CULTURED EPIDERMAL AUTOGRAFTS (CEA) CPT CODING GUIDE

Transcription

1 CULTURED EPIDERMAL AUTOGRAFTS (CEA) CPT CODING GUIDE Select reimbursement codes associated with Epicel and the CEA procedure in burn treatment CPT Code Guide Add Surgical Prep Add CEA Application Add CEA Product Separate Service NA NA NA Each additional 100 cm2 or each additional 1% of body area of infants and children Tissue cultured epidermal autograft, trunk, legs, arms: first 25 cm2, or less Additional 1 cm2 to 75 cm Each additional 100 cm2, or each 1% BSA of infants and children Tissue cultured epidermal autograft, face scalp, eyelids, mouth, neck, ear orbits, genitalia, hands, feet and/or multiple digits: first 25 cm2 or less Additional 1 cm2 to 75 cm Each additional 100 cm, or each 1% BSA of infants and children - Q4100 Skin substitute, not otherwise specified - CPT Process CPT Code1 Description of Service Biopsy Harvest skin for tissue cultured autograft, 100 cm2 or less Surgical preparation or creation of recipient site by excision of open wounds, burn, eschar, or scar (including subcutaneous tissues), or incisional release of scar contracture, trunk, arms, legs; first 100 cm2 or 1% of body area of infants and children Each additional 100 cm2 or each additional 1% of body area of infants and children Surgical preparation or creation of recipient site by excision of open wounds, burn eschar, or scar (including subcutaneous tissues), or incisional release of scar contracture, face, scalp, eyelids, neck ears, orbits, genitalia, hands, feet and/or multiple digits; first 100 cm2 or 1% of body area of infants and children Surgical Preparation CEA Application CEA Product Use in Conjunction Use in Conjunction Use in Conjunction Use in Conjunction 2 Surgical Prep Example Surgical preparation of 125 cm2 on the right thigh and a 125 cm2 on the left thigh would be reported with for the first 100 cm2 and with 2 units for the remainng 150 cm2 CEA Application Example Tissue cultured epidermal graft: A 125 cm2 CEA graft on the right thigh and a 125 cm2 CEA graft on the left thigh would be reported with CPT code for the first 25 cm2, for 75 cm2 and with 2 units for the remaining 150 cm2 CEA Product Q4100 is billed with 1 unit for every 1 cm cm2 on the right thigh and a 125 cm2 on the left thigh would be reported with Q4100 with 250 units Needs Invoice For assistance or additional information regarding Epicel or related procedures, call CEA-SKIN ( ) or visit Epicel.com Please note: This document is not intended to be a directive, nor is it a suggestion about the likelihood of obtaining reimbursement. This list is not all inclusive, and physician and staff may deem other codes more appropriate. Providers should select coding options that most accurately reflect a patient s condition, the provider s system guidelines, payor requirements and services rendered. Humanitarian Device: Epicel (cultured epidermal autografts) is authorized for use in adults and pediatric patients who have deep dermal or full thickness burns comprising a total body surface area greater than or equal to 30%. It may be used in conjunction with split-thickness autografts, or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns. The effectiveness of the device for this use has not been demonstrated. 1 American Medical Association (AMA) Notice CPT codes, descriptions and other data only are copyright 2016 American Medical Association. All rights reserved.

2 INDICATION Epicel (cultured epidermal autografts) is indicated for use in adults and pediatric patients who have deep dermal or full thickness burns comprising a total body surface area greater than or equal to 30%. It may be used in conjunction with split-thickness autografts, or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns. IMPORTANT SAFETY INFORMATION Epicel is contraindicated in patients with a history of anaphylaxis following exposure to vancomycin, amikacin, and amphotericin, as trace quantities of these anti-infective agents may remain in the Epicel autograft. Epicel should not be used in patients with known sensitivities to materials of bovine or murine origin. It is contraindicated for use on clinically infected wounds. Because Epicel is manufactured with and contains residual amounts of murine cells, FDA considers it a xenotransplantation product. Therefore, recipients should not donate whole blood, blood components, source plasma, source leukocytes, tissues, breast milk, ova, sperm, or other body parts for use in humans because there is a potential risk of carrying an infection that is transmitted from mouse cells to humans. Squamous cell carcinoma (SCC) has been reported in patients with burn injury after being grafted with Epicel. Although SCC is a known complication of burn scars, the role of Epicel in the causation of SCC cannot be excluded. The Epicel product is intended solely for autologous use. Patients undergoing the surgical procedure associated with Epicel are not routinely tested for transmissible infectious diseases. Discontinue use if the patient shows evidence of allergic reaction. If clinical signs of infection are present or develop, do not apply Epicel until the infection is adequately treated. The effectiveness of Epicel has not been proven in clinical studies. The long-term safety of Epicel is unknown. Over the past 27 years, the mortality from all causes was 13% before hospital discharge. Men and women who intend to have children should be advised that the effects, if any, of Epicel on fetal development have not been assessed. In addition, the safety of Epicel has not been studied in pregnant and nursing women. Patient information supplied by attending burn teams from 1989 to 1996 reported the adverse events of highest incidence as: death (13%), infection (13.8%), graft tear (7.8%) or graft blister (4.2%) and drainage (3.3%). Some of these events may have been due to the underlying burn injury and not the device itself. From June 1998 through September, 2015 adverse events received by Genzyme Biosurgery (predecessor in interest to Vericel) and Vericel Corporation were similar to the previously identified adverse events. Events that were reported in 1% of patients included multi-organ failure (6.6%), sepsis (5.2%), infection (4%) and skin graft failure/graft complication (2.7%). The relationship of these events to Epicel has not been established. Please see accompanying Directions for Use. 64 Sidney Street Cambridge, MA EPICEL is a registered trademark of Vericel Corporation Vericel Corporation. All rights reserved. Printed in USA. PP.US.EPI.0024

