NEXOBRID 2g powder + gel for gel medication leaflet

NexoBrid 2 g powder and gel for gel

NexoBrid 5 g powder and gel for gel

One vial contains 2 g or 5g of concentrate of proteolytic enzymes enriched in bromelain, corresponding to0.09 g/g concentrate of proteolytic enzymes enriched in bromelain after mixing (or 2 g/22 g gel or 5g/55ggel).

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.

Powder and gel for gel

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

NexoBrid is indicated in all age groups for removal of eschar in patients with deep partial- and full-thickness thermal burns.

This medicinal product should only be applied by trained healthcare professionals in specialist burncentres.

Adults2 g powder in 20 g gel is applied to 1 % Total Body Surface Area (TBSA) that corresponds toapproximately 180 cm2 of an adult with a layer thickness of 1.5 to 3 mm.

5g powder in 50 g gel is applied to 2.5 % TBSA that corresponds to approximately 450 cm2 of an adult,with a gel layer thickness of 1.5 to 3 mm.

NexoBrid should not be applied to more than 15% TBSA (see also section 4.4, Coagulopathy).

Children and adolescents (from birth to 18 years of age)

For paediatric patients aged 4-18 years old NexoBrid should not be applied to more than 15% TBSA.

For paediatric patients aged 0-3 years old this medicine should not be applied to more than 10% TBSA.

It should be left in contact with the burn wound for a duration of 4 hours. There is very limited informationon the use of this medicinal product on areas where eschar remained after the first application.

A second and subsequent application is not recommended.

There is no information on the use in patients with renal impairment. These patients should be carefullymonitored.

There is no information on the use in patients with hepatic impairment. These patients should be carefullymonitored.

Experience in elderly patients (>65 years) is limited. No dose adjustment is required.

Cutaneous use.

Before use, the powder must be mixed with the gel producing a uniform gel. For instructions on mixing seesection 6.6.

Once mixed, the gel should be applied to a clean, keratin-free (blisters removed), and moist wound area.

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

Topically applied medicinal products (such as silver sulfadiazine or povidone-iodine) at the wound sitemust be removed and the wound must be cleansed prior to application of the gel as eschar saturated withmedicinal products and their remains reduce its activity and decrease its efficacy.

For instructions on preparation of the medicinal product before application, see section 6.6.

When mixing this medicinal product powder with the gel, appropriate handling, including wearing ofgloves and protective clothing as well as eye shielding glasses and a surgical mask, is required (see section4.4). The powder should not be inhaled, see section 6.6.

A total wound area of not more than 15% TBSA can be treated with this medicinal product (see alsosection 4.4, Coagulopathy).

* Enzymatic debridement is a painful procedure and requires adequate analgesia and/or anaesthesia.

Pain management must be used as commonly practiced for an extensive dressing change; it shouldbe initiated at least 15 minutes prior to this medicinal product application.

* The wound must be cleaned thoroughly, and the superficial keratin layer or blisters removed fromthe wound area, as the keratin will isolate the eschar from direct contact with the gel and preventeschar removal by it.

* Dressing soaked with an antibacterial solution must be applied for 2 hours.

* All topically applied antibacterial medicinal products must be removed before applying the gel.

Remaining antibacterial medicinal products may reduce the activity of this medicinal product bydecreasing its efficacy.

* The area from which you wish to remove the eschar must be surrounded with a sterile paraffinointment adhesive barrier by applying it a few centimetres outside of the treatment area (using adispenser). The paraffin layer must not come into contact with the area to be treated to avoidcovering the eschar, thus isolating the eschar from direct contact with the gel.

To prevent possible irritation of abraded skin by inadvertent contact with the gel and possiblebleeding from the wound bed, acute wound areas such as lacerations or escharotomy incisions shouldbe 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. Thewound must be kept moist during the application procedure.

Application of the medicinal product

* Moisten the area to be treated by sprinkling sterile saline onto the area bordered by the fatty ointmentadhesive barrier.

* Within 15 minutes of mixing, the gel must be applied topically to the moistened burn wound, at athickness of 1.5 to 3 millimetres.

* The wound must then be covered with a sterile occlusive film dressing that adheres to the sterileadhesive barrier material applied as per the instruction above (see Preparation of patient and woundarea). The medicinal product must fill the entire occlusive dressing, and special care should be takennot to leave air under this occlusive dressing. Gentle pressing of the occlusive dressing at the area ofcontact with the adhesive barrier will ensure adherence between the occlusive film and the sterileadhesive barrier and achieve complete containment of the gel 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 the medicinal product

* Removal of this medicinal product is a painful procedure and requires adequate analgesia and/oranaesthesia. Appropriate preventive analgesia medicinal products must be administered at least 15minutes prior to gel removal.

