger decreases in blood 

pressure than expected. Blood pressure should be monitored in patients receiving ACE inhibitors  

 

Bromelain may increase drowsiness caused by some medicinal products (e.g., benzodiazepines, 

barbiturates, narcotics and antidepressants). This should be taken into account when dosing such 

products. 

 

 

4.6 Fertility, pregnancy and lactation 
 

Pregnancy 

 

There are no data from the use of NexoBrid in pregnant women. 
Animal studies are insufficient to properly assess the potential of NexoBrid to interfere with 

embryonal/foetal development (see section 5.3). 

 

Since the safe use of NexoBrid during pregnancy has not yet been established, NexoBrid is not 

recommended during pregnancy. 

 

Breastfeeding 

 

It is unknown whether concentrate of proteolytic enzymes enriched in bromelain or its metabolites are 

excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be 

discontinued at least 4 days from  NexoBrid application initiation. 

Fertility 

 

No studies were performed to assess the effects of NexoBrid on fertility. 

 

4.7 Effects on ability to drive and use machines 
 

Not relevant. 

 

4.8 Undesirable effects 
 

Summary of the safety profile 

 

The most commonly reported adverse reactions of the use of NexoBrid are local pain and transient 

pyrexia/hyperthermia. When NexoBrid was used in a regimen which included recommended 

preventive analgesia as routinely practiced for extensive dressing changes in burn patients as well as 

antibacterial soaking of the treatment area before and after NexoBrid application (see section 4.2), 

pain was reported in 3.6% of patients, pyrexia/hyperthermia in 19.1% of patients. The frequency of 

pain and pyrexia/hyperthermia was higher without these precautionary measures (see below). 

 

Tabulated list of adverse reactions 

 

The following definitions apply to the frequency terminology used hereafter: 

Very common (≥1/10) 

Common (≥1/100 to <1/10) 

Uncommon (1/1,000 to <1/100) 

Rare (1/10,000 to <1/1,000) 

Very rare (<1/10,000) 

Not known (cannot be estimated from the available data). 

 

The frequencies of the adverse reactions presented below reflect the use of NexoBrid to remove eschar 

from deep partial- or full-thickness burns in a regimen with local antibacterial prophylaxis, 



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recommended analgesia, as well as coverage of the wound area after application of NexoBrid for 

4 hours with an occlusive dressing for containment of NexoBrid on the wound. 

 

An asterisk (*) indicates that additional information on the respective adverse reaction is provided 

below the list of adverse reactions. 

 

Infections and infestations 

Common:  Wound infection 

 

Skin and subcutaneous tissue disorders/  

Common:  Wound complication* 

 

General disorders and administration site conditions 

Very common: Pyrexia/hyperthermia*  

Common: Local pain*  

 

Immune system disorders 

Not known:   Serious allergic reactions including anaphylaxis  

 

 

Description of selected adverse reactions 

 

Pyrexia/hyperthermia  

In studies implementing routine antibacterial soaking of the treatment area before and after NexoBrid 

application (see section 4.2) pyrexia or hyperthermia was reported in 19.1% of patients treated with 

NexoBrid and in 15.8% of the control patients treated according standard of care. In the NexoBrid 

group, the event was graded as mild, moderate or severe in 9.1%, 9.1%, and 0% of patients, 

respectively. 

In studies without antibacterial soaking, pyrexia or hyperthermia was reported in 35.6% of NexoBrid-

treated patients compared with 18.6% in control patients. In the NexoBrid group, the event was graded 

as mild, moderate or severe in 30.0%, 5.6% and 1.1% of patients, respectively. 

 

Pain 

In studies where the NexoBrid regimen included recommended preventive analgesia as routinely 

practiced for extensive dressing changes in burn patients (see section 4.2) local pain was reported in 

3.6% of patients treated with NexoBrid and in 4.0% of the control patients treated according to 

standard of care. In the NexoBrid group, the event was graded as mild, moderate or severe in 0.9%, 

0.9%, and 1.8% of patients, respectively. 

In studies where analgesia was provided in NexoBrid-treated patients on an on-demand basis, local 

pain was reported in 23.3% of patients treated with NexoBrid and in 11.4% of the control patients. In 

the NexoBrid group, the event was graded as mild, moderate or severe in 6.7%, 7.8% and 8.9% of 

patients, respectively. 

 

Wound complications 

 

In phase 2 and phase 3 clinical studies, certain types of wound complications were reported more 

frequently in the NexoBrid group than in the group treated according to the study sites’ Standard of 

Care (SOC). These events included: wound deepening or desiccation (decomposition) in 5 patients 

(2.4%) with NexoBrid and 0 with SOC as well as (partial) graft failure in 6 patients (2.9%) with 

NexoBrid and 2 (1.6%) with SOC (see section 4.4). 

 

General infections 

 

In phase 2 and phase 3 clinical studies general infections (not wound related. e.g. urinary tract 

infections, viral infections) were reported more frequently in the NexoBrid group (0.147 events per 

patient) than in the group treated according to SOC (0.079 events per patient). 

 



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Paediatric population 

 

There is only limited safety data from the use in the paediatric population. From these data it is 

expected that the overall safety profile in children 4 years of age and older and in adolescents is 

similar to the profile in adults. 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V 

 

4.9 Overdose 
 

Treatment with concentrate of proteolytic enzymes enriched in bromelain prepared in a powder:gel 

ratio of 1:5 (0.16g per g of mixed gel) in patients with deep partial- and/or full-thickness burns within 

the framework of a clinical study did not result in significantly different safety findings when 

compared to treatment with concentrate of proteolytic enzymes enriched in bromelain prepared in a 

powder:gel ratio of 1:10 (0.09 g per 1g of mixed gel). 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1  Pharmacodynamic properties 
 

Pharmacotherapeutic group: Preparations for treatment of wounds and ulcers, proteolytic enzymes; 

ATC code: D03BA03.  

 

Concentrate of proteolytic enzymes enriched in bromelain is a debriding agent, applied topically for 

removal of eschar in deep partial- and full-thickness burns.  

 

Mechanism of action 

 

The mixture of enzymes in NexoBrid dissolves burn wound eschar. The specific components 

responsible for this effect have not been identified. The major constituent is stem bromelain. 

 

Clinical efficacy 

 

During clinical development, a total of 362 patients were treated with the concentrate of proteolytic 

enzymes enriched in bromelain.  

The efficacy of NexoBrid in humans was evaluated, compared to standard of care, in a randomised, 

multi-centre, multi-national, open-label, confirmatory phase 3 study in hospitalised patients with deep 

partial- and/or full-thickness thermal burns of 5 to 30% Total Body Surface Area (TBSA), but with 

total burn wounds of no more than 30% TBSA. 

 

NexoBrid (2 g/100 cm2, corresponding to 0.02 g/cm2) was used as described in section 4.2. 

 

Standard of care consisted of primary surgical excision and/or nonsurgical debridement using topical 

medicinal products to induce maceration and autolysis of eschar according to each study site’s 

standard practice. 

 

The age range in the group treated with NexoBrid was 4.4 to 55.7 years. The age range in the SOC 

group was 5.1 to 55.7 years.  

 



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The efficacy of eschar removal was evaluated by determining the percentage of wound area left with 

eschar that required further removal by excision or dermabrasion, and the percentage of wounds 

requiring such surgical removal.  

The effect on the timing of eschar removal was evaluated in patients with successful eschar removal 

(with at least 90% eschar removal in all wounds of a patient combined), by determining the time from 

injury as well as from informed consent to successful removal. 

 

The co-primary endpoints for the efficacy analysis were: 

- the percentage of deep partial thickness wounds requiring excision or dermabrasion, and 
- the percentage of deep partial thickness wounds autografted. 
This endpoint can only be evaluated for deep partial-thickness wounds without full-thickness areas 

because full-thickness burns always require grafting. 

 

Efficacy data generated in this study for all age groups combined as well as from a subgroup analysis 

for children and adolescents are summarised below.  