3 Epicel (cultured epidermal autografts) HDE# BH Directions for Use HUMANITARIAN DEVICE: Authorized by Federal law for use in adult and pediatric patients who have deep dermal or full-thickness burns comprising a total body surface area greater than or equal to 30%. Epicel may be used in conjunction with split-thickness autografts, or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns. The effectiveness of the device for this use has not been demonstrated. CAUTION: Federal law restricts this device to sale by or on the order of a physician. DESCRIPTION Epicel (cultured epidermal autografts) is an aseptically processed wound dressing composed of the patient s own (autologous) keratinocytes grown ex vivo in the presence of proliferationarrested, murine (mouse) fibroblasts. Epicel consists of sheets of proliferative, autologous keratinocytes, ranging from 2 to 8 cell layers thick and is referred to as a cultured epidermal autograft. Each graft of Epicel is attached to petrolatum gauze backing with titanium surgical clips and measures approximately 50 cm 2 in area. Epicel is defined by the Public Health Service (PHS) Guideline on Infectious Disease Issues in enotransplantation and the FDA Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of enotransplantation Products in Humans as a xenotransplantation product because it is manufactured by co-cultivation with proliferationarrested mouse, 3T3, fibroblast feeder cells. Please refer to the FDA xenotransplantation page for these guidelines and further xenotransplantation information: For recommendations regarding Epicel recipient blood and tissue donation, please refer to the Patient Counseling section. The mouse 3T3 cells have been extensively tested for the presence of infectious agents. Those tests include sterility testing for bacterial and fungal contamination, testing for mycoplasma contamination, and screening for viral and retroviral contaminants. Additional evaluations regarding the proliferative potential of the mouse 3T3 cells, their potential to undergo transformation and their karyology have been conducted. Epicel is evaluated for sterility via a pre-release sterility assessment and is verified for sterility by a standard 14-day sterility 1

4 assessment, post-release. Reagents used in the manufacture of Epicel are tested for sterility and endotoxin content. The manufacturing process is periodically monitored for the possibility of mycoplasma contamination. Product manufacture includes reagents derived from U.S. herd animal sources and is tested for sterility and viruses. Patients and the biopsy tissue (autologous cells) harvested from them (to manufacture Epicel) are not routinely tested for transmissible infectious agents. INDICATIONS FOR USE Epicel is indicated for use in adult and pediatric patients who have deep dermal or full thickness burns comprising a total body surface area greater than or equal to 30%. It may be used in conjunction with split-thickness autografts, or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns. CONTRAINDICATIONS Do not use in patients with a history of hypersensitivity following exposure to vancomycin, amikacin, or amphotericin, as trace quantities of these anti-infective agents may remain in the Epicel autograft. Do not use in patients with sensitivities to materials of bovine or murine origin. The cell culture medium used in the culture of Epicel contains bovine serum and the cells are co-cultured with murine 3T3 fibroblasts. The medium used to package and transport Epicel does not contain serum; however, trace quantities of bovine-derived proteins may be present (see the How Supplied section for a listing of manufacturing reagents). Do not use on clinically infected wounds (see also Precautions). WARNINGS Hypersensitivity Reactions Do not continue to graft patients with Epicel if the patient shows evidence of an allergic reaction. Allergic reactions or hypersensitivity reactions may manifest themselves as classical Type I-IV immune responses, e.g., anaphylaxis, hemolysis, antigen/antibody complex formation or a cell-mediated/delayed immune response. Squamous Cell Carcinoma (SCC) Squamous cell carcinoma (SCC) has been reported in patients with burn injury after being grafted with Epicel. Distinctive features of these cases include multicentric location, large size, 2

5 aggressive growth, local recurrence after resection, and fatal outcome in some of the cases. In the reported cases, the SCC occurred in the grafted areas 12 to 19 years after Epicel grafting. A latency period of 32 ± 18 years from the time of burn injuries to occurrence of SCC is described in the literature. 1 A patient with epidermolysis bullosa dystrophica (DEB) developed an invasive SCC a few days after grafting with Epicel. The patient underwent a lower extremity amputation within weeks of diagnosis. Of the three patients diagnosed with SCC with known age, one was an eight-year-old child at the time of treatment with Epicel. The child was diagnosed with SCC in the area of the Epicel graft 11 years and 7 months after treatment, and the outcome was fatal. Although SCC is a known complication of burn scars and DEB, the role of Epicel in the causation of SCC cannot be excluded. Blood and Organ Donations Epicel recipients should not donate whole blood, blood components, source plasma, source leukocytes, tissues, breast milk, ova, sperm, or other body parts for use in humans because Epicel is manufactured by co-cultivation with murine cells and contains residual murine cells; therefore, it is a xenotransplantation product (see Description). Infectious Agent Transmissions Health care providers should employ universal precautions in handling the biopsy samples and the Epicel product. Patients undergoing the surgical procedure associated with Epicel are not routinely tested for transmissible infectious diseases. Therefore, the Epicel biopsy and the autologous Epicel product may carry the risk of transmitting infectious diseases to health care providers handling these tissues. PRECAUTIONS Agents Harmful to Epicel Do not use cytotoxic agents with Epicel. Do not use Hibiclens (chlorhexidine gluconate) to treat wound bed infections in patients who have received or are expected to receive Epicel. Please refer to a list of anti-infective agents in the Pre-Grafting Considerations section in the Directions for Use. These are agents that have been used clinically and have not been observed to cause significant inhibitory effects on keratinocytes in vitro, or for which limited clinical experience has been obtained. 3