* After 4 hours of medicinal product treatment, the occlusive dressing must be removed using aseptictechniques.

* The adhesive barrier must be removed using a sterile blunt-edged instrument (e.g., tonguedepressor).

* The dissolved eschar must be removed from the wound by wiping it away with a sterile blunt-edgedinstrument.

* The wound must be wiped thoroughly first with a large sterile dry gauze or napkin, followed by asterile 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 bleedingpoints or a whitish tissue. Rubbing will not remove adhering undissolved eschar in areas where theeschar still remains.

* A dressing soaked with an antibacterial solution must be applied for an additional 2 hours.

* The debrided area must be covered immediately by temporary or permanent skin substitutes ordressings 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 enzymaticallydebrided 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 refreshedby, 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 afterthe debridement. Careful consideration should also be given to placing permanent skin covers (e.g.autografts) on deep partial thickness wounds soon after the debridement (see section 4.4).

Hypersensitivity to the active substance, to pineapples, or papayas/papain (see also section 4.4), or to any ofthe excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch number of theadministered product should be clearly recorded.

The potential of this medicinal product (a protein product) to cause sensitisation should be taken intoaccount.

There have been reports of serious allergic reactions including anaphylaxis (with manifestations such asrash, erythema, hypotension, tachycardia) in patients undergoing debridement with this medicinal product(see section 4.8). In these cases, a causal relationship to this medicinal product was considered possible, butpossible allergy to concomitant medicinal products such as opioid analgesics should also be considered.

Allergic reactions to inhaled bromelain have been reported in the literature (including anaphylacticreactions and other immediate-type reactions with manifestations such as bronchospasm, angiooedema,urticaria, and mucosal and gastrointestinal reactions). No occupational hazard was found in a studyassessing the amount of airborne particles during this medicinal product preparation.

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 airwayexposure have been reported.

History of allergy needs to be established prior to the administration (see sections 4.3 and 6.6).

In case of skin exposure, this medicinal product should be rinsed off with water to reduce the likelihood ofskin sensitisation (see section 6.6).

Cross-sensitivity between bromelain and papaya/papain as well as latex proteins (known as latex-fruitsyndrome), bee venom, and olive tree pollen has been reported in the literature.

Enzymatic debridement is a painful procedure, and may only be administered after adequate analgesiaand/or anesthesia has been established.

This treatment is not recommended for use on:

- penetrating burn wounds where foreign materials (e.g. implants, pacemakers, and shunts) and/orvital 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 unforeseeablereactions with the product and an increased risk of spreading the noxious substance.

- foot burns in diabetic patients and patients with occlusive vascular disease.

- in electrical burns.

There is no experience of the use of this medicinal product on perineal and genital burns.

This medicinal product should be used with caution in patients with cardiopulmonary and pulmonarydisease, including pulmonary burn trauma and suspected pulmonary burn trauma.

Use in patients with varicose veins

This medicinal product should be used with caution in areas of varicose veins, to prevent erosion of theveins' wall, and the risk of bleeding.

There are literature reports of successful use of this medicinal product on facial burn wounds. Burnsurgeons without experience in using this medicinal product should not start using it on facial burn wounds.

This medicinal product must be used with caution in such patients.

Direct contact with the eyes must be avoided. Eyes must be carefully protected during treatment of facialburns using fatty ophthalmic ointment on the eyes and adhesive barrier petroleum ointment around toinsulate and cover the eyes with occlusive film.

In case of eye exposure, irrigate exposed eyes with copious amounts of water for at least 15 minutes. Anophthalmological exam is recommended prior to and after debridement.

Concentrate of proteolytic enzymes enriched in bromelain is systemically absorbed from burn wound areas(see section 5.2).

There is limited pharmacokinetic data in patients with TBSA of more than 15%. Due to safetyconsiderations (see also section 4.4, Coagulopathy) this medicinal product should not be applied to morethan 15% Total Body Surface Area (TBSA) in adults and paediatric patients aged 4-18 years old.

For paediatric patients aged 0-3 years old this medicinal product should not be applied to more than 10%

TBSA.

General principles of proper burn wound care must be adhered to when using this medicinal product. Thisincludes proper wound cover for the exposed tissue (see section 4.2).