 

 NexoBrid SOC p-value 

Deep partial-thickness wounds requiring excision/dermabrasion (surgery) 

 Number of wounds 106 88  

 % of wounds requiring surgery 15.1% 62.5% <0.0001 

 % of wound area excised or 

dermabraded1 (mean ± SD)  

5.5% ± 14.6 52.0% ± 44.5 <0.0001 

Deep partial-thickness wounds autografted* 

 Number of wounds 106 88  

 % of wounds autografted 17.9% 34.1% 0.0099 

 % of wound area autografted 

(mean ± SD) 

8.4% ± 21.3 21.5% ± 34.8 0.0054 

Deep partial- and/or full-thickness wounds requiring excision/dermabrasion (surgery) 

 Number of wounds 163 170  

 % of wounds requiring surgery 24.5% 70.0% <0.0001 

 % of wound area excised or 

dermabraded1 (mean ± SD)  

13.1% ± 26.9 56.7% ± 43.3 <0.0001 

Time to complete wound closure (time from ICF**) 

 Number of patients2 70 78  

 Days to closure of last wound 

(mean ± SD) 

36.2 ± 18.5 28.8 ± 15.6 0.0185 

Time to successful eschar removal 

 Number of patients 67 73  

  Days (mean ± SD) from 

 injury 

2.2 ± 1.4 8.7 ± 5.7 <0.0001 

 Days (mean ± SD) from 

 consent 

0.8 ± 0.8 6.7 ± 5.8 <0.0001 

Patients not reported to have 

successful eschar removal  

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1 Measured at first session, if there was more than one surgery session.  
2 All randomised patients for whom data for complete wound closure were available.  

*The endpoint can only be evaluated for deep partial-thickness wounds without full-thickness areas 

because full-thickness burns always require grafting. 

** Informed Consent Form 

 

The following table shows results in mixed wounds. The comparisons in mixed wounds should be 

interpreted with caution since they are based on groups that are not fully randomized and the mixed 

wounds treated by NexoBrid were overall larger and had a larger full thickness area. 

 

Mixed wounds (with partial and full-thickness area) requiring excision/dermabrasion (surgery) 

 NexoBrid SOC 



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(Number of wounds) (Number of wounds) 

% of wounds requiring 

surgery 

41.7% (20/48) 78.3% (47/60) 

% of wound area excised or 

dermabraded 

25.5% (n=48) 64.0% (n=60) 

 

Mixed wounds (with partial and full-thickness area) autografted 

 NexoBrid 

(Number of wounds) 

SOC 

(Number of wounds) 

All mixed burns baseline 

characteristics 

48 wounds 60 wounds 

Size: % mean TBSA  7.43 6.33 

Depth:    

  Superficial (%TBSA) 0.67 0.92 

  DPT (% TBSA) 3.85 3.13 

  FT    (% TBSA) 2.90 2.29 

Incidence of autograft 70.8% (34/48) 63.3% (38/60)  

% wound area autografted  55.5% (n=48) 45.8% (n=60)  

 

The following table shows the time to complete wound closure from start of debridement.* 

 

Wound Type  NexoBrid  SOC  

 Days (mean ± SD) 

(Number of wounds)  

Days (mean ± SD) 

(Number of wounds) 

All wounds (ITT1) 30.5 ± 16.9 

(154) 

26.1 ± 16.0  

(164)  

Non-autografted wounds (ITT) 23.9 ± 13.0 

(95) 

24.5 ± 14.1 

(85) 

Autografted wounds (ITT) 41.0 ± 17.3 

(59) 

27.8 ± 17.7 

(79) 

Deep Partial Thickness wounds 26.6 ± 15.4 

(101) 

23.7 ± 13.6 

(87) 

Full Thickness wounds 

 

31.9 ± 10.1 

(7) 

36.3 ± 26.0 

(14) 

Mixed wounds 

(deep partial and full thickness)  

40.2 ± 17.1 

(44) 

27.7 ± 15.8 

(59) 

Non-autografted mixed wounds 29.5 ± 12.1 

(11) 

30.3 ± 15.5 

(22) 

Autografted mixed wounds 43.7 ± 17.3 

(33) 

26.2 ± 16.0 

(37) 

*These comparisons should be interpreted with caution since they are based on groups  

that are not fully randomized. 

1 ITT (Intent To Treat population): all randomized patients 

The difference in time to complete wound closure is mainly related to the wound care strategy applied 

by the physician, where an attempt to minimise grafting and allow for spontaneous epithelialisation of 

the wound areas that still have dermis may prolong time to first autograft (time to autograft: NexoBrid: 

14.7 days vs. SOC: 5.9 days) and hence prolong complete wound closure. 

 

Paediatric population 



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Efficacy data generated in this study from a subgroup analysis for children and adolescents are 

summarised below. The available data are limited and NexoBrid should not be used in patients 

younger than 18 years.  

 

 NexoBrid SOC p-value 

Deep partial-thickness wounds requiring excision/dermabrasion (surgery) 

 Number of wounds 23 22  

 % of wounds requiring surgery 21.7% 68.2% 0.0017 

 % of wound area excised or 

dermabraded1 (mean ± SD)  

7.3% ± 15.7% 64.9% ± 46.4% <0.0001 

Deep partial-thickness wounds autografted* 

 Number of wounds 23 22  

 % of wounds autografted 21.7% 31.8% 0.4447 

 % of wound area autografted 

(mean ± SD) 

6.1% ± 14.7% 24.5% ± 40.6% 0.0754 

Deep partial- and/or full-thickness wounds requiring excision/dermabrasion (surgery) 

 Number of wounds 29 41  

 % of wounds requiring surgery 20.7% 78% <0.0001 

 % of wound area excised or 

dermabraded1 (mean ± SD)  

7.9% ± 17.6% 73.3% ± 41.1% <0.0001 

Time to complete wound closure (time from ICF**) 

 Number of patients2 14 15  

 Days to closure of last wound 

(mean ± SD) 

29.9 ± 14.3 32.1 ± 18.9 0.6075 

Time to successful eschar removal 

 Number of patients 14 15  

  Days (mean ± SD) from 

 injury 

1.9 ± 0.8 8.1 ± 6.3 <0.0001 

 Days (mean ± SD) from 

 consent 

0.9 ± 0.7 6.5 ± 5.9 <0.0001 

Patients not reported to have 

successful eschar removal  

0 1  

1 Measured at first session, if there was more than one surgery session.  
2 All randomised patients for whom data for complete wound closure were available.  

*The endpoint can only be evaluated for deep partial-thickness wounds without full-thickness areas 

because full-thickness burns always require grafting. 

** Informed Consent Form 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

NexoBrid in one or more subsets of the paediatric population in the treatment of burns of external 

body surface (see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

  

Absorption  

The extent of systemic absorption from a burn wound, Cmax, Tmax, AUC, and t½ of bromelain from 

NexoBrid have been investigated in 16 burn patients with partial-thickness (mid- and deep-dermal) 

thermal burns. Average TBSA was 10%. 60% of the treated wounds area was partial thickness and/or 

full thickness. NexoBrid was applied once to the burn wound at a dose of 2 g NexoBrid Powder/20 g 

gel/100 cm2 of skin. 

NexoBrid serum concentrations were determined using a modified sandwich 

electrochemiluminescence (ECL) immunoassay. 

 

The range of total dose applied was 5 to 30 g concentrate of proteolytic enzymes enriched in 

bromelain from NexoBrid. In 4 patients, having received a dose of 5, 9, 12 and 17 g, respectively, 

there were indications of markedly higher systemic absorption. 



13 

 

Cmax was 6020 ± 5020 ng/ml (mean ± SD) for the group of 15 patients, with a range of 888 to 

15,700 ng/ml. In the 4 patients with indications of higher absorption, dose-normalised Cmax ranged 

from 788-900 ng/ml per gram of NexoBrid. In the other patients, dose-normalised Cmax ranged from 

141-523 ng/ml per gram of NexoBrid. 

 

A Cmax of 40µg/ml may be possible in humans administered NexoBrid under licensed conditions, 

when it is considered that PK has only been evaluated in patients with largely superficial burns, 

receiving half the maximum dose. 

 

The AUC from time zero to 48 hours after administration (AUClast) was 43,400 ± 46,100 ngh/ml 

(mean ± SD) for the group of 15 patients, with a range of 4560-167,000 ngh/ml. In the patients with 

indications of higher absorption, dose-normalised (per gram of NexoBrid) AUClast ranged from 

4500-9820 ngh/ml per gram of NexoBrid. In the other patients, dose-normalised AUClast ranged from 

887-3930 ngh/ml per gram of NexoBrid. 

 

These results for Cmax and AUClast indicate that systemic absorption may depend both on the applied 

NexoBrid dose (proportional to the covered wound area) and other, patient-specific factors. 

 

Tmax for 10 of the 15 patients was 2 hours and in 5 patients Tmax was 4 hours. 

 

Distribution  

 

According to a literature report, in plasma, approximately 50% of bromelain binds to the human 

plasma antiproteinases α2-macroglobulin and α1-antichymotrypsin. 

 

Elimination:  

Terminal half-life (determined using data from 16 to 48 hours post-dose for 12 patients) was 

11.7 ± 3.5 hours (mean ± SD), with a range from 8.5 to 19.9 hours. 

 

Paediatric population 

Pharmacokinetic parameters and the extent of absorption have not been studied in children. 

