Nexobrid: Package Insert / Prescribing Info

2.1 Important Administration Information

NEXOBRID is only to be administered by a healthcare provider. Take precautions to avoid exposure to NEXOBRID during preparation and handling (e.g., use gloves, surgical masks, other protective coverings, as needed) [see Warnings and Precautions (5.1)].

Use pain management as practiced for an extensive dressing change of burn wounds 15 minutes prior to and throughout all NEXOBRID-related procedures.

NEXOBRID is available as:

• 2 g of lyophilized powder (containing 1.94 grams of anacaulase-bcdb) with a 20 g gel vehicle, for treatment of up to 180 cm2 of burn area after mixing.
• 5 g lyophilized powder (containing 4.85 grams of anacaulase-bcdb) with a 50 g gel vehicle, for treatment of up to 450 cm2 of burn area after mixing.

NEXOBRID lyophilized powder and gel vehicle must be mixed no more than 15 minutes prior to administration. Discard NEXOBRID if not used within 15 minutes of preparation, as the enzymatic activity of the product decreases progressively following mixing.

Each vial of lyophilized powder, jar of gel vehicle, and the mixed NEXOBRID are for use for only one patient and for one application [see Dosage and Administration (2.4)].

NEXOBRID is for topical use only.

Apply an ointment skin protectant around the treatment area to create an ointment barrier [see Dosage and Administration (2.3)].

2.2 Recommended Dosage

Recommended Dosage in Adults
Apply a 3 mm thick layer (approximate thickness of a tongue depressor) of NEXOBRID to a burn wound area of up to 15% body surface area (BSA) in one application in adult patients. Remove NEXOBRID after 4 hours [see Dosage and Administration (2.5)].

A second application of NEXOBRID may be applied 24 hours following the first application to either the same area previously treated with NEXOBRID or to a new area in adult patients. Apply a second application if:

• The wound area is more than 15% BSA, or
• Multiple wound areas on different body surfaces require two treatments for logistical reasons such as body position, or
• The first application's eschar removal was not complete.

For both applications, the total treated area must not exceed 20% BSA.

Recommended Dosage in Pediatric Patients

Pediatric Patients 6 Years of Age and Older

Apply a 3 mm thick layer (approximate thickness of a tongue depressor) of NEXOBRID to a burn wound area of up to 15% BSA in one application in pediatric patients 6 years of age and older. Remove NEXOBRID after 4 hours [see Dosage and Administration (2.5)]. A second application of NEXOBRID is not recommended.

Pediatric Patients Less Than 6 Years of Age

Apply a 3 mm thick layer (approximate thickness of a tongue depressor) of NEXOBRID to a burn wound area of up to 10% BSA in one application in pediatric patients less than 6 years of age. Remove NEXOBRID after 4 hours [see Dosage and Administration (2.5)]. A second application of NEXOBRID is not recommended.

2.3 Preparation of Patient and Burn Wound Treatment Area

Prepare the wound area as follows:

1. Thoroughly clean the wound to remove any charred tissue, blisters, and any topical products.
2. Apply a dressing soaked with an antibacterial solution to the treatment area for at least 2 hours.
   
3. Ensure the wound bed is clear of any remnants of topical agents (e.g., silver sulfadiazine, povidone iodine).
4. Apply an ointment skin protectant (e.g., petrolatum) 2 to 3 cm outside of the treatment area to create an ointment barrier. Avoid applying the protectant ointment to the treatment area itself, as this would impede direct contact of NEXOBRID with the eschar.
5. Protect any other open wounds (e.g., laceration, abraded skin, escharotomy incision) with skin protectant ointments or ointment gauze to prevent possible exposure to NEXOBRID.
   

2.4 Preparation and Application of NEXOBRID

Gather the following sterile supplies prior to NEXOBRID preparation and application:

• Instrument for mixing (e.g., spatula or tongue depressor)
• Tongue depressor for NEXOBRID application
• 0.9% Sodium Chloride Irrigation
• Occlusive film dressing
• Loose, thick fluffy dressing and bandage

Preparation
Prepare NEXOBRID at the patient’s bedside within 15 minutes of the intended application.

Using aseptic technique, mix NEXOBRID lyophilized powder and gel vehicle as follows:

1. Pour the NEXOBRID lyophilized powder into the gel vehicle jar.
2. Thoroughly mix the NEXOBRID lyophilized powder and gel vehicle using a sterile instrument (e.g., tongue depressor or spatula) until the mixture is uniform. The mixed lyophilized powder and gel vehicle produce NEXOBRID in a final concentration of 8.8% w/w.

DISCARD NEXOBRID IF NOT USED WITHIN 15 MINUTES OF PREPARATION, as the enzymatic activity of NEXOBRID decreases progressively following mixing.