In clinical studies, wounds with visible dermal remnants were allowed to heal by spontaneousepithelialisation. In several cases, adequate healing did not occur, and autografting was required at a laterdate, leading to delays in wound closure which may be associated with increased risk of wound-relatedcomplications. Therefore, wounds with areas of full-thickness and deep burn that will not healspontaneously by epithelialisation in timely manner should be autografted as soon as possible after thismedicinal product debridement (see section 5.1). Careful consideration should also be given to placingpermanent skin covers (e.g. autografts) on deep partial thickness wounds soon after this medicinal productdebridement (see sections 4.2 and 4.8).

As in the case of surgically debrided bed, in order to prevent desiccation and/or formation of pseudoescharand/or infection, the debrided area should be covered immediately by temporary or permanent skinsubstitutes 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 thedebrided bed by, e.g., brushing or scraping to allow dressing adherence.

A reduction of platelet aggregation and plasma fibrinogen levels and a moderate increase in partialthromboplastin and prothrombin times have been reported in the literature as possible effects followingoral administration of bromelain. In vitro and animal data suggest that bromelain can also promotefibrinolysis. During the clinical development of this medicinal product, there was no indication of anincreased bleeding tendency or bleeding at the site of debridement.

The treatment should not be used in patients with uncontrolled disorders of coagulation. It should be usedwith caution in patients under anticoagulant therapy or other medicinal products affecting coagulation, andin patients with low platelet counts and increased risk of bleeding from other causes, e.g. peptic ulcers andsepsis. Patients should be monitored for possible signs of coagulation abnormalities and signs of bleeding.

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 this medicinalproduct 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 this medicinal product application

All topically applied antibacterial medicinal products must be removed before applying this medicinalproduct. Remaining antibacterial medicinal products reduce the activity of this medicinal product bydecreasing its efficacy.

No interaction studies have been performed.

Reduction of platelet aggregation and plasma fibrinogen levels and a moderate increase in partialthromboplastin and prothrombin times have been reported as possible effects following oral administrationof bromelain. In vitro and animal data suggest that bromelain can also promote fibrinolysis. Caution andmonitoring is therefore needed when prescribing concomitant medicinal products that affect coagulation(see also section 4.4.).

The medicinal product, when absorbed, is an inhibitor of cytochrome P450 2C8 (CYP2C8) and P450 2C9(CYP2C9). This should be taken into account if this medicinal product is used in patients receiving

CYP2C8 substrates (including amiodarone, amodiaquine, chloroquine, fluvastatin, paclitaxel, pioglitazone,repaglinide, , 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) maydecrease the efficacy of this medicinal product (see section 4.4).

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

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

No interaction studies have been performed in children/adolescents.

There are no data from the use of concentrate of proteolytic enzymes enriched in bromelain in pregnantwomen.

Animal studies are insufficient to properly assess the potential of this medicinal product to interfere withembryonal/foetal development (see section 5.3).

Since the safe use of medicinal product during pregnancy has not yet been established, it is notrecommended during pregnancy.

It is unknown whether concentrate of proteolytic enzymes enriched in bromelain or its metabolites areexcreted in human milk. A risk to new-borns/infants cannot be excluded. Breast-feeding should bediscontinued at least 4 days from NexoBrid application initiation.

No studies were performed to assess the effects of this medicinal product on fertility.

Not relevant.

The most commonly reported adverse reactions in pooled adult population from studies MW2004,

MW2005, MW2008 and MW2010 in the medicinal product arm (203 patients in total) are pyrexia and pain(incidence of 13.3 and 3.9%, respectively).

The most commonly reported adverse reactions in the pooled paediatric population (0-18 years) (89patients in total) from studies, MW2004, MW2008 and MW2012 in the medicinal product arm werepyrexia and pain (incidence of 16.9% and 7.9%, respectively).

Tabulated list of adverse reactions up to 3 months post wound closure

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 this medicinal product toremove eschar from deep partial- or full-thickness burns in a regimen with local antibacterial prophylaxis,recommended analgesia/anaesthesia, as well as coverage of the wound area after application of thetreatment for 4 hours with an occlusive dressing for containment of this medicinal product on the wound.

Common: Wound infection including cellulitis*

Common: Non serious allergic reactions such as rasha

Not known: Serious allergic reactions including anaphylaxisa

Common: Tachycardia*

Common: Wound complications*, local rash, local pruritus,

Uncommon: intradermal haematoma

Very common: Pyrexia/hyperthermia*

Common: Local pain*

*see Description of selected adverse reactions below.a see section 4.4.