 

5.3 Preclinical safety data 
 

NexoBrid was well tolerated when applied to intact mini-pig skin but caused severe irritation and pain 

when applied to damaged (abraded) skin. 

A single intravenous infusion of a solution prepared from NexoBrid powder in the mini-pig was well 

tolerated at dose levels of up to 12 mg/kg (achieving plasma levels 2.5fold of the human plasma level 

after application of the clinical proposed dosage to 15% TBSA) but higher doses were overtly toxic, 

causing haemorrhage in several tissues. Repeated intravenous injections of doses up to 12 mg/kg every 

third day in the mini-pig were well tolerated for the first three injections but severe clinical signs of 

toxicity (e.g. haemorrhages in several organs) were observed following the remaining three injections. 

Such effects could still be seen after the recovery period of 2 weeks. 

In embryo-foetal development studies in rats and rabbits, intravenously administered NexoBrid 

revealed no evidence of indirect and direct toxicity to the developing embryo/foetus. However, 

maternal exposure levels were considerably lower than those maximally reported in clinical setting 

(10–500 times lower than human AUC, 3–50 times lower than the human Cmax). Since NexoBrid was 

poorly tolerated by the parent animals, these studies are not considered relevant for human risk 

assessment. NexoBrid showed no genotoxic activity when investigated in the standard set of in vitro 

and in vivo studies. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 



14 

NexoBrid powder 

Ammonium sulphate  

Acetic acid  

 

Gel 

Carbomer 980 

disodium phosphate anhydrous 

Sodium hydroxide  

Water for injections 

 

6.2 Incompatibilities 
 

Topically applied medicinal products (such as silver sulfadiazine or povidone-iodine) at the wound 

site must be removed and the wound cleansed prior to NexoBrid application. Remaining antibacterial 

medicinal products may interfere with the activity of NexoBrid by decreasing its efficacy. 

 

This medicinal product must not be mixed with other medicinal products. 

 

6.3 Shelf life 
 

3 years. 

 

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). 

 

6.4 Special precautions for storage 
 

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

 

Store upright to keep the gel at the bottom of the bottle and in the original package to protect from 

light. 

 

Do not freeze. 

 

6.5 Nature and contents of container 
 

2 g powder in a vial (glass type II) sealed with a rubber (bromobutyl), stopper and covered with a cap 

(aluminium), and 20 g gel in a bottle (borosilicate, glass type I), sealed with a rubber stopper and 

covered with a screw cap (tamper-proof polypropylene). 

 

Pack size of 1 vial of powder and 1 bottle of gel. 

 

6.6 Special precautions for disposal and other handling 
 

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. This should be considered when 

mixing NexoBrid powder with the gel. The powder should not be inhaled.. See also section 4.4.  

 

Accidental eye exposure must be avoided. In case of eye exposure, exposed eyes must be irrigated 

with copious amounts of water for at least 15 minutes. In case of skin exposure, NexoBrid must be 

rinsed off with water. 

 

NexoBrid gel preparation (mixing powder with gel) 

 

DGD (N=49) 



15 

 The NexoBrid powder and gel are sterile. An aseptic technique must be used when mixing the 
powder with the gel. 

 The 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. 

 The powder is then transferred into the corresponding gel bottle.  

 Powder and gel must be mixed thoroughly until a uniform, slightly tan to slightly brown mixture 
is obtained. This usually requires mixing the powder and the gel for 1 to 2 minutes. 

 The gel should be prepared at the patient’s bedside. 
 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

MediWound Germany GmbH 

Eisenstrasse 5 

65428 Rüsselsheim 

Germany 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/803/001 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 18.12.2012 

 

Date of latest renewal: 10.11.2017 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

  



16 

 This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

NexoBrid 5 g powder and gel for gel 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

One vial contains 5 g of concentrate of proteolytic enzymes enriched in bromelain, corresponding to 

0.09 g/g concentrate of proteolytic enzymes enriched in bromelain after mixing (or 5 g/55 g gel). 

 

The proteolytic enzymes are a mixture of enzymes from the stem of Ananas comosus (pineapple 

plant). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Powder and gel for gel. 

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

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

NexoBrid is indicated for removal of eschar in adults with deep partial- and full-thickness thermal 

burns. 

 

4.2 Posology and method of administration 
 

NexoBrid should only be applied by trained healthcare professionals in specialist burn centres. 

 

Posology 

5 g NexoBrid powder in 50 g gel is applied to a burn wound area of 250 cm2.  

 

NexoBrid should not be applied to more than 15% Total Body Surface Area (TBSA) (see also section 

4.4, Coagulopathy). 

 

NexoBrid should be left in contact with the burn for a duration of 4 hours. There is very limited 

information on the use of NexoBrid on areas where eschar remained after the first application. 

A second and subsequent application is not recommended. 

 

Special populations 

 

Renal impairment 

There is no information on the use of NexoBrid in patients with renal impairment. These patients 

should be carefully monitored. 

 

Hepatic impairment 

There is no information on the use of NexoBrid in patients with hepatic impairment. These patients 

should be carefully monitored. 

 



17 

Elderly patients 

Experience with NexoBrid in elderly patients (>65 years) is limited. Benefit/risk assessment should 

include consideration of the greater frequency of concomitant disease or other medicinal product 

therapy in the elderly. No dose adjustment is required. 

 

Paediatric population 

The safety and efficacy of NexoBrid in children and adolescents younger than 18 years have not yet 

been established. Currently available data are described in section 4.8 and 5.1 but no recommendation 

on a posology can be made. 

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

 

Method of administration 

 

Cutaneous use. 

 

Before use, the powder must be mixed with the gel producing a uniform gel. 

 

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. 

See section 6.6 for instructions on NexoBrid gel preparation. 

 

Preparation of patient and wound area 

A total wound area of not more than 15% TBSA can be treated with NexoBrid (see also section 4.4, 

Coagulopathy). 

 

 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 interfere with 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 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 application 

 Within 15 minutes of mixing, NexoBrid must be applied topically to the moistened 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 must 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 sterile adhesive barrier and achieve complete containment of NexoBrid on the treatment 

area. 



18 

 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 

 Appropriate preventive analgesia medicinal products must be administered. 

 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 must be applied.  

 Before application of the grafts or 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. 

 See section 4.4. 

 

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

 

4.3 Contraindications 
 

Hypersensitivity to the active substance, to pineapples or papain (see also section 4.4), or to any of the 

excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

Concentrate of proteolytic enzymes enriched in bromelain is systemically absorbed from burn wound 

areas (see section 5.2). 

 

NexoBrid is not recommended for use on: 

- penetrating burn wounds where foreign materials (e.g. implants, pacemakers, and shunts) and/ 
or vital structures (e.g. larger vessels, eyes) are or could become exposed during debridement. 

- chemical burn wounds. 
- wounds contaminated with radioactive and other hazardous substances to avoid unforeseeable 

reactions with the product and an increased risk of spreading the noxious substance. 

 

Use in patients with cardiopulmonary and pulmonary disease 

NexoBrid should be used with caution in patients with cardiopulmonary and pulmonary disease, 

including pulmonary burn trauma and suspected pulmonary burn trauma. 

 

General principles of proper burn wound care must be adhered to when using NexoBrid. This includes 

proper wound cover for the exposed tissue. 



19 

 

Burns for which there is limited or no experience 

 

There is no experience of the use of NexoBrid on: 

- perineal and genital burns. 
- electrical burns. 
 

There is limited information on the use of NexoBrid on facial burn wounds. 

 

NexoBrid must be used with caution in such patients. Eyes should be carefully protected during 

treatment of facial burns using adhesive barrier petroleum ointment. 

There is limited pharmacokinetic data in patients with TBSA of more than 15%. Due to safety 

considerations (see also section 4.4, Coagulopathy) NexoBrid should not be applied to more than 

15%Total Body Surface Area (TBSA). 

 

Prevention of wound complications 

 

In NexoBrid studies wounds with visible dermal remnants were allowed to heal by spontaneous 

epithelialisation. In several cases adequate healing did not occur and autografting was required at a 

later date, leading to significant delays in wound closure which is associated with increased risk of 

wound-related complications. Therefore, wounds with areas of full-thickness and deep burn should be 

autografted as soon as possible after NexoBrid debridement (see section 5.1 for study results). Careful 

consideration should also be given to placing permanent skin covers (e.g. autografts) on deep partial 

thickness wounds soon after NexoBrid debridement. See also section 4.2 and 4.8. 