Application
Apply NEXOBRID within 15 minutes of preparation as follows:

1. Moisten the treatment area by sprinkling sterile 0.9% Sodium Chloride Irrigation onto the burn wound.
2. Using a sterile tongue depressor, completely cover the moistened burn wound treatment area with the mixed NEXOBRID in a 3 mm thick layer (approximate thickness of a tongue depressor). Ensure NEXOBRID covers the entire target treatment area.
3. Cover the treated wound with a sterile occlusive film dressing.
4. Gently press the occlusive film dressing at the area of contact with the ointment barrier to ensure adherence between the occlusive film dressing and the ointment barrier and to achieve complete containment of NEXOBRID on the treatment area. There should be no visible air under the occlusive film dressing.
5. Cover the occlusive film dressing with a sterile loose, thick, fluffy dressing and secure with a sterile bandage.
6. Discard any unused portions of NEXOBRID.

2.5 Removal of NEXOBRID

Remove NEXOBRID after 4 hours. Gather the following sterile supplies prior to NEXOBRID removal:

• Blunt-edged instruments (e.g., tongue depressor)
• Large dry gauze
• Gauze soaked with 0.9% Sodium Chloride Irrigation
• Dressing soaked with an antibacterial solution

1. Remove the occlusive film dressing using aseptic technique.
2. Remove the ointment barrier using a sterile blunt-edged instrument.
3. Remove the dissolved eschar from the wound by scraping it away with a sterile blunt-edged instrument.
4. Wipe the wound thoroughly with a large sterile dry gauze, then wipe with a sterile gauze that has been soaked with sterile 0.9% Sodium Chloride Irrigation. Rub the treated area until the appearance of a clean dermis or subcutaneous tissues with pinpoint bleeding.
5. To remove remnants of dissolved eschar, apply a dressing soaked with an antibacterial solution for at least 2 hours.

2.6 Monitoring

Monitor patients for signs of local or systemic allergic reactions. If a hypersensitivity reaction occurs, remove NEXOBRID (if applicable) from the treatment area and initiate appropriate therapy [see Contraindications (4), Warnings and Precautions (5.1)].

5.1 Hypersensitivity Reactions

NEXOBRID-Treated Patients

Serious hypersensitivity reactions, including anaphylaxis, have been reported with postmarketing use of NEXOBRID. If a hypersensitivity reaction occurs, remove NEXOBRID (if applicable) and initiate appropriate therapy.

NEXOBRID is contraindicated in patients with a known hypersensitivity to anacaulase- bcdb, bromelain, pineapples or to any other component of NEXOBRID. NEXOBRID is also contraindicated in patients with known hypersensitivity to papayas or papain because of the risk of cross-sensitivity.

Healthcare Providers Preparing and Applying NEXOBRID

Healthcare personnel should take appropriate precautions to avoid exposure when preparing and handling NEXOBRID (e.g., gloves, surgical masks, other protective coverings, as needed). In the event of inadvertent skin exposure, rinse NEXOBRID off with water to reduce the likelihood of skin sensitization.

5.2 Coagulopathy

A 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, a component of NEXOBRID. In vitro and animal data suggest that bromelain can also promote fibrinolysis.

Avoid use of NEXOBRID in patients with uncontrolled disorders of coagulation. Use NEXOBRID with caution in patients on anticoagulant therapy or other drugs affecting coagulation, and in patients with low platelet counts and increased risk of bleeding from other causes (e.g., peptic ulcers and sepsis). Monitor patients for possible signs of coagulation abnormalities and signs of bleeding.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice.

Adults:

Studies 1 and 2 evaluated subjects undergoing eschar removal for deep partial thickness (DPT) and/or full thickness (FT) thermal burns [see Clinical Studies (14)]. An integrated analysis of safety data from Studies 1 and 2 compared NEXOBRID (n=177) to standard of care (SOC) (n=149). The SOC treatment included both surgical and non-surgical eschar removal methods.

The mean age of the safety population was 35.6 years; 73% were male; 81% were White, 9% were Black, 6% were other races, and 3% were Asian. Regarding burn etiology, 65% had fire/flame burns, 26% had scald burns, 8% had contact burns, and <1% had burns of other etiology. The mean body surface area (BSA) of wounds that received study treatment was 9.2±5.07%. Mean BSA of all burn wounds was 12.0±6.05%. Of the 177 subjects who were treated with NEXOBRID in Studies 1 and 2, 159 (90%) received one treatment of NEXOBRID, and 18 (10%) received 2 treatments.

Table 1 presents adverse reactions that occurred in ≥ 1% of subjects in the NEXOBRID arm and at a higher incidence than the SOC arm, up to 3 months following wound closure.