In pooled adult population from studies MW2004, MW2005, MW2008 and MW2010 with routineantibacterial soaking of the treatment area before and after this medicinal product application (see section4.2), pyrexia hyperthermia and increased body temperature were reported in 13.3.% of the adult patientstreated with this medicinal product vs. 9.7%, of the patients treated according to standard of care (SOC).

In early studies without antibacterial soaking (Studies MW2001and MW2002), pyrexia or hyperthermiawas reported in (this medicinal product vs. SOC): 35.1% vs. 8.6% of adult patients.

In pooled paediatric population from studies MW2004, MW2008, and MW2012, with routine antibacterialsoaking before and after treatment, fever-pyrexia or hyperthermia were reported in 16.9% of patientstreated with this medicinal product vs. 9.3% of patients treated according to SOC.

In pooled adults patients from studies MW2004, MW2005, MW2008 and MW2010 where preventiveanalgesia was practiced (as specified in section 4.2), pain related AEs were reported in 3.9% of -patientstreated with this medicinal product vs. 3.5% of SOC-patients.

In early studies before implementation of the preventive actions (Studies MW2001 and MW2002)including adult patients, where analgesia was provided on an on-demand basis, pain was reported in 23.4%of patients treated with this medicinal product and in 5.7% in the SOC group.

In pooled paediatric population from studies MW2004, MW2008, and MW2012 (after implementation ofpreventive actions), pain was reported in (treated with this medicinal product vs. SOC): 7.9% vs. 9.3% ofpatients.

In pooled adult studies with routine antibacterial soaking of the treatment area before and after medicinalproduct application (studies MW2004, MW2005, MW2008 and MW2010), the incidence of woundinfection was higher in the SOC group: 5.9% in the medicinal product group vs. 6.3% in the SOC group,and the incidence of cellulitis was 1.1% vs. 0.6% in medicinal product vs. SOC, respectively.

In pooled paediatric population from studies 2004, MW2008, and MW2012, wound infection were reportedin 1.1% of this medicinal product patients vs. 8.1% of SOC-patients.

Wound complications reported include the following: wound deepening, wound desiccation, wound re-opening, graft loss/ graft failure.

In pooled adult populations from phase 2 and 3 studies including studies pre- and post-implementation ofantibacterial soaking (MW2001, MW2002, MW2004, MW2005, MW2008, and MW2010) including 280patients treated with this medicinal product and 179 patients treated with SOC, the following incidenceswere reported (medicinal product vs. SOC): wound complication: 3.2% vs. 1.7%, wound decomposition:1.1% vs. 0.6%, skin graft failure/graft loss 2.9% vs 2.2% .

In pooled paediatric only population from studies MW2004, MW2008, and MW2012, wound complicationwas reported with similar incidence (medicinal product vs. SOC): 5.6% vs. 5.8%, skin graft failure/graftloss in this medicinal product vs SOC: 1.1% vs. 2.4%.

In pooled adult population from phase 2 and 3 studies (MW2001, MW2002, MW2004, MW2005,

MW2008 and MW2010), 2.9% of patients experienced tachycardia in temporal proximity to this medicinalproduct treatment. No tachycardia was reported in the SOC and gel vehicle arms.

In pooled paediatric population from studies MW2004, MW2008, and MW2012, tachycardia was reportedwith lower incidence in the medicinal product treated patients (1.1 %) compared SOC treated patients(3.5%).

Alternative causes of tachycardia (e.g., the general burn condition, procedures causing pain, fever anddehydration) should be considered.

Clinical trial experience in paediatric patients (newborn up to 18 years of age) includes use of thismedicinal product in a dedicated SOC-controlled study (MW2012), in which 69 patients were exposed tothis medicinal product (age range new born-18 years; see section 5.1 for age distribution) and use inpaediatric patients in studies MW2004 and MW2008, which included 17 and 3 paediatric patients,respectively (age range 4-17 years).

Overall, the safety profile in paediatric patients is similar to the safety profile in adults.

Due to the low numbers of adverse reactions reported in each age group, it is not possible to draw validconclusions regarding potential age-related differences in the safety profile.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Treatment with concentrate of proteolytic enzymes enriched in bromelain prepared in a powder:gel ratio of1:5 (0.16g per g of mixed gel) in patients with deep partial- and/or full-thickness burns within theframework of a clinical study did not result in significantly different safety findings when compared totreatment with concentrate of proteolytic enzymes enriched in bromelain prepared in a powder:gel ratio of1:10 (0.09 g per 1g of mixed gel).