As in the case of surgically debrided bed, in order to prevent desiccation and/or formation of 

pseudoeschar and/or infection, the debrided area should be covered immediately by temporary or 

permanent skin substitutes or dressings. When applying a permanent skin cover (e.g., autograft) or 

temporary skin substitute (e.g., allograft) to a freshly enzymatically debrided area, care should be 

taken to clean and refresh the debrided bed by, e.g., brushing or scraping to allow dressing adherence. 

 

Eye protection 

 

Direct contact with the eyes should be avoided. If there is a risk of eye contact, the patient’s eyes 

should be protected with fatty ophthalmic ointment. 

In case of eye exposure, irrigate exposed eyes with copious amounts of water for at least 15 minutes.  

 

Hypersensitivity reactions, skin exposure 

 

There have been reports of serious allergic reactions including anaphylaxis (with manifestations such 

as rash, erythema, hypotension, tachycardia) in patients undergoing debridement with NexoBrid. 

 

Allergic reactions to bromelain have been reported in the literature (including anaphylactic reactions 

and other immediate-type reactions with manifestations such as bronchospasm, angiooedema, urticaria, 

and mucosal and gastrointestinal reactions). In addition, a delayed-type allergic skin reaction (cheilitis) 

after longer-term dermal exposure (mouthwash) as well as suspected sensitisation following oral 

exposure and following repeated occupational airway exposure have been reported..  

 

The potential of NexoBrid (a protein product) to cause sensitisation should be taken into account when 

re-exposing patients to bromelain-containing products at a later point in time. The use of NexoBrid in 

subsequent burn injury is not recommended. 

 

In case of skin exposure, NexoBrid should be rinsed off with water to reduce the likelihood of skin 

sensitisation (see section 6.6). 

 

Cross-sensitivity 

 



20 

Cross-sensitivity between bromelain and papain as well as latex proteins (known as latex-fruit 

syndrome), bee venom, and olive tree pollen has been reported in the literature. 

 

Coagulopathy 

 

It is not known if NexoBrid application has any clinically relevant effect on haemostasis. 

An increase in heart rate (including tachycardia), reduction of platelet aggregation and plasma 

fibrinogen levels and a moderate increase in partial thromboplastin and prothrombin times have been 

reported in the literature as possible effects following oral administration of bromelain. In vitro and 

animal data suggest that bromelain can also promote fibrinolysis. During the clinical development of 

NexoBrid, there was no indication of an increased bleeding tendency or bleeding at the site of 

debridement.  

 

NexoBrid should be used with caution in patients with disorders of coagulation, low platelet counts 

and increased risk of bleeding from other causes e.g. peptic ulcers and sepsis. 

Patients should be monitored for possible signs of coagulation abnormalities. 

 

Monitoring 

 

In addition to routine monitoring for burn patients (e.g., vital signs, volume/water/electrolyte status, 

complete blood count, serum albumin and hepatic enzyme levels), patients treated with NexoBrid 

should be monitored for: 

- Rise in body temperature.  
- Signs of local and systemic inflammatory and infectious processes.  
- Conditions that could be precipitated or worsened by analgesic premedication (e.g., gastric 

dilatation, nausea and risk of sudden vomiting, constipation) or antibiotic prophylaxis (e.g., 

diarrhoea).  

- Signs of local or systemic allergic reactions. 
- Potential effects on haemostasis (see above). 
 

Removal of topically applied antibacterial medicinal products before NexoBrid application 

 

All topically applied antibacterial medicinal products must be removed before applying NexoBrid. 

Remaining antibacterial medicinal products may interfere with the activity of NexoBrid by decreasing 

its efficacy. 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

No interaction studies with NexoBrid have been performed.  

 

Reduction of platelet aggregation and plasma fibrinogen levels and a moderate increase in partial 

thromboplastin and prothrombin times have been reported as possible effects following oral 

administration of bromelain. In vitro and animal data suggest that bromelain can also promote 

fibrinolysis. Caution and monitoring is therefore needed when prescribing concomitant medicinal 

products that affect coagulation. See also section 4.4. 

 

NexoBrid, when absorbed, is an inhibitor of cytochrome P 450 2C8 (CYP2C8) and P450 2C9 

(CYP2C9). This should be taken into account if NexoBrid is used in patients receiving CYP2C8 

substrates (including amiodarone, amodiaquine, chloroquine, fluvastatin, paclitaxel, pioglitazone, 

repaglinide, rosiglitazone, sorafenib and torasemide) and CYP2C9 substrates (including ibuprofen, 

tolbutamide, glipizide, losartan, celecoxib, warfarin, and phenytoin).  

 

Topically applied antibacterial medicinal products (e.g. silver sulfadiazine or povidone iodine) may 

decrease the efficacy of NexoBrid (see section 4.4). 

 

Bromelain may enhance the actions of fluorouracil and vincristine. Patients should be monitored for 

increased toxicity 



21 

 

Bromelain may enhance the hypotensive effect of ACE inhibitors, causing larger decreases in blood 

pressure than expected. Blood pressure should be monitored in patients receiving ACE inhibitors 

Bromelain may increase drowsiness caused by some medicinal products (e.g., benzodiazepines, 

barbiturates, narcotics and antidepressants). This should be taken into account when dosing such 

products 

 

4.6 Fertility, pregnancy and lactation 
 

Pregnancy 

 

There are no data from the use of NexoBrid in pregnant women. 
Animal studies are insufficient to properly assess the potential of NexoBrid to interfere with 

embryonal/foetal development (see section 5.3). 

 

Since the safe use of NexoBrid during pregnancy has not yet been established, NexoBrid is not 

recommended during pregnancy. 

 

Breastfeeding 

 

It is unknown whether concentrate of proteolytic enzymes enriched in bromelain or its metabolites are 

excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be 

discontinued at least 4 days from NexoBrid application initiation. 

 

Fertility 

 

No studies were performed to assess the effects of NexoBrid on fertility. 

 

4.7 Effects on ability to drive and use machines 
 

Not relevant. 

 

4.8 Undesirable effects 
 

Summary of the safety profile 

 

The most commonly reported adverse reactions of the use of NexoBrid are local pain and transient 

pyrexia/hyperthermia. When NexoBrid was used in a regimen which included recommended 

preventive analgesia as routinely practiced for extensive dressing changes in burn patients as well as 

antibacterial soaking of the treatment area before and after NexoBrid application (see section 4.2), 

pain was reported in 3.6% of patients, pyrexia/hyperthermia in 19.1% of patients. The frequency of 

pain and pyrexia/hyperthermia was higher without these precautionary measures (see below). 

 

Tabulated list of adverse reactions 

 

The following definitions apply to the frequency terminology used hereafter: 

Very common (≥1/10) 

Common (≥1/100 to <1/10) 

Uncommon (1/1,000 to <1/100) 

Rare (1/10,000 to <1/1,000) 

Very rare (<1/10,000) 

Not known (cannot be estimated from the available data) 

 

The frequencies of the adverse reactions presented below reflect the use of NexoBrid to remove eschar 

from deep partial- or full-thickness burns in a regimen with local antibacterial prophylaxis, 

recommended analgesia, as well as coverage of the wound area after application of NexoBrid for 

4 hours with an occlusive dressing for containment of NexoBrid on the wound. 



22 

 

An asterisk (*) indicates that additional information on the respective adverse reaction is provided 

below the list of adverse reactions. 

 

Infections and infestations 

Common:  Wound infection 

 

Skin and subcutaneous tissue disorders 

Common:  Wound complication* 

 

General disorders and administration site conditions 

Very common: Pyrexia/hyperthermia*  

Common: Local pain*  

 

Immune system disorders 

Not known:   Serious allergic reactions including anaphylaxis  

 

Description of selected adverse reactions 

 

Pyrexia/hyperthermia  

In studies implementing routine antibacterial soaking of the treatment area before and after NexoBrid 

application (see section 4.2) pyrexia or hyperthermia was reported in 19.1% of patients treated with 

NexoBrid and in 15.8% of the control patients treated according standard of care. In the NexoBrid 

group, the event was graded as mild, moderate or severe in 9.1%, 9.1%, and 0% of patients, 

respectively. 

In studies without antibacterial soaking, pyrexia or hyperthermia was reported in 35.6% of NexoBrid-

treated patients compared with 18.6% in control patients. In the NexoBrid group, the event was graded 

as mild, moderate or severe in 30.0%, 5.6% and 1.1% of patients, respectively. 

 

Pain 

In studies where the NexoBrid regimen included recommended preventive analgesia as routinely 

practiced for extensive dressing changes in burn patients (see section 4.2) local pain was reported in 

3.6% of patients treated with NexoBrid and in 4.0% of the control patients treated according to 

standard of care. In the NexoBrid group, the event was graded as mild, moderate or severe in 0.9%, 

0.9%, and 1.8% of patients, respectively. 