Pediatric Subjects:

Study 3 (CIDS study) evaluated pediatric subjects undergoing eschar removal for deep partial thickness (DPT) and/or full thickness (FT) thermal burns [see Clinical Studies (14)]. A total of 139 subjects (69 NEXOBRID, 70 SOC) were treated in the study. The SOC treatment included both surgical and non-surgical eschar removal methods.

The mean age was comparable in the NEXOBRID (5.89 years) and SOC (5.75 years) arms. The majority of subjects were male (59% NEXOBRID, 69% SOC). For race, 70% NEXOBRID and 69% SOC subjects were White, 25% NEXOBRID and 23% SOC subjects were Asian, 4% NEXOBRID and 3% SOC subjects were Black or African American, and 1% NEXOBRID and 4% SOC subjects were other races. For ethnicity, 4% NEXOBRID and 10% SOC subjects identified as Hispanic or Latino. The majority of burns in both treatment arms (NEXOBRID and SOC) were due to scald (68% and 67%). The majority of patients in both treatment groups (NEXOBRID and SOC) had 1 treated wound (71% and 80%, respectively).

Table 2 presents adverse reactions that occurred in ≥ 1% of subjects in the NEXOBRID arm and at a higher incidence than the SOC arm, up to 3 months following wound closure.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of anacaulase-bcdb outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: Hypersensitivity, including anaphylaxis and urticaria

8.1 Pregnancy

Risk Summary

There are no available data on NEXOBRID use in pregnant women to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In embryofetal developmental studies in rats and rabbits, intravenous doses up to 4 and 0.1 mg/kg/day NEXOBRID were administered to pregnant rats and rabbits, respectively, during organogenesis. No significant developmental toxicities were observed in these studies. However, severe maternal toxicities were noted and the tolerable maternal exposure levels were much lower compared with the maximum human exposure in clinical setting.

8.2 Lactation

Risk Summary

There are no data on the presence of anacaulase-bcdb in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEXOBRID and any potential adverse effects on the breastfed infant from NEXOBRID or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of NEXOBRID for eschar removal have been established in pediatric patients with deep partial thickness and/or full thickness thermal burns. Use of NEXOBRID for this indication is supported by evidence from one adequate and well-controlled trial in 69 pediatric subjects treated with NEXOBRID [see Clinical Studies (14)].

8.5 Geriatric Use

Of the 177 subjects exposed to NEXOBRID for eschar removal in deep partial thickness (DPT) and/or full thickness (FT) thermal burns, 6 (3%) subjects were 65 years or older, and 1 (< 1%) subject was 75 years or older [see Clinical Studies (14)]. Clinical trials of NEXOBRID did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

12.1 Mechanism of Action

The mixture of enzymes in NEXOBRID dissolves burn wound eschar. The specific components responsible for this effect have not been identified.

12.2 Pharmacodynamics

The pharmacodynamics of NEXOBRID are unknown.

Cardiac Electrophysiology

At the approved recommended dose, NEXOBRID did not prolong the QT interval in humans to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

For adults and pediatric subjects 4 years of age and older, NEXOBRID applied to deep partial and full thickness burn wounds is absorbed, with median serum Tmax of 4 hours (during the treatment application). Systemic exposure (i.e., AUC) of bromelain, a component of anacaulase-bcdb is correlated with the size of the treated area and NEXOBRID dose, but not the depth of the burn wound. The systemic exposure in pediatric subjects was comparable to adults.

In adult subjects, Cmax and the dose‑normalized Cmax values after the first and second application (mean dosing interval of 17 hours) are comparable and only slight accumulation (less than 2-fold difference) is seen in AUC0-4 and AUC0-4 dose‑normalized levels after the second application, compared to the first application.

Elimination

A majority of adults and pediatric subjects had no quantifiable serum concentrations after 72 hours. The mean ± SD terminal half-life of bromelain, a component of anacaulase-bcdb, is 12 ± 4.4 hours.

Drug Interaction Studies

Effect of NEXOBRID on Other Drugs

Bromelain, a component of anacaulase-bcdb, exhibited CYP2C8 time-dependent inhibition in human hepatocytes and inhibited human microsomal CYP2C9. No clinical studies have been conducted to assess the potential for systemic drug interactions.

12.6 Immunogenicity

There is insufficient information to characterize the anti-drug antibody response to anacaulase- bcdb and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of NEXOBRID.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity or fertility studies have not been conducted with anacaulase-bcdb.

Anacaulase-bcdb was not genotoxic in a bacterial reverse mutation assay and an in vitro mammalian chromosome aberration assay.

14.1 Adults

The efficacy of NEXOBRID for the eschar removal of deep partial thickness (DPT) and full thickness (FT) thermal burns has been investigated in two trials.