Pharmacotherapeutic group: Preparations for treatment of wounds and ulcers, proteolytic enzymes; ATCcode: D03BA03.

The mixture of enzymes in this medicinal product dissolves burn wound eschar. The specific componentsresponsible for this effect have not been identified. The major constituent is stem bromelain.

During clinical development, a total of 536 patients were treated with the concentrate of proteolyticenzymes enriched in bromelain.

DETECT study (MW2010) - (Phase 3b)

This was a randomized, controlled, assessor-blinded, three-arm study comparing this medicinal product,standard of care (SOC), and gel vehicle treatment in adult subjects with DPT and/or FT thermal burns.

SOC included both surgical and non-surgical methods for eschar removal per the investigators’ discretion.

Subjects on the medicinal product and gel vehicle arms who had eschar remaining following the topicaltreatment period were treated with SOC.

A total of 175 subjects were randomized in a 3:3:1 ratio (this medicinal product: SOC : gel vehicle) and169 subjects were treated. The mean age was 41 years, 70% of subjects were male and 30% were female.

Sixteen patients ≥ 65 years old (9.1%) were included in the study. Seven (7) (9.3%) patients in themedicinal product arm, 5 (6.7%) patients in the SOC arm, and 4 (16%) patients in the gel vehicle arm.

Subjects had one or more target wounds (TWs) to be treated for eschar removal. The mean percentage BSAof all TWs per subject was 6.1%. The majority of subjects (82%) had one to two TWs.

Primary endpoint was incidence of complete (>95%) eschar removal as compared with Gel Vehicle.

Secondary endpoints included time to complete eschar removal, Incidence of surgical excision, anddebridement related blood loss as compared to SOC. Time to complete wound closure, long term cosmesisand function measures by the Modified Vancouver Scar Scale (MVSS) after the 12 months follow-upperiod were analysed as safety endpoints.

In cidence of Complete Eschar Removal in the DETECT Study

NexoBrid Gel Vehicle P-value(ER/N) (ER/N)

Incidence of 93.3% 4.0% p < 0.0001complete (70/75) (1/25)escharr emoval

ER=Eschar removal

Compared to SOC, this medicinal product resulted in significant reductions in the incidence of surgicaleschar removal (tangential/minor/avulsion/Versajet and/or dermabrasion excision), time to complete escharremoval, and actual blood loss related to eschar removal, as shown below. Similar efficacy of escharremoval was observed in the elderly population.

Incidence of surgical eschar excision, time to complete eschar removal, and blood loss in the

D ETECT study

NexoBrid Standard of(N=75) Care (N=75)

Incidence of surgical excision 4.0% (3) 72.0% (54)(number of subjects)

Median time to complete eschar 1.0 days 3.8 daysremoval

Blood loss related to eschar 14.2 ±512.4 mL 814.5 ±1020.3removal mL

Long-term data (12 and 24 months after wound closure)

The Phase 3 trial (DETECT) included long-term follow up to assess cosmesis and function at 12 and 24month follow up visits. At 12 months, scar assessment using the Modified Vancouver Scar Score (MVSS)demonstrated comparable outcomes between this medicinal product, SOC, and Gel Vehicle, with meanscores of 3.70, 5.08, and 5.63, respectively. At 24 months, MVSS mean scores were 3.04, 3.30 and 2.93respectively. Statistical analyses indicated non-inferiority (pre-defined NI margin of 1.9 points) of thismedicinal product treatment compared to SOC and showed that treatment with this medicinal product doesnot have any clinically meaningful deleterious effect on burn scar cosmesis and function compared with the

SOC treatment at 24 months after wound closure.

Functionality and quality of life (QOL) measurements at 12 and 24 months were similar across treatmentgroups. The mean Lower Extremity Functional Scale (LEFS) scores, the mean QuickDASH scores, therange of motion (ROM) evaluations as well as long-term QOL, as measured by EQ-5D VAS (visualanalogue scale) and Burn Specific Health Scale-Brief (BSHS-B) were similar among treatment arms.

In a cardiac safety sub study, the ECGs of up to 150 patients were used to evaluate potential effects of thismedicinal product on ECG parameters. The study showed no clear effect of this medicinal product on heartrate, PR interval, QRS duration (cardiac depolarisation), and cardiac repolarisation (QTc). There were nonew clinically relevant morphological ECG changes demonstrating a signal of concern.