In studies where analgesia was provided in NexoBrid-treated patients on an on-demand basis, local 

pain was reported in 23.3% of patients treated with NexoBrid and in 11.4% of the control patients. In 

the NexoBrid group, the event was graded as mild, moderate or severe in 6.7%, 7.8% and 8.9% of 

patients, respectively. 

 

Wound complications 

 

In phase 2 and phase 3 clinical studies, certain types of wound complications were reported more 

frequently in the NexoBrid group than in the group treated according to the study sites’ Standard of 

Care (SOC). These events included: Wound deepening or desiccation (decomposition) in 5 patients 

(2.4%) with NexoBrid and 0 with SOC as well as (partial) graft failure in 6 patients (2.9%) with 

NexoBrid and 2 (1.6%) with SOC (see section 4.4). 
 

General Infections 

 

In phase 2 and phase 3 clinical studies general infections (not wound related. e.g. urinary tract 

infections, viral infections) were reported more frequently in the NexoBrid group (0.147 events per 

patient) than in the group treated according to SOC (0.079 events per patient). 

 

Paediatric population 

 



23 

There is only limited safety data from the use in the paediatric population. From these data it is 

expected that the overall safety profile in children 4 years of age and older and in adolescents is 

similar to the profile in adults. 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V 

 

4.9 Overdose 
 

Treatment with concentrate of proteolytic enzymes enriched in bromelain prepared in a powder:gel 

ratio of 1:5 (0.16g per g of mixed gel) in patients with deep partial- and/or full-thickness burns within 

the framework of a clinical study did not result in significantly different safety findings when 

compared to treatment with concentrate of proteolytic enzymes enriched in bromelain prepared in a 

powder:gel ratio of 1:10 (0.09 g per 1g of mixed gel). 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1  Pharmacodynamic properties 
 

Pharmacotherapeutic group: Preparations for treatment of wounds and ulcers, proteolytic enzymes; 

ATC code: D03BA03 

 

Concentrate of proteolytic enzymes enriched in bromelain is a debriding agent, applied topically for 

removal of eschar in deep partial- and full-thickness burns.  

 

Mechanism of action 

 

The mixture of enzymes in NexoBrid dissolves burn wound eschar. The specific components 

responsible for this effect have not been identified. The major constituent is stem bromelain. 

 

Clinical efficacy 

 

During clinical development, a total of 362 patients were treated with the concentrate of proteolytic 

enzymes enriched in bromelain.  

The efficacy of NexoBrid in humans was evaluated, compared to standard of care, in a randomised, 

multi-centre, multi-national, open-label, confirmatory phase 3 study in hospitalised patients with deep 

partial- and/or full-thickness thermal burns of 5 to 30% Total Body Surface Area (TBSA), but with 

total burn wounds of no more than 30% TBSA. 

 

NexoBrid (2 g/100 cm2, corresponding to 0.02 g/cm2) was used as described in section 4.2. 

 

Standard of care consisted of primary surgical excision and/or nonsurgical debridement using topical 

medicinal products to induce maceration and autolysis of eschar according to each study site’s 

standard practice. 

 

The age range in the group treated with NexoBrid was 4.4 to 55.7 years. The age range in the SOC 

group was 5.1 to 55.7 years.  

 

The efficacy of eschar removal was evaluated by determining the percentage of wound area left with 

eschar that required further removal by excision or dermabrasion, and the percentage of wounds 

requiring such surgical removal.  



24 

The effect on the timing of eschar removal was evaluated in patients with successful eschar removal 

(with at least 90% eschar removal in all wounds of a patient combined), by determining the time from 

injury as well as from informed consent to successful removal. 

 

The co-primary endpoints for the efficacy analysis were: 

- the percentage of deep partial thickness wounds requiring excision or dermabrasion, and 
- the percentage of deep partial thickness wounds autografted. 
This endpoint can only be evaluated for deep partial-thickness wounds without full-thickness areas 

because full-thickness burns always require grafting. 

 

Efficacy data generated in this study for all age groups combined as well as from a subgroup analysis 

for children and adolescents are summarised below.  

 

 NexoBrid SOC p-value 

Deep partial-thickness wounds requiring excision/dermabrasion (surgery) 

 Number of wounds 106 88  

 % of wounds requiring surgery 15.1% 62.5% <0.0001 

 % of wound area excised or 

dermabraded1 (mean ± SD)  

5.5% ± 14.6 52.0% ± 44.5 <0.0001 

Deep partial-thickness wounds autografted* 

 Number of wounds 106 88  

 % of wounds autografted 17.9% 34.1% 0.0099 

 % of wound area autografted 

(mean ± SD) 

8.4% ± 21.3 21.5% ± 34.8 0.0054 

Deep partial- and/or full-thickness wounds requiring excision/dermabrasion (surgery) 

 Number of wounds 163 170  

 % of wounds requiring surgery 24.5% 70.0% <0.0001 

 % of wound area excised or 

dermabraded1 (mean ± SD)  

13.1% ± 26.9 56.7% ± 43.3 <0.0001 

Time to complete wound closure (time from ICF**) 

 Number of patients2 70 78  

 Days to closure of last wound 

(mean ± SD) 

36.2 ± 18.5 28.8 ± 15.6 0.0185 

Time to successful eschar removal 

 Number of patients 67 73  

  Days (mean ± SD) from 

 injury 

2.2 ± 1.4 8.7 ± 5.7 <0.0001 

 Days (mean ± SD) from 

 consent 

0.8 ± 0.8 6.7 ± 5.8 <0.0001 

Patients not reported to have 

successful eschar removal  

7 8  

1 Measured at first session, if there was more than one surgery session.  
2 All randomised patients for whom data for complete wound closure were available.  

*The endpoint can only be evaluated for deep partial-thickness wounds without full-thickness areas 

because full-thickness burns always require grafting. 

** Informed Consent Form 

 

The following table shows results in mixed wounds. The comparisons in mixed wounds should be 

interpreted with caution since they are based on groups that are not fully randomized and the mixed 

wounds treated by NexoBrid were overall larger and had a larger full thickness area. 

 

Mixed wounds (with partial and full-thickness area) requiring excision/dermabrasion (surgery) 

 NexoBrid 

(Number of wounds) 

SOC 

(Number of wounds) 

% of wounds requiring 

surgery 

41.7% (20/48) 78.3% (47/60) 



25 

% of wound area excised or 

dermabraded 

25.5% (n=48) 64.0% (n=60) 

 

Mixed wounds (with partial and full-thickness area) autografted 

 NexoBrid 

(Number of wounds) 

SOC 

(Number of wounds) 

All mixed burns baseline 

characteristics 

48 wounds 60 wounds 

Size: % mean TBSA  7.43 6.33 

Depth:    

  Superficial (%TBSA) 0.67 0.92 

  DPT (% TBSA) 3.85 3.13 

  FT    (% TBSA) 2.90 2.29 

Incidence of autograft 70.8% (34/48) 63.3% (38/60)  

% wound area autografted  55.5% (n=48) 45.8% (n=60)  

 

The following table shows the time to complete wound closure from start of debridement.* 

 

Wound Type  NexoBrid  SOC  

 Days (mean ± SD) 

(Number of wounds)  

Days (mean ± SD) 

(Number of wounds) 

All wounds (ITT1) 30.5 ± 16.9 

(154) 

26.1 ± 16.0  

(164)  

Non-autografted wounds (ITT) 23.9 ± 13.0 

(95) 

24.5 ± 14.1 

(85) 

Autografted wounds (ITT) 41.0 ± 17.3 

(59) 

27.8 ± 17.7 

(79) 

Deep Partial Thickness wounds 26.6 ± 15.4 

(101) 

23.7 ± 13.6 

(87) 

Full Thickness wounds 

 

31.9 ± 10.1 

(7) 

36.3 ± 26.0 

(14) 

Mixed wounds 

(deep partial and full thickness)  

40.2 ± 17.1 

(44) 

27.7 ± 15.8 

(59) 

Non-autografted mixed wounds 29.5 ± 12.1 

(11) 

30.3 ± 15.5 

(22) 

Autografted mixed wounds 43.7 ± 17.3 

(33) 

26.2 ± 16.0 

(37) 

*These comparisons should be interpreted with caution since they are based on groups  

that are not fully randomized. 

1 ITT (Intent To Treat population): all randomized patients 

The difference in time to complete wound closure is mainly related to the wound care strategy applied 

by the physician, where an attempt to minimise grafting and allow for spontaneous epithelialisation of 

the wound areas that still have dermis may prolong time to first autograft (time to autograft: NexoBrid: 

14.7 days vs. SOC: 5.9 days) and hence prolong complete wound closure. 

