VYJUVEK

1 INDICATIONS AND USAGE VYJUVEK is indicated for the treatment of wounds in adult and pediatric patients with dystrophic epidermolysis bullosa (DEB) with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene. VYJUVEK is a herpes-simplex virus type 1 (HSV-1) vector-based gene therapy indicated for the treatment of wounds in adult and pediatric patients with dystrophic epidermolysis bullosa (DEB) with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene. (1)

2 DOSAGE AND ADMINISTRATION For topical application only. Age Range Maximum Weekly Dose (PFU) Maximum Weekly Volume (mL)* <3 years old 2×10 9 1 ≥3 years old 4×10 9 2 PFU=plaque forming units; mL=milliliter *Maximum weekly volume after mixing VYJUVEK biological suspension with excipient gel Apply VYJUVEK gel to the selected wound(s) in droplets spaced evenly within the wound, approximately 1cm-by-1cm apart. (2.3) Apply VYJUVEK gel on wounds once a week. (2.1) See full prescribing information for instructions on preparation and handling, (2.2) and administration (2.3) . 2.1 Dose For topical application on wounds only. The recommended dose of VYJUVEK gel is based on age (Table 1). VYJUVEK gel is applied topically to wound(s) once a week. Table 1 Maximum Weekly Dose of VYJUVEK by Age Age Range Maximum Weekly Dose (PFU) Maximum Weekly Volume (mL)* <3 years old 2×10 9 1 ≥3 years old 4×10 9 2 PFU=plaque forming unit; mL=milliliter *Maximum weekly volume is the volume after mixing VYJUVEK biological suspension with excipient gel. It may not be possible to apply VYJUVEK gel to all the wounds at each treatment visit. Apply VYJUVEK gel to wounds until they are closed before selecting new wound(s) to treat. Prioritize weekly treatment to previously treated wounds if they re-open. [ see Administration (2.3) ] If a dose is missed, apply VYJUVEK gel as soon as possible and resume weekly dosing thereafter. 2.2 Preparation Important Preparation Instructions Prepare VYJUVEK gel at the pharmacy by mixing the VYJUVEK biological suspension into the excipient gel for immediate use. [see Storage and Handling ( 16.2 )] The VYJUVEK gel prepared at the pharmacy, should be applied by a healthcare professional (HCP), patient, or caregiver either at a healthcare professional setting (e.g., clinic) or at a home setting. Individuals who are pregnant should not prepare or apply VYJUVEK gel and should avoid direct contact with the treated wounds or dressings from treated wounds [see Accidental Exposure to VYJUVEK ( 5.1 )]. Below is the list of supplies needed for VYJUVEK gel preparation: One (1) carton containing one (1) VYJUVEK biological suspension vial and one (1) excipient gel vial (Figure 1) Two (2) 18-gauge needles Two (2) to four (4) 1 mL administration syringes One (1) 3 mL preparation syringe Two (2) to four (4) syringe caps Protective gloves 70% isopropyl alcohol pads Biohazard container Labels for administration syringes Virucidal agent for clean-up Follow the steps below for VYJUVEK gel preparation. PREPARE THE PREPARATION SYRINGE 1. Wash hands and put on protective gloves. 2. Remove both vials from the carton and thaw the VYJUVEK biological suspension vial and the excipient gel vial at room temperature for AT LEAST 20 minutes (Figure 1). Figure 1 Carton containing the VYJUVEK biological suspension vial and excipient gel vial Note: Visually inspect the vials to ensure both are in liquid form and completely thawed. Excipient gel is more viscous and will take longer to thaw (Figure 2). Figure 2 Timelapse of excipient gel thaw from 0 minutes to 20 minutes Note: Once either the VYJUVEK biological suspension or the excipient gel is thawed, do not refreeze. 3. Invert the VYJUVEK biological suspension vial 4-5 times. Do not invert the excipient gel vial. 4. Remove the caps from the vials and clean each vial stopper with a 70% isopropyl alcohol pad. Allow them to dry. 5. Aseptically connect an 18-gauge needle to the 3 mL preparation syringe. 6. Remove the needle cap and puncture the VYJUVEK biological suspension vial stopper. 7. Hold the vial at 45 to 90 degrees and withdraw 1 mL of VYJUVEK biological suspension into the preparation syringe (Figure 3). 8. Remove the preparation syringe (still connected to the needle) containing 1 mL of VYJUVEK biological suspension from the vial. Do NOT engage the safety lock. Figure 3 The removal of 1 mL of biological suspension using the preparation syringe 9. Discard the VYJUVEK biological suspension vial in the biohazard waste. 