6 Wound Bed Infection If clinical signs of infection (pain, edema, erythema, warmth, drainage, odor or unexplained fever) are present or developing, do not apply Epicel until the infection is adequately treated. Epicel is more susceptible to wound bed conditions and bacterial colonization, compared to meshed split-thickness autografts. All infections should be evaluated and treated according to standard clinical practice. Potential Infection from Murine Cells Although the murine cells used in the manufacture of Epicel have been tested and found to have no detectable bacteria, fungi and viruses, the possibility of Epicel containing an infectious agent(s) cannot be excluded. The risk of infection transmitted by Epicel is unknown. It is also possible that symptoms or signs of an infection transmitted by Epicel may not be reported or seen for months or years. To date, Vericel is not aware of any infections related to murine cells. Impairment of Fertility Pregnancy Nursing Mothers Men and women who intend to have children should be advised that the effects, if any, of Epicel on fetal development have not been assessed. In addition, the safety of Epicel has not been studied in pregnant and nursing women. ADVERSE REACTIONS The mortality from all causes was 13% before hospital discharge. The most common adverse reactions, occurring in 2% of patients with deep dermal or full thickness burn injuries treated with Epicel were infection, graft shear, blister, drainage, sepsis, graft detachment, and renal failure. Epicel Clinical Experience Because data are collected under widely varying conditions, adverse reactions observed for Epicel cannot be directly compared to rates in the clinical trials of another device and may not reflect the rates observed in practice. The overall safety information for Epicel is derived from two Epicel safety databases, comprised of pediatric and adult patients who received Epicel treatment. The data are summarized in Table 1 and Table 2. Table 1 ( , n=552) includes 205 children (aged 21 years and younger, with 71% males) and 347 adults (mean age of 39 years with 76% males). The adverse reactions were collected from treating physicians or burn teams. Total number of deaths was 74 (13%). 4

7 Table 1: Adverse Reactions Reported in 1% of Patients with Deep Dermal or Full Thickness Burn Injuries (n = 552) Treated with Epicel Number of Patients with any AE n (%) and total number of AEs Pediatric (n = 205) Number of Patients (%) Adult (n = 347) 94 (45.9%) 185 (53.3%) Total (n = 552) 279 (50.5%) Number of Adverse Reactions Pediatric Adult Total Colonization/Infection 31 (15.1%) 45 (13.0%) 76 (13.8%) Graft Shear 11 (5.4%) 32 (9.2%) 43 (7.8%) Blister 9 (4.4%) 14 (4.0%) 23 (4.2%) Drainage, wet or macerated Cleaning damage or unclean bed 8 (3.9%) 10 (2.9%) 18 (3.3%) (3.9%) 9 (2.6%) 17 (3.1%) Sepsis, Septic Shock 7 (3.4%) 10 (2.9%) 17 (3.1%) Epicel Damage 6 (2.9%) 8 (2.3%) 14 (2.5%) Graft Detachment 6 (2.9%) 8 (2.3%) 14 (2.5%) Grafts Debrided with Dressing 2 (1.0%) 9 (2.6%) 11 (2.0%) Renal Failure or Disorder 0 11 (3.2%) 11 (2.0%) Wound heal impaired or slow Poor blood (platelets, RBCs) 2 (1.0%) 5 (1.4%) 7 (1.3%) (0.5%) 5 (1.4%) 6 (1.1%) Multi-organ failure 1 (0.5%) 5 (1.4%) 6 (1.1%) Pressure/friction on site 2 (1.0%) 4 (1.2%) 6 (1.1%) Takedown improper 2 (1.0%) 4 (1.2%) 6 (1.1%) Unfavorable topical agents 3 (1.5%) 3 (0.9%) 6 (1.1%) Allergy, allergic reaction 2 (1.0%) 3 (0.9%) 5 (0.9%) Decreased vascular flow 0 5 (1.4%) 5 (0.9%)

8 Table 1: Adverse Reactions Reported in 1% of Patients with Deep Dermal or Full Thickness Burn Injuries (n = 552) Treated with Epicel Blood pressure (low, high) Pediatric (n = 205) Number of Patients (%) Adult (n = 347) Total (n = 552) Number of Adverse Reactions Pediatric Adult Total 0 4 (1.2%) 4 (0.7%) Hypothermia 0 4 (1.2%) 4 (0.7%) Febrile, Fever 3 (1.5%) 0 3 (0.5%) Contractures 3 (1.5%) 0 3 (0.5%) Hematoma 2 (1.0%) 1 (0.3%) 3 (0.5%) Movement/manipulation of graft 2 (1.0%) 0 2 (0.4%) Table 2 ( , n=1662), which represents the number of devices from tracking/sales data, includes 589 children (aged 21 years and younger) and 1073 adults. The reporting sources for the adverse reactions include spontaneous reports via medical device reports, reports from burn sites, and published literature. Because of the potential underreporting of adverse reactions from these sources, the percentages of adverse reactions should be interpreted with caution. It is not always possible to estimate adverse reaction frequencies reliably or establish a causal relationship to device exposure. The total number of deaths was 147 (8.8%). The most common adverse reactions in 2% of patients were multi-organ failure, sepsis, infection, and graft procedure complications. 6