 

Paediatric population 

Efficacy data generated in this study from a subgroup analysis for children and adolescents are 

summarised below. The available data are limited and NexoBrid should not be used in patients 

younger than 18 years.  

 



26 

 NexoBrid SOC p-value 

Deep partial-thickness wounds requiring excision/dermabrasion (surgery) 

 Number of wounds 23 22  

 % of wounds requiring surgery 21.7% 68.2% 0.0017 

 % of wound area excised or 

dermabraded1 (mean ± SD)  

7.3% ± 15.7% 64.9% ± 46.4% <0.0001 

Deep partial-thickness wounds autografted* 

 Number of wounds 23 22  

 % of wounds autografted 21.7% 31.8% 0.4447 

 % of wound area autografted 

(mean ± SD) 

6.1% ± 14.7% 24.5% ± 40.6% 0.0754 

Deep partial- and/or full-thickness wounds requiring excision/dermabrasion (surgery) 

 Number of wounds 29 41  

 % of wounds requiring surgery 20.7% 78% <0.0001 

 % of wound area excised or 

dermabraded1 (mean ± SD)  

7.9% ± 17.6% 73.3% ± 41.1% <0.0001 

Time to complete wound closure (time from ICF**) 

 Number of patients2 14 15  

 Days to closure of last wound 

(mean ± SD) 

29.9 ± 14.3 32.1 ± 18.9 0.6075 

Time to successful eschar removal 

 Number of patients 14 15  

  Days (mean ± SD) from 

 injury 

1.9 ± 0.8 8.1 ± 6.3 <0.0001 

 Days (mean ± SD) from 

 consent 

0.9 ± 0.7 6.5 ± 5.9 <0.0001 

Patients not reported to have 

successful eschar removal  

0 1  

1 Measured at first session, if there was more than one surgery session.  
2 All randomised patients for whom data for complete wound closure were available.  

*The endpoint can only be evaluated for deep partial-thickness wounds without full-thickness areas 

because full-thickness burns always require grafting. 

** Informed Consent Form 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

NexoBrid in one or more subsets of the paediatric population in the treatment of burns of external 

body surface (see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

The extent of systemic absorption from a burn wound, Cmax, Tmax, AUC, and t½ of bromelain from 

NexoBrid have been investigated in 16 burn patients with partial-thickness (mid- and deep-dermal) 

thermal burns. Average TBSA was 10%. 60% of the treated wounds area was partial thickness and/or 

full thickness. NexoBrid was applied once to the burn wound at a dose of 2 g NexoBrid Powder/20 g 

gel/100 cm2 of skin. 

NexoBrid serum concentrations were determined using a modified sandwich 

electrochemiluminescence (ECL) immunoassay. 

 

The range of total dose applied was 5 to 30 g concentrate of proteolytic enzymes enriched in 

bromelain from NexoBrid. In 4 patients, having received a dose of 5, 9, 12 and 17 g, respectively, 

there were indications of markedly higher systemic absorption. 

 

Cmax was 6020 ± 5020 ng/ml (mean ± SD) for the group of 15 patients, with a range of 888 to 

15,700 ng/ml. In the 4 patients with indications of higher absorption, dose-normalised Cmax ranged 



27 

from 788-900 ng/ml per gram of NexoBrid. In the other patients, dose-normalised Cmax ranged from 

141-523 ng/ml per gram of NexoBrid. 

 

A Cmax of 40µg/ml may be possible in humans administered NexoBrid under licensed conditions, 

when it is considered that PK has only been evaluated in patients with largely superficial burns, 

receiving half the maximum dose. 

 

The AUC from time zero to 48 hours after administration (AUClast) was 43,400 ± 46,100 ngh/ml 

(mean ± SD) for the group of 15 patients, with a range of 4560-167,000 ngh/ml. In the patients with 

indications of higher absorption, dose-normalised (per gram of NexoBrid) AUClast ranged from 

4500-9820 ngh/ml per gram of NexoBrid. In the other patients, dose-normalised AUClast ranged from 

887-3930 ngh/ml per gram of NexoBrid. 

 

These results for Cmax and AUClast indicate that systemic absorption may depend both on the applied 

NexoBrid dose (proportional to the covered wound area) and other, patient-specific factors. 

 

Tmax for 10 of the 15 patients was 2 hours and in 5 patients Tmax was 4 hours. 

 

Distribution 

According to a literature report, in plasma, approximately 50% of bromelain binds to the human 

plasma antiproteinases α2-macroglobulin and α1-antichymotrypsin. 

 

Elimination 

Terminal half-life (determined using data from 16 to 48 hours post-dose for 12 patients) was 

11.7 ± 3.5 hours (mean ± SD), with a range from 8.5 to 19.9 hours. 

 

 

Paediatric population 

Pharmacokinetic parameters and the extent of absorption have not been studied in children. 

 

5.3 Preclinical safety data 
 

NexoBrid was well tolerated when applied to intact mini-pig skin but caused severe irritation and pain 

when applied to damaged (abraded) skin. 

A single intravenous infusion of a solution prepared from NexoBrid powder in the mini-pig was well 

tolerated at dose levels of up to 12 mg/kg (achieving plasma levels 2.5fold of the human plasma level 

after application of the clinical proposed dosage to 15% TBSA) but higher doses were overtly toxic, 

causing haemorrhage in several tissues. Repeated intravenous injections of doses up to 12 mg/kg every 

third day in the mini-pig were well tolerated for the first three injections but severe clinical signs of 

toxicity (e.g. haemorrhages in several organs) were observed following the remaining three injections. 

Such effects could still be seen after the recovery period of 2 weeks. 

In embryo-foetal development studies in rats and rabbits, intravenously administered NexoBrid 

revealed no evidence of indirect and direct toxicity to the developing embryo/foetus. However, 

maternal exposure levels were considerably lower than those maximally reported in clinical setting 

(10–500 times lower than human AUC, 3–50 times lower than the human Cmax). Since NexoBrid was 

poorly tolerated by the parent animals, these studies are not considered relevant for human risk 

assessment. NexoBrid showed no genotoxic activity when investigated in the standard set of in vitro 

and in vivo studies. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

NexoBrid powder 

Ammonium sulphate  

Acetic acid  



28 

 

Gel 

Carbomer 980 

disodium phosphate anhydrous 

Sodium hydroxide  

Water for injections 

 

6.2 Incompatibilities 
 

Topically applied medicinal products (such as silver sulfadiazine or povidone-iodine) at the wound 

site must be removed and the wound cleansed prior to NexoBrid application. Remaining antibacterial 

medicinal products may interfere with the activity of NexoBrid by decreasing its efficacy. 

 

This medicinal product must not be mixed with other medicinal products. 

 

6.3 Shelf life 
 

3 years. 

 

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). 

 

6.4 Special precautions for storage 
 

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

 

Store upright to keep the gel at the bottom of the bottle and in the original package to protect from 

light. 

 

Do not freeze. 

 

6.5 Nature and contents of container 

 

5 g powder in a vial (glass type II) sealed with a rubber (bromobutyl), stopper and covered with a cap 

(aluminium), and 50 g gel in a bottle (borosilicate, glass type I), sealed with a rubber stopper and 

covered with a screw cap (tamper-proof polypropylene). 

 

Pack size of 1 vial of powder and 1 bottle of gel. 

 

6.6 Special precautions for disposal and other handling 
 

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. This should be considered when 

mixing NexoBrid powder with the gel. The powder should not be inhaled. See also section 4.4.  

 

Accidental eye exposure must be avoided. In case of eye exposure, exposed eyes must be irrigated 

with copious amounts of water for at least 15 minutes. In case of skin exposure, NexoBrid must be 

rinsed off with water. 

 

NexoBrid gel preparation (mixing powder with gel) 

 

 The NexoBrid powder and gel are sterile. An aseptic technique must be used when mixing the 
powder with the gel. 

DGD (N=49) 



29 

 The 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. 

 The powder is then transferred into the corresponding gel bottle.  

 Powder and gel must be mixed thoroughly until a uniform, slightly tan to slightly brown mixture 
is obtained. This usually requires mixing the powder and the gel for 1 to 2 minutes. 

 The gel should be prepared at the patient’s bedside. 
 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

MediWound Germany GmbH 

Eisenstrasse 5 

65428 Rüsselsheim 

Germany 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

EU/1/12/803/002 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 18.12.2012 

Date of latest renewal: 10.11.2017 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

 

  



30 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

 AUTHORISATION 

 

 

 



31 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers of the biological active substance 

 

MediWound Ltd. 