10. Puncture the clean excipient gel stopper and transfer the VYJUVEK biological suspension into the excipient gel vial (Figure 4). Figure 4 Transferring VYJUVEK biological suspension to excipient gel vial 11. WITHOUT REMOVING THE NEEDLE from the excipient gel vial, lift the tip of the needle above the liquid (Figure 5)and pull the plunger back to the 1 mL mark (Figure 6) to vent the gel vial following the addition of the 1 mL of suspension. Figure 5 The needle above the liquid without removal of any material Figure 6 Pulling the plunger back to the 1 mL mark to remove air pocket 12. Remove the preparation syringe with the 1 mL of air and engage the safety lock. 13. Discard the preparation syringe and needle into the biohazard waste. 14. Place a 70% isopropyl alcohol pad on top of the excipient gel stopper and hold it tightly in place. 15.Shake VIGOROUSLY for 10 SECONDS (Figure 7). Figure 7 Manually mixing the excipient gel vial Note: The mixture of VYJUVEK biological suspension and excipient gel is referred to as VYJUVEK gel. PREPARE THE ADMINISTRATION SYRINGES 16. Aseptically connect an 18-gauge needle to the first 1 mL administration syringe and remove the needle cap. 17. Insert the 18-gauge needle into the excipient vial containing VYJUVEK gel (Figure 8). Figure 8 Needle within VYJUVEK gel prior to withdraw 18. Tilt the vial 45 to 90 degrees and withdraw 0.5 mL of VYJUVEK gel (Figure 9). Figure 9 Administration syringe withdrawing 0.5 mL of VYJUVEK gel with air pocket visible Note: An air pocket may form near the plunger when extracting VYJUVEK gel. 19. DO NOT REMOVE THE NEEDLE FROM THE VIAL; lift the tip of the needle above the VYJUVEK gel and disconnect the administration syringe containing 0.5 mL of mixed VYJUVEK (Figure 10). Figure 10 Disconnecting the administration syringe containing VYJUVEK gel with air pocket visible Note: Leave the needle in the excipient gel vial stopper. 20. DO NOT flick the syringe to remove the air pocket. Manipulate the plunger up and down, until all air pockets have been removed (Figure 11) Figure 11 Manipulation of administration syringe plunger to remove air pockets 21. Cap the administration syringe and set aside (Figure 12). Figure 12 Capped syringe 22. Connect a new 1 mL administration syringe to the needle that remains in the excipient gel vial stopper (with the tip of the needle ABOVE the VYJUVEK gel) (Figure 13). Figure 13 Connecting an administration syringe to the needle within the excipient gel vial stopper 23. Place the bevel of the needle in the VYJUVEK gel, tilt the vial 45 to 90 degrees and withdraw 0.5 mL of VYJUVEK gel into the administration syringe [see steps 17 and 18: Figure 8 and Figure 9)]. 24. Complete steps 19, 20, and 21 above to disconnect the administration syringe and remove the air pockets, prior to capping the administration syringe (Figure 10, Figure 11, and Figure 12). 25. Repeat steps 22, 23, and 24 if two (2) additional administration syringes are required (each containing 0.5 mL of VYJUVEK gel). Note: Administration syringes are labeled as syringe #1, #2, #3, and #4. 26. Discard the excipient gel vial (with the needle within the vial stopper) into the biohazard container. 27. Clean all surfaces that may have come in contact with VYJUVEK biological suspension or gel and treat all spills with a virucidal agent such as 70% isopropyl alcohol, 6% hydrogen peroxide, or <0.4% ammonium chloride. Blot using absorbent materials. 28. Dispose all materials (e.g., vial, syringe, needle, cleaning materials) that may have come in contact with VYJUVEK biological suspension or gel into a biohazard container. 29. Place the capped administration syringes containing the VYJUVEK gel in a sealable plastic bag. 30. Place the sealable plastic bag with administration syringes into an appropriate insulated or temperature regulated secondary container at 2° to 8°C (35.6° to 46.4°F) for transport from the preparation site to the administration site. fig1 fig2 fig3 fig4 fig5 fig6 fig7 fig8 fig9 fig10 fig11 fig12 fig13 2.3 Administration Below is the list of supplies needed for VYJUVEK gel administration: The administration syringes Hydrophobic dressing Scissors Standard dressing Protective gloves Biohazard container Virucidal agent for clean-up VYJUVEK GEL ADMINISTRATION Note: The administration syringe should be primed prior to the initial application by pulling the plunger down and pushing it upwards, so that a small droplet of VYJUVEK gel forms at the tip of the syringe. Follow the steps below for VYJUVEK gel administration. 