9 Table 2: Frequency of Spontaneous Reports of Adverse Reactions in 1% of Adult or Pediatric Patients with Deep Dermal and Full Thickness Burn Injuries (n = 1662) Treated with Epicel from June 24, 1998 to September 17, 2015 Pediatric Cases n = 589 Adult Cases n = 1073 Multi-organ failure 14 (2.4%) 45 (4.2%) Sepsis 8 (1.4%) 41 (3.8%) Infections 12 (2%) 21 (2%) Graft Procedure Complications 4 (0.7%) 21 (2%) Respiratory Disorders 6 (1%) 16 (1.5%) Cardiac arrest 2 (0.3%) 11 (1%) Vascular Disorders 0 11 (1%) Renal failure 0 11 (1%) CLINICAL STUDIES The probable benefit of Epicel, mainly related to survival, was demonstrated in two Epicel databases and one physician-sponsored study, as shown in Table 3, Table 4, and Table 5. Table 3 ( , n=552) includes 205 children (aged 21 years and younger with 71% males). Demographics, clinical outcome (survival), and adverse reactions (see Table 1) data were recorded for patients who received Epicel (mean number of grafts=104, range of 4-408) from 1989 to The survival rate for overall patients was 86.6% (478/552) at three months postinitial surgery. The survival rate was 89.3% (183/205) for pediatric patients (21 years and younger). 7

10 Table 3: Epicel Database ( ): Demographics and Survival Data in Pediatric and Overall Population Overall Pediatric patients Total Treated Patients n Survived n (%) Total Treated Patients n Survived n (%) Number of Patients (86.6) (89.3) Sex Male n (%) 409 (74.1) 355 (86.8) 145 (70.7) 132 (91.0) Female n (%) 116 (21.0) 98 (84.5) 50 (24.4) 43 (86.0) No Data n (%) 27 (4.9) 25 (92.6) 10 (4.9) 8 (80.0) TBSA 3rd Degree Burn 1 (Mean % TBSA ± SD) 56.1 ± ± ± ± 21.0 Mean TBSA 2 (% ± SD) 68.6 ± ± ± ± 17.0 Inhalation Injury 3 n (%) 195 (35.3) 159 (81.5) 69 (33.7) 56 (81.2) 1 3 rd Degree Burn: also referred to as full-thickness burns, are characterized by total irreversible destruction of all skin, dermal appendages, and epithelial elements. Spontaneous regeneration of epithelium is not possible. 2 TBSA: Total Body Surface Area including third degree burn area. 3 Based on available recorded information for moderate or severe inhalation injury. Table 4 (October 2007-June 22, 2015, n=402) demonstrates Epicel tracking data as per FDA requirement following Epicel approval in Demographics and survival information have been collected under this database. During the period from October 2007 to June 2015, a total of 402 patients received Epicel in the US according to the labeled indication, with average age of 32 years; 73% were males, and the average burn size was 66% of TBSA. Of these 402, there were 120 pediatric patients with average age of 12 years; 71% were males, and the average burn size was 66% of TBSA. The survival rate in this pediatric population was 88.3% (106/120) as compared with the overall survival rate of 81.3% in the total population (327/402). 8

11 Table 4: Epicel Database (October 2007 to June 2015): Patient Demographics and Survival Data in Pediatric and Overall Population Overall Pediatric patients Total Treated Patients n Survived n (%) Total Treated Patients n Survived n (%) Number of Patients (81.3) (88.3) Sex Male n (%) 293 (72.9) 238 (81.2) 85 (70.8) 74 (87.1) Female n (%) 101 (25.1) 81 (80.2) 32 (26.7) 29 (90.6) No Data n (%) 8 (2.0) - 3 (2.5) - Mean Age (yrs ± SD) 32.0 ± ± Mean TBSA 1 (% ± SD) 66.0 ± ± TBSA: Total Body Surface Area including third degree burn area. Table 5 summarizes published data from a randomized, controlled, independent, physiciansponsored study conducted by Dr. Andrew Munster. This study compared the outcome of therapy in patients with massive burns with or without cultured epidermal autografts (Epicel). 2 Two groups of patients were studied over a seven-year period. One group received standard care (excision plus allografting and/or split thickness autografting) and the other group received standard care plus Epicel. All patients in the study had to satisfy the following entry criteria: 1. a minimum burn size of 50% TBSA with a substantial third-degree component, and 2. survival beyond the first operative procedure for excision and initial coverage. The data from Table 5 were collected by Genzyme Biosurgery (previous owner of Epicel) from medical records of 44 patients in the study. 9