Study MW2004 (Phase 3)

This was a randomised, multi-centre, multi-national, open-label, confirmatory phase 3 study evaluating thismedicinal product compared to SOC in hospitalised patients with deep partial- and/or full-thicknessthermal burns of 5 to 30% TBSA, but with total burn wounds of no more than 30% TBSA. The mean TWarea treated in % TBSA was 5.1±3.5 for this medicinal product and 5.2±3.4 for SOC.

The age range in the group treated with this medicinal product was 4.4 to 55.7 years. The age range in the

SOC group was 5.1 to 55.7 years.

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.

The second co-primary 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 forchildren 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 5.5% ± 14.6 52.0% ± 44.5 <0.0001dermabraded1 (mean ± SD)

Deep partial-thickness wounds autografted*

Number of wounds 106 88% of wounds autografted 17.9% 34.1% 0.0099% of wound area autografted 8.4% ± 21.3 21.5% ± 34.8 0.0054(mean ± SD)

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 13.1% ± 26.9 56.7% ± 43.3 <0.0001dermabraded1 (mean ± SD)

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

Number of patients2 70 78

Days to closure of last wound 36.2 ± 18.5 28.8 ± 15.6(mean ± SD)

Time to successful eschar removal

Number of patients 67 73

Days (mean ± SD) from 0.8 ± 0.8 6.7 ± 5.8consent

Patients not reported to have 7 8successful eschar removal1 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 areasbecause full-thickness burns always require grafting.

** Informed Consent Form

The long-term scar formation and quality of life in adults and children who participated in study MW2004were evaluated in a non-interventional, assessor-blinded extension study to MW2004.

The enrolled population of 89 subjects including 72 adults and 17 paediatric subjects (<18 years) wasrepresentative of the MW2004 study population.

Scar assessment at 2-5 years using the MVSS demonstrated comparable outcomes between study groupswith a mean total overall score of 3.12 vs. 3.38 for the medicinal product vs. SOC, respectively (p=0.88).

QOL was assessed in adults using the SF-36 questionnaire. Mean scores for the various parameters weresimilar in both groups. The overall physical component score (51.1 vs. 51.3, respectively) and the overallmental component score (51.8 vs. 49.1, respectively) were comparable between both groups.

MW2012 Paediatric study (CIDS)

This study is a randomised (1:1), open-label, SOC-controlled, parallel group study in 145 hospitalisedsubjects (0-18 years of age) with deep partial or full thickness thermal burns affecting 1% to 30% of totalbody surface area (average TW area: 5.57% TBSA). Subjects were randomized to this medicinal product (2g powder in 20 g gel per 180 cm2 for 4 hours) or SOC (surgical and/or nonsurgical eschar removalprocedures). There were three co-primary endpoints: the median time to complete eschar removal, the % ofwound area surgically excised, and the cosmesis and function of the skin at 12 months after wound closure(Modified Vancouver Scar Scale score). Demographics and main results are presented in the table below.

A total of 145 patients were randomised and included in the full analysis set (FAS): 72 in the medicinalproduct arm and 73 in the SOC arm. Of these, 139 (95.9%) patients were treated and included in the safetyanalysis set (SAS): 69 (95.8%) in the medicinal product arm and 70 (95.9%) in the SOC treatment arm.

Age distribution was as follows (medicinal product vs. SOC): 0-11 months 4 vs. 4, 12-23 months 19 vs. 18,24 months-3 years: 15 vs. 15, 4-11 y. 25 vs. 25 and 12-18 years: 9 vs. 11.

Overall, patients’ age, ethnicity, height, weight and body mass index (BMI) were similar between treatmentarms. On a patient level, the mean % TBSA of TWs was 5.85% for patients in the medicinal product armvs. 5.30% in the SOC arm.

Compared to SOC, the medicinal product- treatment resulted in significantly shorter median time tocomplete eschar removal, significantly smaller mean percentage of the wound area surgically excised foreschar removal. Patients treated with this medicinal product had less surgical excisions compared to SOC.(see table)

Long term results (12 months)

With regard to cosmesis and function evaluated at 12 months, as measured by MVSS, non-inferiority oftreatment with the medicinal product compared with SOC was demonstrated (p-value <0.0001), using anon-inferiority margin of 1.9.