1. Apply VYJUVEK gel to the selected wound(s) in droplets spaced evenly within the wound, approximately 1cm-by-1cm apart (width of a fingertip). The resulting droplet pattern should loosely resemble a grid. Avoid touching the administration syringe to the skin and/or wound (Figure 14). Figure 14 Application of VYJUVEK gel to the wound Table 2below provides a reference on dose per approximate size of the wound. Dose by Wound Size PFU= plaque forming unit; mL= milliliter; cm= centimeter * For wound area over 60 cm 2 , recommend calculating the total dose based on Table 2 until the maximum weekly dose in Table 1 is reached. Wound Area (cm 2 ) Dose (PFU) Volume (mL) < 20 4×10 8 0.2 20 to < 40 8×10 8 0.4 40 to 60 1.2×10 9 0.6 2. Use the clean scissors to cut the hydrophobic dressing to a size slightly larger than the wound and place the dressing atop the VYJUVEK gel droplets (Figure 15). Figure 15 Placing the hydrophobic dressing over the treated wound 3. Use the scissors to cut the standard dressing used by the patient to a size slightly larger than the hydrophobic dressing and place the standard dressing atop the hydrophobic dressing (Figure 16). Figure 16 Placing the standard dressing over the hydrophobic dressing 4. Clean all surfaces that may have come in contact with VYJUVEK gel and treat all spills with a virucidal agent such as 70% isopropyl alcohol, 6% hydrogen peroxide or <0.4% ammonium chloride. Blot using absorbent materials. 5. Dispose all materials (e.g., syringe, cleaning materials) that may have come in contact with VYJUVEK biological suspension or gel into a biohazard container. 6. Discard unused administration syringes containing the VYJUVEK gel after preparation into a biohazard container [ see Storage and Handling (16.2) ] . 7. The dressing should be left in place until the next dressing change after VYJUVEK gel application. Once the VYJUVEK dressings are removed, the patient may continue with their standard of care. fig14 fig15 fig16 2.1 Dose For topical application on wounds only. The recommended dose of VYJUVEK gel is based on age (Table 1). VYJUVEK gel is applied topically to wound(s) once a week. Table 1 Maximum Weekly Dose of VYJUVEK by Age Age Range Maximum Weekly Dose (PFU) Maximum Weekly Volume (mL)* <3 years old 2×10 9 1 ≥3 years old 4×10 9 2 PFU=plaque forming unit; mL=milliliter *Maximum weekly volume is the volume after mixing VYJUVEK biological suspension with excipient gel. It may not be possible to apply VYJUVEK gel to all the wounds at each treatment visit. Apply VYJUVEK gel to wounds until they are closed before selecting new wound(s) to treat. Prioritize weekly treatment to previously treated wounds if they re-open. [ see Administration (2.3) ] If a dose is missed, apply VYJUVEK gel as soon as possible and resume weekly dosing thereafter. 2.2 Preparation Important Preparation Instructions Prepare VYJUVEK gel at the pharmacy by mixing the VYJUVEK biological suspension into the excipient gel for immediate use. [see Storage and Handling ( 16.2 )] The VYJUVEK gel prepared at the pharmacy, should be applied by a healthcare professional (HCP), patient, or caregiver either at a healthcare professional setting (e.g., clinic) or at a home setting. Individuals who are pregnant should not prepare or apply VYJUVEK gel and should avoid direct contact with the treated wounds or dressings from treated wounds [see Accidental Exposure to VYJUVEK ( 5.1 )]. Below is the list of supplies needed for VYJUVEK gel preparation: One (1) carton containing one (1) VYJUVEK biological suspension vial and one (1) excipient gel vial (Figure 1) Two (2) 18-gauge needles Two (2) to four (4) 1 mL administration syringes One (1) 3 mL preparation syringe Two (2) to four (4) syringe caps Protective gloves 70% isopropyl alcohol pads Biohazard container Labels for administration syringes Virucidal agent for clean-up Follow the steps below for VYJUVEK gel preparation. PREPARE THE PREPARATION SYRINGE 1. Wash hands and put on protective gloves. 2. Remove both vials from the carton and thaw the VYJUVEK biological suspension vial and the excipient gel vial at room temperature for AT LEAST 20 minutes (Figure 1). Figure 1 Carton containing the VYJUVEK biological suspension vial and excipient gel vial Note: Visually inspect the vials to ensure both are in liquid form and completely thawed. Excipient gel is more viscous and will take longer to thaw (Figure 2). Figure 2 Timelapse of excipient gel thaw from 0 minutes to 20 minutes Note: Once either the VYJUVEK biological suspension or the excipient gel is thawed, do not refreeze. 