42 Hayarkon St.  

81227 Yavne 

Israel 

 

Name and address of the manufacturer responsible for batch release 

 

Hälsa Pharma GmbH 

Hafenweg 18-20 

D-48155 MünsterGermany 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

 AUTHORISATION  

 

Pharmacovigilance system 

The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the 

Marketing Authorisation is in place and functioning before and whilst the medicinal product is on the 

market. 

 

Risk Management Plan (RMP) 

The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as 

agreed in the Risk Management Plan presented in Module 1.8.2. of the Marketing Authorisation and 

any subsequent updates of the RMP agreed by the Committee for Medicinal Products for Human Use 

(CHMP). 

 

As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 

updated RMP should be submitted at the same time as the next Periodic Safety Update Report 

(PSUR). 

 

In addition, an updated RMP should be submitted 

 When new information is received that may impact on the current Safety Specification, 

Pharmacovigilance Plan or risk minimisation activities 

 Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 

reached 

 At the request of the European Medicines Agency. 

 

PSURs 

The PSUR cycle for the medicinal product should follow the standard requirements until otherwise 

agreed by the CHMP.  

 

 CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
USE OF THE MEDICINAL PRODUCT 

 

Prior to launch in each Member State, the Marketing Authorisation Holder MAH shall agree the 

content and format of the educational programme with the national competent authority. The 

Marketing Authorisation Holder (MAH) should ensure that, at launch, all Healthcare Professionals in 



32 

specialist burn centres who are expected to use and/or prescribe NexoBrid  receive a specific training 

and are provided with an Educational pack.  

 

The MAH should undertake a controlled distribution of NexoBrid to ensure that the product is not 

available for use at a centre until at least one surgeon at the centre has received formal training in the 

use of  NexoBrid.  This is in addition to the educational material which all potential users should 

receive. 

 

The educational pack should contain the following: 

 Summary of Product Characteristics and Patient Information Leaflet  

 Healthcare Professional information pack 

  

The Healthcare Professional information pack should be a step by step treatment guide that includes 

information on the following key elements: 

 

Before prescribing NexoBrid 

 The limitation of the  total area than can be treated to 15% TBSA  

 The risk of allergic reaction and of cross reactivity and  the contraindication in patients 
allergic to  pineapple and papain or to previous application of the product 

 The risk of increased mortality in patients with cardiopulmonary diseases 

 

Before applying NexoBrid 

 The need for  pain management  

 The need for wound cleansing and preparation before treatment with  

o Application of a dressing soaked with an antibacterial solution for two hours before 
NexoBrid application 

o Protection of surrounding skin areas  

 The method of preparation of NexoBrid and of its application to wound area 

 

After applying NexoBrid  

 The removal of NexoBrid and of dissolved eschar 

 The wound assessment and the warning against any repeat treatment 

 The wound management after NexoBrid treatment with 

o Application of a dressing soaked with an antibacterial solution for two hours  

o Performance of grafting procedures as soon as possible after debridement 

 The fact that NexoBrid may cause an allergic reaction, an increased tendency to bleed and 
severe local irritation and that  patients should be monitored for signs or symptoms of these 

  The fact that patients should be monitored for signs and symptoms of wound and 
systemic infections 

 

 OBLIGATION TO CONDUCT POST-AUTHORISATION MEASURES 
 

The MAH shall complete, within the stated timeframe, the following measures: 

 

Description Due date 



33 

The MAH shall conducts a study on enzymatic debridement in burns patients 

(children and adults): A comparison to standard of care (protocol MW2010-03-

02), based on a CHMP approved protocol. 

31/12/2020 

 

  



34 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



35 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
  



36 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

NexoBrid 2 g powder and gel for gel 

 

Concentrate of proteolytic enzymes enriched in bromelain 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One vial contains 2 g of concentrate of proteolytic enzymes enriched in bromelain, corresponding to 

0.09 g/g concentrate of proteolytic enzymes enriched in bromelain after mixing (or 2 g/22 g gel). 
 

 

3. LIST OF EXCIPIENTS 

 

Excipients for the powder: Acetic acid, ammonium sulphate. 

Excipients for the gel: Carbomer 980, disodium phosphate anhydrous, sodium hydroxide, water for 

injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder and gel for gel 

 

1 vial of 2 g powder 

1 bottle of 20 g of gel 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Powder and gel to be mixed before application. 

 

Read the package leaflet before use. 

 

For single use only. 

 

Cutaneous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 



37 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

Do not freeze. 

Store in the original package in order to protect from light. Store upright. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

MediWound Germany GmbH 

65428 Rüsselsheim 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/803/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

Justification for not including Braille accepted 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

<2D barcode carrying the unique identifier included.> 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

< PC: {number}  

SN: {number}  

NN: {number} > 
  



38 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

NexoBrid 5 g powder and gel for gel 

 

Concentrate of proteolytic enzymes enriched in bromelain 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One vial contains 5 g of concentrate of proteolytic enzymes enriched in bromelain, corresponding to 

0.09 g/g concentrate of proteolytic enzymes enriched in bromelain after mixing (or 5 g/55 g gel). 
 

 

3. LIST OF EXCIPIENTS 

 

Excipients for the powder: Acetic acid, ammonium sulphate. 

Excipients for the gel: Carbomer 980, disodium phosphate anhydrous, sodium hydroxide, water for 

injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder and gel for gel 

 

1 vial of 5 g powder 

1 bottle of 50 g of gel 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Powder and gel to be mixed before application. 

 

Read the package leaflet before use. 

 

For single use only. 

 

Cutaneous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 



39 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

Do not freeze. 

Store in the original package in order to protect from light. Store upright. 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

MediWound Germany GmbH 

65428 Rüsselsheim 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/803/002 

 

 

13. BATCH NUMBER 

 

Lot 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

Justification for not including Braille accepted 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

<2D barcode carrying the unique identifier included.> 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

< PC: {number}  

SN: {number}  
NN: {number} >  



40 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING UNITS 

 

NexoBrid powder (vial) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

NexoBrid 2 g powder 

 

Concentrate of proteolytic enzymes enriched in bromelain 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

One vial contains 2 g of concentrate of proteolytic enzymes enriched in bromelain, corresponding to 

0.09 g/g concentrate of proteolytic enzymes enriched in bromelain after mixing (or 2 g/22 g gel). 
 

 

3. LIST OF EXCIPIENTS 

 

Excipients: Acetic acid, ammonium sulphate. 

 

 

4. PHARMACEUTICAL FORM AND CONTENT 

 

Powder 
2 g 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Powder and gel to be mixed before application. 

 

Read the package leaflet before use. 

 

For single use only. 

 

Cutaneous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 



41 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSEDMEDICINAL PRODUCTS 

OR WASTE MATERIALS DEREIvED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

MediWound Germany GmbH 

65428 Rüsselsheim 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/803/001  

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS FOR USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

<Not applicable.> 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

<Not applicable.> 

  



42 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING UNITS 

 

NexoBrid powder (vial) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

NexoBrid 5 g powder  

 

Concentrate of proteolytic enzymes enriched in bromelain 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

One vial contains 5 g of concentrate of proteolytic enzymes enriched in bromelain, corresponding to 

0.09 g/g concentrate of proteolytic enzymes enriched in bromelain after mixing (or 5 g/55 g gel). 
 

 

3. LIST OF EXCIPIENTS 

 

Excipients: Acetic acid, ammonium sulphate. 

 

 

4. PHARMACEUTICAL FORM AND CONTENT 

 

Powder 
5 g  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Powder and gel to be mixed before application. 

 

Read the package leaflet before use. 

 

For single use only. 

 

Cutaneous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 



43 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSEDMEDICINAL PRODUCTS 

OR WASTE MATERIALS DEREIvED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

MediWound Germany GmbH 

65428 Rüsselsheim 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/803/002  

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS FOR USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

<Not applicable.> 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

<Not applicable.> 

 

 

  



44 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING UNITS 

 

Gel for NexoBrid powder 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Gel for NexoBrid 2 g 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Concentrate of proteolytic enzymes enriched in bromelain: 0.09 g/g (or 2 g/22 g gel) after mixing. 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: Carbomer 980, disodium phosphate anhydrous, sodium hydroxide, water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Gel 

20 g 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Powder and gel to be mixed before application. 

 

Read the package leaflet before use. 

 

For single use only. 

 

Cutaneous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

Do not freeze. 



45 

Store in the original package in order to protect from light. Store upright. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF MARKETING AUTHORISATION HOLDER 

 

MediWound Germany GmbH 

65428 Rüsselsheim 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/803/001 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS FOR USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

<Not applicable.> 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

<Not applicable.> 

 

  



46 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING UNITS 

 

Gel for NexoBrid powder 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Gel for NexoBrid 5 g 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Concentrate of proteolytic enzymes enriched in bromelain: 0.09 g/g (or 5 g/55 g gel) after mixing. 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: Carbomer 980, disodium phosphate anhydrous, sodium hydroxide, water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Gel 

50 g 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Powder and gel to be mixed before application. 

