NexoBrid · 4.4 Special warnings and precautions for use · 1

HOS-155233 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile 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) (89 patients in total) from studies, MW2004, MW2008 and MW2012 in the medicinal product arm were pyrexia 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 to remove 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 the treatment for 4 hours with an occlusive dressing for containment of this medicinal product on the wound. Infections and infestations Common: Wound infection including cellulitis* Immune system disorders Common: Non serious allergic reactions such as rasha Not known: Serious allergic reactions including anaphylaxisa 8 Cardiac disorders Common: Tachycardia* Skin and subcutaneous tissue disorders Common: Wound complications*, local rash, local pruritus, Uncommon: intradermal haematoma General disorders and administration site conditions Very common: Pyrexia/hyperthermia* Common: Local pain* *see Description of selected adverse reactions below. a see section 4.4. Description of selected adverse reactions Pyrexia/hyperthermia In pooled adult population from studies MW2004, MW2005, MW2008 and MW2010 with routine antibacterial soaking of the treatment area before and after this medicinal product application (see section 4.2), pyrexia hyperthermia and increased body temperature were reported in 13.3.% of the adult patients treated with this medicinal product vs. 9.7%, of the patients treated according to standard of care (SOC). In early studies without antibacterial soaking (

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HOS-155229 · has-contraindication-information · PDF-Seite 4

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

HOS-155228 · has-indication-information · PDF-Seite 2

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

HOS-155231 · has-interaction-information · PDF-Seite 7

No interaction studies have been performed. Medicinal products that affect coagulation 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.). CYP2C8 and CYP 2C9 substrates 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). Topical antibacterial medicinal products Topically applied antibacterial medicinal products (e.g. silver sulfadiazine or povidone iodine) may decrease the efficacy of this medicinal product (see section 4.4). Fluorouracil and vincristine Bromelain may enhance the actions of fluorouracil and vincristine. Patients should be monitored for increased toxicity. ACE inhibitors 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. Benzodiazepines, barbiturates, narcotics and antidepressants 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. Paediatric population 7 No interaction studies have been performed in children/adolescents.

HOS-155232 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are no data from the use of concentrate of proteolytic enzymes enriched in bromelain in pregnant women. Animal studies are insufficient to properly assess the potential of this medicinal product to interfere with embryonal/foetal development (see section 5.3). Since the safe use of medicinal product during pregnancy has not yet been established, it 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 new-borns/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 this medicinal product on fertility.

HOS-155230 · has-warning-information · PDF-Seite 4

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Hypersensitivity reactions 4 The potential of this medicinal product (a protein product) to cause sensitisation should be taken into account. There have been reports of serious allergic reactions including anaphylaxis (with manifestations such as rash, 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, but possible 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 anaphylactic reactions and other immediate-type reactions with manifestations such as bronchospasm, angiooedema, urticaria, and mucosal and gastrointestinal reactions). No occupational hazard was found in a study assessing 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 airway exposure have been reported. History of allergy needs to be established prior to the administration (see sections 4.3 and 6.6). Skin exposure In case of skin exposure, this medicinal product should be rinsed off with water to reduce the likelihood of skin sensitisation (see section 6.6). Cross-sensitivity Cross-sensitivity between bromelain and papaya/papain as well as latex proteins (known as latex-fruit syndrome), bee venom, and olive tree pollen has been reported in the literature. Analgesia Enzymatic debridement is a painful procedure, and may only be administered after adequate analgesia and/or anesthesia has been established. Burn wounds for which this medicinal product is not recommended This treatment 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

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