12 Table 5: Available Data from Munster Study Parameter Epicel Control Number of Patients (n) Sex Male n (%) 15 (75.0) 22 (91.7) Female n (%) 5 (25.0) 2 (8.3) Mean 3rd Degree Burn (%) Risk Factors Mean Age (yrs) Mean TBSA (%) Inhalation Injury n (%) Final Status at 7 years 18 (90.0) 19 (79.2) Survival n (%) 18 (90.0) 9 (37.5) HOW SUPPLIED/STORAGE AND HANDLING Epicel is intended solely for autologous use. Epicel consists of viable, autologous cells packaged and labeled for use within specified time limits. Each Epicel graft consists of a sheet of cultured epidermal cells attached with titanium surgical clips to a backing of petrolatum gauze. The petrolatum gauze backing serves to support and protect the autograft during transport, the grafting procedure, and the early post-grafting period. Each graft is rectangular in shape and has a surface area of approximately 50 cm 2. A silver orientation tag is attached to the petrolatum gauze indicating that the gauze should be placed facing up. Each graft is individually packaged in sterile, buffered, serum-free, unsupplemented Dulbecco s Modified Eagle Medium (DMEM) and shipped within secondary packaging capable of maintaining the appropriate storage temperature for up to 24 hours. DMEM is a physiological nutrient-rich buffer medium primarily containing salts, amino acids, and vitamins, as well as phenol red. Its salt composition is very similar to human plasma salt composition and effectively maintains physiological osmolality. None of the components of DMEM are of animal origin. 10

13 The following components are used during the manufacture of Epicel: anti-infective agents such as vancomycin, amikacin or amphotericin B; bovine serum; culture media supplements such as insulin, triiodothyronine, hydrocortisone, cholera enterotoxin, and epidermal growth factor; and proliferation-arrested murine fibroblasts. To maintain cell viability, Epicel is aseptically manufactured, but is not terminally sterilized. Epicel is shipped following a preliminary pre-release sterility test to confirm the absence of microbial growth. Final (14-day incubation) sterility test results are completed after the time of device application. Storage and Handling Inspect the Epicel packaging and ensure that it is intact. Do not use Epicel if package is opened or damaged. Store Epicel in the original shipping container in which it is received. Maintain the shipping carton closed and at cool room temperature (13C to 23C, 55F to 73F). Do not refrigerate, freeze, or incubate the Epicel shipping container or its contents. Do not remove from original shipping container until ready for use. Keep Epicel out of the operating room until ready for application. Do not reuse, freeze, refrigerate, or sterilize Epicel after opening. Inspect the medium in which Epicel is transported. Do not use Epicel if the medium appears cloudy. Do not use Epicel past its expiration date (24 hours). PEEL-OFF LABEL The peel-off label provided with the Epicel product should be applied to the patient s medical record to document that the patient has been treated with Epicel that is manufactured using murine cells. 11

14 DIRECTIONS FOR USE Pre-Grafting Considerations The recipient wound bed may influence the success of keratinocyte graft application. Spontaneous blister formation may occur in patients grafted with keratinocytes alone and may result in graft loss. The use of a dermal substitute may improve final graft take, however the use of Epicel with dermal substitutes has not been studied. The application of a dermal substitute should be conducted according to established, standard operating procedures. The wound must be clean, well vascularized and dry (nonexuding). If a dermal substitute such as cadaver allograft is being used, the epidermal layer must be removed from engrafted allograft prior to the application of Epicel. Since this layer is very thin, care must be taken not to remove the engrafted dermis. The epidermal layer is generally removed with a dermatome, but the removal process should be determined by standard operating procedures within the burn unit. The anatomic site intended for graft application may influence graft success. Mechanical stress may be one of the reasons for graft blister formation. Epicel is more sensitive to wound bed conditions and colonization, compared to the sensitivity of meshed split-thickness grafts. Staphylococcus, Pseudomonas, and Candida have been shown to be particularly detrimental to the adherence and viability of cultured keratinocytes. Acinetobacter, Enterococcus, Proteus, Serratia and Aspergillus have also demonstrated detrimental effects on graft take. Anti-infectives commonly used to treat wound bed infection vary widely in their effects on cultured keratinocytes. The optimal clinical use of systemic and/or topical antibiotic therapy before and after grafting has not been determined. Agents that have been used clinically and have not demonstrated significant inhibitory effects on keratinocyte growth and differentiation in a cell culture assay are listed in Table 6. Agents that have demonstrated significant inhibitory effects on keratinocyte growth and differentiation in cell culture are listed in Table 7. Anti-infective agents were tested in cell culture using a colony forming efficiency (CFE) assay. Keratinocytes were cultured with irradiated 3T3 feeder cells in media containing the desired concentration of antibiotic. After 12 days, the cultures were stained and cell colonies were evaluated and scored. Controlled clinical trials on the effect of any of the anti-infectives on Epicel or prepared wound beds have not been conducted. 12

15 Table 6: Anti-infective Agents Tested on Epicel In Vitro No Significant Inhibitory Effects Agent Maximum Dose 1 Amphotericin B Cefoperazone Ciprofloxacin Gentamicin Sulfate Neomycin Sulfate Nystatin Polymyxin B Sulfate Polysporin (Polymyxin B Sulfate & Bacitracin zinc) Triple Antibiotic (Polymyxin B Sulfate, Bacitracin zinc and Neomycin Sulfate) Tobramycin sulfate Vancomycin hydrochloride 24 g/ml 100 g/ml 5 g/ml 1 mg/ml 2 mg/ml 480 U/mL 1000 U/mL 200 U/mL, 10 U/mL 100 U/mL, 25 U/mL, 0.6 mg/ml 6 g/ml 1 mg/ml Bibiotic (Polymyxin B Sulfate & Bacitracin zinc) 200 U/mL, 50 /ml 1 Maximum dose that did not inhibit keratinocyte growth and differentiation resulting in the number of growing colonies greater than or equal to 50% of the control and the average growing colony size greater than or equal to 50% of the control. 13