 

Read the package leaflet before use. 

 

For single use only. 

 

Cutaneous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

Do not freeze. 



47 

Store in the original package in order to protect from light. Store upright. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF MARKETING AUTHORISATION HOLDER 

 

MediWound Germany GmbH 

65428 Rüsselsheim 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/803/002  

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS FOR USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

<Not applicable.> 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

<Not applicable.> 

 

 

  



48 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



49 

Package leaflet: Information for the user 
 

NexoBrid 2 g powder and gel for gel 

Concentrate of proteolytic enzymes enriched in bromelain 

 

 This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

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 further questions, ask your doctor. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 
in this leaflet. 

 

What is in this leaflet 

 

1. What NexoBrid is and what it is used for 

2. What you need to know before NexoBrid is used 

3. How NexoBrid is used 

4. Possible side effects 

5. How NexoBrid is stored 
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 “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 a lung disease; 

- your lung has been, or may have been damaged by inhalation of smoke;  

-  



50 

- 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 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, 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). 



51 

- 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 tranquilizers, 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 to a burn wound area of 100 cm2. 

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.  

 

•  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. 



52 

 

 

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 

and failure of skin grafts to heal properly 

 

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 the national reporting system listed in 

Appendix V. 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. 

 

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. 

 



53 

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 

Eisenstrasse 5 

65428 Rüsselsheim 

Germany 

 

Manufacturer: 

Hälsa Pharma GmbH 

Hafenweg 18-20 

D-48155 MünsterGermany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

MediWound GmbH 

Tél/Tel: +800 22232425 

 

Lietuva 

MediWound GmbH 

Tel: +800 22232425 
 

България 

MediWound GmbH 

Teл: +800 22232425 

 

Luxembourg/Luxemburg 

MediWound GmbH  

Tél/Tel: +800 22232425 
 

Česká republika 

MediWound GmbH 

Tel: +800 22232425 

 

Magyarország 

MediWound GmbH 

Tel.: +800 22232425 

Danmark 

MediWound GmbH 

Tlf: +800 22232425 
 

Malta 

MediWound GmbH 

Tel: +800 22232425 

Deutschland 

MediWound GmbH 

Tel: +800 22232425 

 

Nederland 

MediWound GmbH 

Tel: +800 22232425 

 

Eesti 

MediWound GmbH 

Tel: +800 22232425 

 

Norge 

MediWound GmbH 

Tlf: +800 22232425 

 

Ελλάδα 

MediWound GmbH 

Τηλ: +2111990962 

 

Österreich 

MediWound GmbH 

Tel: +800 22232425 

 

España 

MediWound GmbH 

Tél: +800 22232425 

Polska 

MediWound GmbH 

Tel.: +800 22232425 
 

France 

MediWound GmbH 

Tél: +800 22232425 

Portugal 

MediWound GmbH 

Tel: +800 22232425 



54 

  

Hrvatska 

MediWound GmbH 

Tel: +15517564 
 

România 

MediWound GmbH 

Tel: +40 0312295632 

 

Ireland 

MediWound GmbH 

Tel: +800 22232425 
 

Slovenija 

MediWound GmbH 

Tel: +800 22232425 
 

Ísland 

MediWound GmbH 

Sími: +800 22232425 

 

Slovenská republika 

MediWound GmbH 

Tel: +800 22232425 

 

Italia 

MediWound GmbH 

Tel: +800 22232425 

 

Suomi/Finland 

MediWound GmbH 

Puh/Tel: +800 22232425 
 

Κύπρος 

MediWound GmbH 

Τηλ: +800 22232425 

 

Sverige 

MediWound GmbH 

Tel: +800 22232425 

 

Latvija 

MediWound GmbH 

Tel: +800 22232425 
 

United Kingdom 

MediWound GmbH 

Tel: +800 22232425 
 

  

 

 

 

This leaflet was last revised in <{MM/YYYY}> <{month YYYY}.> 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

 

--------------------------------------------------------------------------------------------------------------------------- 

 

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. 

 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. 



55 

 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 interfere with 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. 

 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 

 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 

 Appropriate preventive analgesia medicinal products must be administered. 

 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 



56 

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. This should be considered when 

mixing NexoBrid powder with the gel.  

 

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. 

 



57 

Package leaflet: Information for the user 
 

NexoBrid 5 g powder and gel for gel 

Concentrate of proteolytic enzymes enriched in bromelain 

 

 This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

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 further questions, ask your doctor. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 
in this leaflet. 

 

What is in this leaflet 

 

1. What NexoBrid is and what it is used for 

2. What you need to know before NexoBrid is used 

3. How NexoBrid is used 

4. Possible side effects 

6. How NexoBrid is stored 
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 “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 a lung disease; 

- your lung has been, or may have been damaged by inhalation of smoke;  

-  



58 

- 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 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, 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). 



59 

- 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 tranquilizers, 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.  

 

5 g NexoBrid powder mixed in 50 g gel is applied to a burn wound area of 250 cm2. 

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.  

 

•  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. 

 

 



60 

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 

and failure of skin grafts to heal properly 

 

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 the national reporting system listed in 

Appendix V. 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. 
 

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: 5 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 infections. 

 

What NexoBrid looks like and contents of the pack 



61 

NexoBrid is provided as a powder and gel for gel (powder in a vial (5 g) and gel in a bottle (50 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 

Eisenstrasse 5 

65428 Rüsselsheim 

Germany 

 

Manufacturer: 

Hälsa Pharma GmbH 

Hafenweg 18-20 

D-48155 Münster 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder 

 

België/Belgique/Belgien 

MediWound GmbH 

Tél/Tel: +800 22232425 

 

Lietuva 

MediWound GmbH 

Tel: +800 22232425 
 

България 

MediWound GmbH 

Teл: +800 22232425 

 

Luxembourg/Luxemburg 

MediWound GmbH  

Tél/Tel: +800 22232425 
 

Česká republika 

MediWound GmbH 

Tel: +800 22232425 

 

Magyarország 

MediWound GmbH 

Tel.: +800 22232425 

Danmark 

MediWound GmbH 

Tlf: +800 22232425 
 

Malta 

MediWound GmbH 

Tel: +800 22232425 

Deutschland 

MediWound GmbH 

Tel: +800 22232425 

 

Nederland 

MediWound GmbH 

Tel: +800 22232425 

 

Eesti 

MediWound GmbH 

Tel: +800 22232425 

 

Norge 

MediWound GmbH 

Tlf: +800 22232425 

 

Ελλάδα 

MediWound GmbH 
Τηλ: +2111990962 

Österreich 

MediWound GmbH 

Tel: +800 22232425 

 

España 

MediWound GmbH 

Tél: +800 22232425 

Polska 

MediWound GmbH 

Tel.: +800 22232425 
 

France 

MediWound GmbH 

Tél: +800 22232425 

Portugal 

MediWound GmbH 

Tel: +800 22232425 



62 

  

Hrvatska 

MediWound GmbH 

Tel: +15517564 

România 

MediWound GmbH 

Tel: +40 0312295632 

 

Ireland 

MediWound GmbH 

Tel: +800 22232425 
 

Slovenija 

MediWound GmbH 

Tel: +800 22232425 
 

Ísland 

MediWound GmbH 

Sími: +800 22232425 

 

Slovenská republika 

MediWound GmbH 

Tel: +800 22232425 

 

Italia 

MediWound GmbH 

Tel: +800 22232425 

 

Suomi/Finland 

MediWound GmbH 

Puh/Tel: +800 22232425 
 

Κύπρος 

MediWound GmbH 

Τηλ: +800 22232425 

 

Sverige 

MediWound GmbH 

Tel: +800 22232425 

 

Latvija 

MediWound GmbH 

Tel: +800 22232425 
 

United Kingdom 

MediWound GmbH 

Tel: +800 22232425 
 

  

 

 

 

This leaflet was last revised in <{MM/YYYY}> <{month YYYY}.> 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

 

--------------------------------------------------------------------------------------------------------------------------- 

 

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. 

 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. 



63 

 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 interfere with 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. 

 . 

 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 

 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 

 Appropriate preventive analgesia medicinal products must be administered. 

 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 



64 

(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. This should be considered when 

mixing NexoBrid powder with the gel..  

 

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. 

  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	OBLIGATION TO CONDUCT POST-AUTHORISATION MEASURES
	A. LABELLING
	B. PACKAGE LEAFLET