3. Invert the VYJUVEK biological suspension vial 4-5 times. Do not invert the excipient gel vial. 4. Remove the caps from the vials and clean each vial stopper with a 70% isopropyl alcohol pad. Allow them to dry. 5. Aseptically connect an 18-gauge needle to the 3 mL preparation syringe. 6. Remove the needle cap and puncture the VYJUVEK biological suspension vial stopper. 7. Hold the vial at 45 to 90 degrees and withdraw 1 mL of VYJUVEK biological suspension into the preparation syringe (Figure 3). 8. Remove the preparation syringe (still connected to the needle) containing 1 mL of VYJUVEK biological suspension from the vial. Do NOT engage the safety lock. Figure 3 The removal of 1 mL of biological suspension using the preparation syringe 9. Discard the VYJUVEK biological suspension vial in the biohazard waste. 10. Puncture the clean excipient gel stopper and transfer the VYJUVEK biological suspension into the excipient gel vial (Figure 4). Figure 4 Transferring VYJUVEK biological suspension to excipient gel vial 11. WITHOUT REMOVING THE NEEDLE from the excipient gel vial, lift the tip of the needle above the liquid (Figure 5)and pull the plunger back to the 1 mL mark (Figure 6) to vent the gel vial following the addition of the 1 mL of suspension. Figure 5 The needle above the liquid without removal of any material Figure 6 Pulling the plunger back to the 1 mL mark to remove air pocket 12. Remove the preparation syringe with the 1 mL of air and engage the safety lock. 13. Discard the preparation syringe and needle into the biohazard waste. 14. Place a 70% isopropyl alcohol pad on top of the excipient gel stopper and hold it tightly in place. 15.Shake VIGOROUSLY for 10 SECONDS (Figure 7). Figure 7 Manually mixing the excipient gel vial Note: The mixture of VYJUVEK biological suspension and excipient gel is referred to as VYJUVEK gel. PREPARE THE ADMINISTRATION SYRINGES 16. Aseptically connect an 18-gauge needle to the first 1 mL administration syringe and remove the needle cap. 17. Insert the 18-gauge needle into the excipient vial containing VYJUVEK gel (Figure 8). Figure 8 Needle within VYJUVEK gel prior to withdraw 18. Tilt the vial 45 to 90 degrees and withdraw 0.5 mL of VYJUVEK gel (Figure 9). Figure 9 Administration syringe withdrawing 0.5 mL of VYJUVEK gel with air pocket visible Note: An air pocket may form near the plunger when extracting VYJUVEK gel. 19. DO NOT REMOVE THE NEEDLE FROM THE VIAL; lift the tip of the needle above the VYJUVEK gel and disconnect the administration syringe containing 0.5 mL of mixed VYJUVEK (Figure 10). Figure 10 Disconnecting the administration syringe containing VYJUVEK gel with air pocket visible Note: Leave the needle in the excipient gel vial stopper. 20. DO NOT flick the syringe to remove the air pocket. Manipulate the plunger up and down, until all air pockets have been removed (Figure 11) Figure 11 Manipulation of administration syringe plunger to remove air pockets 21. Cap the administration syringe and set aside (Figure 12). Figure 12 Capped syringe 22. Connect a new 1 mL administration syringe to the needle that remains in the excipient gel vial stopper (with the tip of the needle ABOVE the VYJUVEK gel) (Figure 13). Figure 13 Connecting an administration syringe to the needle within the excipient gel vial stopper 23. Place the bevel of the needle in the VYJUVEK gel, tilt the vial 45 to 90 degrees and withdraw 0.5 mL of VYJUVEK gel into the administration syringe [see steps 17 and 18: Figure 8 and Figure 9)]. 24. Complete steps 19, 20, and 21 above to disconnect the administration syringe and remove the air pockets, prior to capping the administration syringe (Figure 10, Figure 11, and Figure 12). 25. Repeat steps 22, 23, and 24 if two (2) additional administration syringes are required (each containing 0.5 mL of VYJUVEK gel). Note: Administration syringes are labeled as syringe #1, #2, #3, and #4. 26. Discard the excipient gel vial (with the needle within the vial stopper) into the biohazard container. 27. Clean all surfaces that may have come in contact with VYJUVEK biological suspension or gel and treat all spills with a virucidal agent such as 70% isopropyl alcohol, 6% hydrogen peroxide, or <0.4% ammonium chloride. Blot using absorbent materials. 28. Dispose all materials (e.g., vial, syringe, needle, cleaning materials) that may have come in contact with VYJUVEK biological suspension or gel into a biohazard container. 