16 Table 7: Anti-infective Agents Tested on Epicel In Vitro Significant Inhibitory Effects Agent Minimum Dose 1 AK-Spore HC 2 (Polymyxin B sulfate, Neomycin sulfate, Hydrocortisone) 20 U/mL, U/mL, 0.02 mg/ml Acetic Acid 0.5% Clostrimazole 0.1% Miconazole 0.1% 1 Minimum dose that inhibited keratinocyte growth and differentiation resulting in the number of growing colonies less than 50% of the control or the average growing colony size less than 50% of the control. 2 The stated dilution of AK-Spore HC did show acceptable colony growth. However, since this concentration is too low to be of any clinical value, and all higher concentrations were unacceptable, the antibiotic was deemed unacceptable. In addition, there is limited clinical experience with topical administration of the following agents in regard to potential effects on the cultured keratinocytes in Epicel: bacitracin zinc, clavulanate potassium, fluconazole, imipenem, kanamycin sulfate, ketoconazole, mupirocin, ticarcillin disodium. Epicel may be applied in a single operation or in a series of operations, beginning approximately 15 days after cultures are initiated. The number of Epicel grafts required for each operation will be determined in advance based on the judgment of the treating physician, considering the patient s condition and the area of the wound to be covered. Graft Application Apply Epicel grafts topically to a prepared wound bed and attach Epicel securely in place with sutures or staples. During the grafting procedure, open the graft dishes only one at a time. Do not allow the grafts to dry before application to the wound bed. 1. Before treatment, obtain 3 to 5 aliquots (0.5 ml) of citrated or EDTA-anticoagulated plasma and 2 aliquots of viable, cryopreserved leukocytes (1 x 10 7 cells) blood samples for archival purposes. In the event that a xenogeneic infectious disease is suspected, baseline patient plasma and cells may be critical to determining etiology. 2. Once the wound bed is fully prepared, open the first graft dish. The Epicel graft will be lying in nutrient transport medium with the growing cells facing up. 14

17 3. Gently lift the graft by its backing using two forceps. A small silver orientation tag will be attached to the back of the graft. 4. Apply the graft to the wound bed with the growing cells against the wound and the supporting petrolatum gauze on the outside. The silver orientation tag should be facing up. Keep the handling of the graft to a minimum. Do not move the graft across the surface of the wound once it is applied. 5. Repeat the application procedure until all of the grafts are in place on the wound. Place the grafts as close together as possible without overlapping one another. 6. Once all of the grafts are applied, use a sufficient number of staples or sutures to firmly attach the grafts to the wound bed. 7. Apply a single layer of sterile nylon net over the supporting petrolatum gauze of the grafts. Staple the sterile nylon net in place and leave it undisturbed for 7-10 days. 8. Apply four to five layers of absorbent gauze as a secondary outer dressing. Postoperative Treatment During the early postoperative period, avoid mechanical trauma and friction. Do not disrupt the underlying sterile nylon net or Epicel when changing the outer dressings. Avoid frequent irrigation, particularly in the early stages after grafting due to the possibility of cell damage. Change the outer absorbent dressing at least once daily to prevent accumulation of fluid and bacteria. Wounds having excessive discharge may require more frequent dressing changes and, if infected, may also require the use of topical antibiotics or other standard medical treatment. The outer absorbent dressings can be soaked in an antibiotic solution prior to application to the graft area and changed approximately twice a day. Refer to the Pre-Grafting Considerations portion of the Directions for Use section to choose an anti-infective agent that will not adversely affect the newly adherent grafts. Seven to ten days after grafting, the sterile nylon net and petrolatum gauze can normally be teased away from the wound bed. The sterile nylon net and petrolatum gauze should be soaked in saline or Shur-Clens to facilitate removal. If the petrolatum gauze is firmly adherent, the graft should be rewrapped with the gauze left in place. Attempt to remove the petrolatum gauze again in several days. Extreme care must be taken when removing the petrolatum gauze to prevent damage to the graft. If any portion of the grafted area is pulled away by removal of the petrolatum gauze, removal should be stopped. After skin integrity has been established, medical judgment should be used in the choice of long-term care. Bathing with mild soaps and moisturizing with mild lotions are encouraged. Pressure garments are generally used beginning approximately six weeks post-grafting. Activity can be permitted as tolerated by the patient, recognizing that patients who have suffered 15