Study 1
NEXOBRID was investigated in the DETECT randomized, controlled, assessor-blinded, three-arm trial, comparing NEXOBRID, standard of care (SOC), and gel vehicle treatment in subjects with DPT and/or FT thermal burns of 3 - 30% BSA (Study 1, NCT02148705). SOC included both surgical and non-surgical methods for eschar removal per the investigators’ discretion. Subjects on the NEXOBRID and gel vehicle arms who had eschar remaining following the topical treatment period were treated with SOC. NEXOBRID was compared to gel vehicle for the incidence of ≥95% eschar removal at the end of the topical treatment period. NEXOBRID was also compared with SOC for the incidence of surgical eschar removal (tangential, minor, avulsion, Versajet and/or dermabrasion excision) and time to eschar removal.

A total of 175 subjects were randomized in a 3:3:1 ratio (NEXOBRID : SOC : gel vehicle) and 169 subjects were treated. The mean age was 41 years, 70% of subjects were male and 30% were female, and 81% were White, 14% were Black or African American, 5% were other races, and 1% were Asian. Seventeen percent of subjects were Hispanic or Latino. Subjects had one or more target wounds (TWs) to be treated for eschar removal. The mean percentage BSA of all TWs per subject was 6.1%. The majority of subjects (82%) had one to two TWs.

The incidence of ≥95% eschar removal at the end of the topical treatment period for subjects in the NEXOBRID and gel vehicle groups is shown in Table 3.

The incidence of surgical eschar removal (tangential, minor, avulsion, Versajet and/or dermabrasion excision) and time to ≥95% eschar removal for the NEXOBRID and SOC groups are shown in Table 4.

The median time to eschar removal was 1 day on the NEXOBRID arm and 3.8 days on the SOC arm.

The estimated median time to ≥95% wound closure for all TWs on a subject was 31 days for the NEXOBRID arm and 36 days for the SOC treatment arm. Subjects were not evaluated frequently enough after achieving ≥95% wound closure to adequately assess time to 100% wound closure.

Study 2
NEXOBRID was investigated in a multicenter, open-label, randomized, two-arm trial, comparing NEXOBRID to SOC treatment in subjects with DPT and/or FT thermal burns of 5 - 24% BSA (Study 2; NCT00324311). SOC included both surgical and non-surgical methods for eschar removal per the investigators’ discretion. The trial enrolled 182 subjects. The first subject at each site (26 subjects) was not randomized and was treated with NEXOBRID. The remaining 156 subjects were randomized to NEXOBRID or SOC. The efficacy assessments were analyzed on DPT burns only.

Demographics were similar across both arms. The mean age was 29.9 years. Approximately 80% of the study subjects were adults (≥18 years), 74% were male and 26% were female, 82% were White, 7% were other races, 6% were Black, and 5% were Asian.

The incidence of surgical eschar removal (tangential, minor, avulsion, Versajet and/or dermabrasion excision) for the NEXOBRID and SOC groups is shown in Table 5.

In randomized subjects, the estimated median time to ≥95% wound closure was 33 days for the NEXOBRID arm and 24 days for the SOC treatment arm. Subjects were not evaluated frequently enough after achieving ≥95% wound closure to adequately assess time to 100% wound closure.

14.2 Pediatric Subjects

Study 3
NEXOBRID was investigated in the CIDS study which was an open label, randomized, controlled, two arm trial comparing NEXOBRID and standard of care (SOC) treatment in subjects 7 months to 18 years of age with DPT and/or FT thermal burns of ≥1% - 30% BSA (Study 3, NCT02278718). SOC included both surgical and nonsurgical methods for eschar removal per the investigator’s discretion. Subjects on the NEXOBRID arm who had eschar remaining following the topical treatment period were treated with SOC. NEXOBRID was compared with SOC for the time to eschar removal and for the incidence of surgical eschar removal (tangential, minor, avulsion, Versajet and/or dermabrasion excision).

A total of 145 subjects were randomized in a 1:1 ratio (NEXOBRID:SOC) and 139 subjects were treated. The mean age was approximately 6 years, with a median of 3.4 years in the NEXOBRID group and 3.9 years in the SOC group. In the trial, 62% were male, 70% were White, 23% were Asian, 4% were Black or African American, and 3% were other races; for ethnicity, 7% identified as Hispanic or Latino. Subjects had one or more target wounds (TWs) to be treated for eschar removal. The mean percentage BSA of all TWs per subject was 5.6%. The majority of subjects in both treatment groups had 1 TW (71.0% for NEXOBRID and 80.0% for SOC).

The median time to ≥95% eschar removal is shown in Table 6.

The incidence of surgical eschar removal (tangential, minor, avulsion, Versajet and/or dermabrasion excision) is shown in Table 7.

The estimated median time to ≥95% wound closure for all target wounds on a subject was 32 days for the NEXOBRID arm and 34 days for the SOC treatment arm. The estimated median time reach 100% wound closure on a target wound level was 44 days for NexoBrid arm and 43 days for the SOC arm.