Paediatric study MW2012 (CIDS)

NexoBrid SOC p-value(N = 72) (N = 73)

Age (mean, SD) 5.71 (4.84) 5.83 (4.91)

Outcomes

Time to complete eschar removal

Median, days (FAS) 0.99 5.99 0.0008

Percent wound area surgically excised (FAS)

Mean ± SD (FAS) 1.5 ± 12.13 48.1 ± 46.58 < 0.0001

MVSS at 12 months

Mean ± SD (FAS) 3.83 ± 2.876 4.86 ± 3.256 < 0.0001(Non-inferiority shown)

Incidence of surgical excision (%)

The proportion and number of patientswho required surgical excision for 8.33 64.38eschar removal (FAS)*

Mean time to last wound closure - observed data (days)

Mean ± SD (FAS) 28.65 ± 16.56 27.74 ± 18.154

*In a subgroup analysis by age group, superiority of this medicinal product over SOC was consistently demonstratedin each age group.

The mean change in haemoglobin following eschar removal procedures on both patient level and procedurelevel was lower for patients treated with the medicinal product compared to SOC.

Time to Reach Complete Wound Closure

The time to reach complete (>95%) wound closure on a TW level was comparable between this medicinalproduct and SOC treatment arms. In the pooled adult population, the Kaplan‑Meier estimated median timeto complete wound closure (clustered data of TWs in a patient), was (this medicinal product [N=280] vs.

SOC [N=179]): 32 (95% CI: 29.0 - 34.0) days vs. 28 (95% CI: 24.0 - 29.0) days, respectively.

In the pooled paediatric population, the time to reach complete (>95%) wound closure on a TW level wascomparable in the medicinal product and SOC treatment arms. The Kaplan‑Meier estimated median timewas (this medicinal product [N=89] vs. SOC [N=86]): 31 (95% CI: 27.0 - 36.0) days vs. 31 (95% CI: 24.0 -37.0) days, respectively.

Results from both populations support the non-inferiority of the medicinal product compared with SOCbased on a 7-day non-inferiority margin.

Adults population

Exploratory pharmacokinetic analyses were performed in a subset of patients treated with this medicinalproduct who participated in study MW2010 (DETECT)

Evidence of systemic serum exposure was observed in all patients after topical administration of thismedicinal product. In general, it appears to be rapidly absorbed, with a median Tmax value of 4.0 hours(duration of treatment application). medicinal product exposure was observed with quantifiable serumconcentrations through 48 hours post dose administration.

Exposure results from study MW2010are listed in the table below.

Not all patients had values beyond 4 hours, as such the AUClast values for some patients only cover 4 hoursof exposure versus 48 hours of exposure for other patients.

There was a statistically significant correlation between serum Cmax and AUC0-4 values versus dose or%TBSA, suggesting a dose/treatment area dependent increase in exposure. The depth of the treatedwound has negligible impact on systemic exposure.

Summary of PK parameters* measured in all patients from Study MW2010

Study ID N Tmax Cmax Cmax/Dose AUC0-4 AUC0-4/Dose AUClast AUClast/Dose

Median (range) (h) (ng/mL) (ng/mL/g) (h*ng/mL) (h*ng/mL/g) (h*ng/mL) (h*ng/mL/g)

MW2010 21 4.0 (0.50 - 12) 200±184 16.4±11.9 516±546 39.8±29.7 2500±2330 215±202(Min=30.7)(Max=830)

*Values are reported as Mean ± SD, which the exception of Tmax, which is reported as Median (Min-Max).

AUClast=area under the curve until last measurable time-point, AUC0-4=area under the concentration-time curve from time zero totime 4h, Cmax=maximum observed concentration, Tmax=time at which the maximum concentration was observed

According to a literature report, in plasma, approximately 50% of bromelain binds to the human plasmaantiproteinases α2-macroglobulin and α1-antichymotrypsin.

The mean elimination half-life values ranged between 12 and 17 hours, supporting the decreased presencein serum at 72 hours post treatment.

When evaluated, a majority of patients had no quantifiable concentrations after 72 hours.

Exploratory pharmacokinetic analyses were performed in a PK sub-study of study MW2012 (CIDS). Theanalyses were performed on serum medicinal product concentration versus time data.

PK blood samples were collected from 16 patients treated with the medicinal product. All patients weretreated with a single application.

Evidence of systemic serum exposure was observed in all 16 patients for which PK samples were available.

Concentrations increased relatively rapidly, with median Tmax values between 2 to 4 hours, correspondingto the period of topical administration.