18 extensive full-thickness burns or injuries may exhibit intolerance to heat and/or strenuous activity. PATIENT COUNSELING INFORMATION Each patient receiving Epicel should be informed that murine (mouse) cells are used during the manufacture of Epicel. These cells have been extensively tested for the presence of infectious agents and shown to be negative; however, there exists a potential risk of exposure to unknown murine-derived infectious agents. Patients should be instructed to notify their physician of any symptoms of an allergic reaction. Patients should also be counseled to notify their treating physician of their prior treatment with Epicel if they develop skin cancers and/or unusual/unidentified infectious disease. Epicel is considered to be a xenotransplantation product by the PHS and FDA. As such, Epicel recipients, but not their intimate contacts or healthcare providers, should not donate whole blood, blood components, source plasma, source leukocytes, tissues, breast milk, ova, sperm, or other body parts for use in humans. A small amount of blood (around 30 ml, which is equivalent to about 6 teaspoons) will be collected from patients before Epicel surgery. These blood samples will be further processed and stored indefinitely. The reason for collecting and storing this blood prior to skin grafting is to provide a baseline blood sample that may be needed in the future to assess any possible public health issues related to the treatment. Vericel will not use these blood samples for any purpose other than responding to a request by the regulatory agencies. The risks of having blood taken from a vein include bruising and bleeding. Additional risks include discomfort, pain, swelling, redness, and infection. Also, all patients should be asked to consider allowing autopsy to be performed after death, regardless of the cause of death (even if it is a car accident, for example). A patient does not have to allow this, but it would let researchers investigate in the event of a public health concern. If a patient decides to allow this, it is important for the patient to share this information with their family and/or legal entity, since they will need to support this decision. FDA requires manufacturers of certain medical devices to track those devices, and the patients who receive them, so they can notify the patients and their health care professionals promptly if a safety concern associated with the device is identified. The FDA has determined that Epicel is a medical device that must be tracked. Vericel requests patient contact information of all Epicel recipients. 16

19 REFERENCES 1. Kowal-Vern A, Criswell BK. Burn scar neoplasms: literature review and statistical analysis. Burns : Munster A. Cultured skin for massive burns: a prospective, controlled trial. Ann. Surg September. 224:

20 MANUFACTURED BY: Vericel Corporation 64 Sidney Street Cambridge, MA USA (USA only) Epicel is a registered trademark of Vericel Corporation in the U.S Revision G February/

21 Epicel (cultured epidermal autografts) HDE# BH Patient Information This leaflet is designed to help you understand Epicel (cultured epidermal autografts) and its use for the treatment of burn wound. This leaflet does not take the place of talking with your healthcare provider about Epicel. If you have questions about Epicel, talk to your healthcare provider. Epicel is a Humanitarian Device: Authorized by Federal law for use in patients who have deep dermal or full thickness burns comprising a total body surface area of greater than or equal to 30%. It may be used in conjunction with split-thickness autografts, or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns. The effectiveness of the device for this use has not been demonstrated. Federal Law restricts this device to sale by or on order of a physician. Manufactured By: Vericel Corporation 64 Sidney Street Cambridge, MA USA Epicel is a Registered Trademark of Vericel Corporation, Cambridge, MA 1

22 Glossary/Definitions of Terms Anaphylaxis: Immediate, transient kind of allergic reaction. Autograft: A tissue transferred from one place on the body to a new location. Autologous: When a tissue is moved from one place on the body to another location on the same body, the tissue is referred to as autologous. Cultured: The maintenance or growth of cells in an incubator after removal from the body. Cultured Epidermal Autograft: A tissue grown from one s own skin cells for use in placing on the person s own body. Epidermis: The outer cell layers of the skin. Epidermal: Relating to the outer cell layers of the skin. Dermal: Relating to the skin. Dermis: Skin, the layer of skin lying under the epidermis, it contains blood vessels, nerves, sweat glands, and hair follicles. Full thickness burn: A burn of the skin that involves all of the layers of skin, i.e., epidermis and dermis, down to the underlying muscle and fat tissues. A full thickness skin burn is a third degree burn. Harvest: Word used to indicate removal of skin tissue for use in covering burns on other parts of the body. Hypersensitivity: Condition in which there is an exaggerated response by the body to a foreign agent. Irradiated or Irradiation: The use of or process of using gamma-ray energy to inactivate cells used in the manufacture of Epicel; cells treated with this process cannot reproduce but remain alive. Media or Medium: Liquid or solid reagents used for the growth of cells outside of the body. Mouse cells (3T3 cells): Cells from mice used to help the patient s keratinocytes/skin cells grow. Regeneration: Growth of skin cells to replace the patient s own skin lost to burn. 2

23 Skin grafts: Skin used for replacing skin lost to burn; also can refer to skin cells grown outside of the body to replace skin lost to burn. Split-thickness autograft: Process of removing part of patient s own skin for immediate placement onto burned areas of the patient s own body. Tissue: A collection of similar cells grown or growing together. Tissue culture: The process of growing cells outside of the body in an incubator. Total Body Surface Area (TBSA): A percent estimate of the total surface of the body that is burned. Burns are judged by the size of the burn in relation to the whole body and by the depth of the burn injury. Different methods exist to calculate the extent or size of a burn injury. It is important to know the percentage of the total skin surface involved in the burn. One method to determine the percentage of total skin surface involved in a burn is to divide the adult body into regions. Each region represents approximately nine percent of the total body surface. These regions are the head and neck, each upper limb, the chest, the abdomen, the upper back, the lower back and buttocks, the front of each lower limb, and the back of each lower limb. This makes up 99 percent of the total body surface area. The remaining one percent is the genital area. Front Right Left Back 3

24 enogeneic: Referring to being derived or obtained from an organism of a different species, e.g., tissue grafts. enotransplantation: Used to refer to tissues being placed from one species to another species, e.g., from mouse to human; the process of placing tissues from one species onto another species. 4