Systemic exposure to the medicinal product was in correlation with the topical dose applied.

Exposure results are listed in the table below.

Summary of PK parameters measured in patients from study MW2012(Age N* Tmax (h) Cmax Cmax/Dos AUC 0-4 AUC 0-4/ AUClast AUClast/Dgroup (ng/mL) e (h*ng/mL) Dose (h*ng/mL) oseyears) (ng/mL/g) (h*ng/mL/ (h*ng/mL/g) g)<2a 2 2.00 200 66.7 476 159 876 2924-11b 5 4.0 (2.0- 205±169 32.8±23.9 416±259 67.9±44.7 2240±2220 366±3504.0)12-18c 3 4.0 (2.0- 180±114 19.2±7.50 499±315 53.3±20.4 1560±887 174±67.44.0)

* Ten subjects were included in the main PK analyzes.

A majority of the patients had no quantifiable concentrations of the medicinal product after 48 hours, withno quantifiable concentrations in any patient at 72 hours

This medicinal product did not cause significant irritation when applied to intact mini-pig skin but causedsevere irritation and pain when applied to damaged (abraded) skin.

A single intravenous infusion of a solution prepared from the medicinal product powder in the mini-pigwas well tolerated at dose levels of up to 12 mg/kg (achieving plasma levels 2.5 fold of the human plasmalevel after application of the clinical proposed dose to 15% TBSA) but higher doses were overtly toxic,causing haemorrhage in several tissues. Repeated intravenous injections of doses up to 12 mg/kg everythird day in the mini-pig were well tolerated for the first four injections but severe clinical signs of toxicity(e.g. haemorrhages in several organs) were observed following the remaining two injections. Such effectscould still be seen after the recovery period of 2 weeks.

The medicinal product toxicological findings in juvenile minipigs were similar to that of adults. Topicalapplication of the medicinal product (0.09 g/g) to young pigs (2 months of age) did not cause any local andsystemic toxicological relevant findings when applied to burn wounds in a formulation and in a dosageregimen relevant for the human use of the product. Following repeated intravenous injections of doses 4, 8and 12 mg/kg every third day in juvenile mini-pigs, related changes were noted after the fifth dose on Day10 in all dose groups. The findings included convulsions and reddening of the skin, as well as findings suchas activity decreased, breathing difficulty, and ataxia in some of the animals.

A trend of increasing QT and QTc intervals was seen on Day 10 post dose in the treated animals. Thesevalues were obtained following significant clinical observations, described above.

In embryo-foetal development studies in rats and rabbits, intravenously administered this medicinalproduct 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 this medicinal productwas poorly tolerated by the parent animals, these studies are not considered relevant for human riskassessment. This medicinal product showed no genotoxic activity when investigated in the standard set ofin vitro and in vivo studies.

Ammonium sulphate

Acetic acid

Carbomer 980disodium phosphate anhydrous

Sodium hydroxide

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section6.6.

3 years.

From a microbiological point of view and as the enzymatic activity of the product decreases progressivelyfollowing mixing, the reconstituted product should be used immediately after preparation (within15 minutes).

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.

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 coveredwith a screw cap (tamper-proof polypropylene).

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

There are reports of occupational exposure to bromelain leading to sensitisation. Sensitisation may haveoccurred due to inhalation of bromelain powder. Allergic reactions to bromelain include anaphylacticreactions and other immediate-type reactions with manifestations such as bronchospasm, angiooedema,urticaria, and mucosal and gastrointestinal reactions. When mixing this medicinal product powder with thegel, appropriate handling, including wearing of gloves and protective clothing as well as eye shieldingglasses and a surgical mask, is required (see section 4.4). The powder should not be inhaled, see section 4.2

Accidental eye exposure must be avoided. In case of eye exposure, exposed eyes must be irrigated withcopious amounts of water for at least 15 minutes. In case of skin exposure, this medicinal product must berinsed off with water.

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

* The powder vial must be opened by carefully tearing off the aluminium cap and removing the rubberstopper.

* When opening the gel bottle, it must be confirmed that the tamper-evident ring is separating from thebottle’s cap. If the tamper-evident ring was already separated from the cap before opening, the gelbottle 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 isobtained. 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 localrequirements.

MediWound Germany GmbH

Hans-Sachs-Strasse 10065428 Rüsselsheim

Germanye-mail: info@mediwound.com

EU/1/12/803/001

EU/1/12/803/002

Date of first authorisation: 18.12.2012

Date of latest renewal: 12.08.2022

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

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