25 What is Epicel? Epicel grafts are sheets of skin cells ranging from 2 to 8 cell layers thick. The grafts are grown or cultured from a postage stamp sized sample of your own healthy skin. During this culture process, irradiated mouse cells, also referred to as 3T3 cells, are used to promote cell growth and to ensure that there will be a sufficient number of grafts available as soon as possible for treatment. The mouse cells used in the culture process have been extensively tested for the presence of infectious agents such as bacteria, fungi, and viruses. The mouse cells are irradiated before their use in the process to prevent them from multiplying. Other substances used during the manufacture of Epicel include: antibiotics such as vancomycin, amikacin or amphotericin B; bovine (cow) serum; hormones such as insulin, triiodothyronine, hydrocortisone, epidermal growth factor; and also cholera enterotoxin. Who should use Epicel? You may need Epicel if you have deep burns over a total body surface area of greater than or equal to 30%. A doctor may use Epicel together with your own skin graft, or use Epicel alone to cover your burn wound when your own graft is not available or sufficient due to the severity and extent of your burn wound. Epicel can be used for adults and children. Why Epicel may help your condition In deep burns, the outermost layer of the skin and all of the inner layer of the skin is destroyed. Due to the depth of the injury, regeneration of the skin is greatly reduced. The usual treatment for these deep wounds is removal of the damaged tissue and placement of a fresh skin graft. These skin grafts are taken from an area of the individual s unburned skin. This donor skin is placed on the burn wounds. Wound healing may occur fairly rapidly in patients with small total body surface area burns where there is enough unburned skin to harvest for a graft. In a larger total body surface area (usually greater than 30%) the patient does not have enough donor skin available to cover the wounds. The physician may need to consider another means of permanent wound closure, such as Epicel. The Epicel graft replaces the top layer of the skin. This layer of skin is required to close or heal your wounds. This permanent wound coverage must be performed in a timely fashion to avoid the many complications of the burn wound injury. 5

26 When Epicel Should Not be Used You should NOT get Epicel if you have any of the following problems or conditions: severe allergy to substances used in the manufacture of Epicel severe allergy to antibiotics, vancomycin, amikacin or amphotericin because Epicel is grown in media containing these antibiotics severe allergy to materials of cow or mouse origin infected wounds What is xenotransplantation and what are the issues related to xenotransplantation? Although Epicel is grown from your own skin cells, it is grown together with mouse cells and contains residual mouse cells. Therefore, FDA considers it a xenotransplantation product. If you received Epicel, you should never donate blood or blood parts, tissue, breast milk, egg, sperm, or other body parts for use in humans because of the potential risk of carrying an infection that is transmitted from mouse cells to humans. This restriction does not extend to your intimate contacts and the medical team taking care of you. You should notify your healthcare provider immediately of any symptoms of an infection or allergic reaction. A small amount of blood (around 30 ml, which is equivalent to about 6 teaspoons) may be drawn from you before Epicel surgery. This blood sample will be used as a baseline blood sample to assess any possible public health issues related to the treatment. You may consider allowing autopsy to be performed after death, regardless of the cause of death. In the event of a public health concern, you may share this information with your family and/or legal entity. To date, there has been no identified public health hazard associated with the use of xenogeneic cells in the Epicel manufacturing process. Why we track your personal information FDA requires manufacturers of certain medical devices to track those devices, and the patients who receive them, so they can notify the patients and their health care professionals promptly if a safety concern associated with the device is identified. The FDA has determined that Epicel is a medical device that must be tracked. Therefore, you should provide your contact information, such as your name, address, phone number, and information about your next of kin. 6

27 What are the Potential Complications of Burns and Skin Grafting? Deep and extensive burns may cause many complications to both the skin and other parts of the body. These complications can be very serious and life threatening. The following outcomes were reported in the past clinical experience: infection, sepsis, drainage, multiorgan failure, and death. Complications associated with skin grafting include: blister formation, graft tearing, graft detachment, graft contracture, or skin tightening, and skin graft failure. Squamous Cell Carcinoma (SCC), one type of skin cancer, is a possible long-term complication of extensive burns. SCC was reported in a few patients who received grafting with Epicel. SCC in these cases developed in more than one area on the body approximately 12 to 19 years from the time of grafting. How to Take Long-Term Care of Your Healed Burn Wound After your burn wound has healed, your healthcare provider will decide on the best long term care for you, including: bathe with mild soaps and moisturize with mild lotions use pressure garments approximately six weeks post grafting conduct activity of daily living as tolerated SCC has been reported in patients who have received Epicel. You may have risk for the development of skin cancers such as SCC over the burn scars. This skin cancer may look like growing lumps, often with a rough, scaly, or crusted surface. It may also look like flat reddish patches in the skin that grow slowly. You should see your health care provider for any skin changes in a timely manner. To protect your skin, remember the following whenever you are in the sun, even for short periods of time: wear long clothing to cover your skin apply sunscreen to all exposed areas wear a hat and sunglasses In addition: avoid tanning beds and sun lamps avoid harmful chemicals If you notice any changes in your skin, see your healthcare provider. 7

28 Additional Information and Questions Please refer to the Epicel package insert for additional information. This can be obtained from your physician or by contacting Vericel Corporation CEA- SKIN or (USA only) or from For any concerns regarding treatment with Epicel please contact your physician. For any product-related questions, please contact Vericel Corporation CEA-SKIN or (USA only) Revision D 04/2016 8