29. Place the capped administration syringes containing the VYJUVEK gel in a sealable plastic bag. 30. Place the sealable plastic bag with administration syringes into an appropriate insulated or temperature regulated secondary container at 2° to 8°C (35.6° to 46.4°F) for transport from the preparation site to the administration site. fig1 fig2 fig3 fig4 fig5 fig6 fig7 fig8 fig9 fig10 fig11 fig12 fig13 2.3 Administration Below is the list of supplies needed for VYJUVEK gel administration: The administration syringes Hydrophobic dressing Scissors Standard dressing Protective gloves Biohazard container Virucidal agent for clean-up VYJUVEK GEL ADMINISTRATION Note: The administration syringe should be primed prior to the initial application by pulling the plunger down and pushing it upwards, so that a small droplet of VYJUVEK gel forms at the tip of the syringe. Follow the steps below for VYJUVEK gel administration. 1. Apply VYJUVEK gel to the selected wound(s) in droplets spaced evenly within the wound, approximately 1cm-by-1cm apart (width of a fingertip). The resulting droplet pattern should loosely resemble a grid. Avoid touching the administration syringe to the skin and/or wound (Figure 14). Figure 14 Application of VYJUVEK gel to the wound Table 2below provides a reference on dose per approximate size of the wound. Dose by Wound Size PFU= plaque forming unit; mL= milliliter; cm= centimeter * For wound area over 60 cm 2 , recommend calculating the total dose based on Table 2 until the maximum weekly dose in Table 1 is reached. Wound Area (cm 2 ) Dose (PFU) Volume (mL) < 20 4×10 8 0.2 20 to < 40 8×10 8 0.4 40 to 60 1.2×10 9 0.6 2. Use the clean scissors to cut the hydrophobic dressing to a size slightly larger than the wound and place the dressing atop the VYJUVEK gel droplets (Figure 15). Figure 15 Placing the hydrophobic dressing over the treated wound 3. Use the scissors to cut the standard dressing used by the patient to a size slightly larger than the hydrophobic dressing and place the standard dressing atop the hydrophobic dressing (Figure 16). Figure 16 Placing the standard dressing over the hydrophobic dressing 4. Clean all surfaces that may have come in contact with VYJUVEK gel and treat all spills with a virucidal agent such as 70% isopropyl alcohol, 6% hydrogen peroxide or <0.4% ammonium chloride. Blot using absorbent materials. 5. Dispose all materials (e.g., syringe, cleaning materials) that may have come in contact with VYJUVEK biological suspension or gel into a biohazard container. 6. Discard unused administration syringes containing the VYJUVEK gel after preparation into a biohazard container [ see Storage and Handling (16.2) ] . 7. The dressing should be left in place until the next dressing change after VYJUVEK gel application. Once the VYJUVEK dressings are removed, the patient may continue with their standard of care. fig14 fig15 fig16

4 CONTRAINDICATIONS None. None. (4)

5 WARNINGS AND PRECAUTIONS Accidental Exposure to VYJUVEK: Avoid direct contact with treated wounds and dressings of treated wounds until the next dressing change, following application. Clean the affected area if accidental exposure occurs. (5.1) 5.1 Accidental Exposure to VYJUVEK Accidental exposure to VYJUVEK may occur to close contacts and caregivers. VYJUVEK is a genetically modified, herpes-simplex virus type 1 vector-based, replication-deficient, non-integrating gene therapy. VYJUVEK will not replicate in the patient’s cells and does not integrate into the patient cells’ native genetic material. For precautions, Avoid direct contact with treated wounds (e.g., touching or scratching) and dressings of treated wounds until the next dressing change. Wear protective gloves when assisting patients with changing wound dressings and handling the disposal. In the event of an accidental exposure through a splash to the eyes or mucous membranes, flush with clean water for at least 15 minutes. 5.1 Accidental Exposure to VYJUVEK Accidental exposure to VYJUVEK may occur to close contacts and caregivers. VYJUVEK is a genetically modified, herpes-simplex virus type 1 vector-based, replication-deficient, non-integrating gene therapy. VYJUVEK will not replicate in the patient’s cells and does not integrate into the patient cells’ native genetic material. For precautions, Avoid direct contact with treated wounds (e.g., touching or scratching) and dressings of treated wounds until the next dressing change. Wear protective gloves when assisting patients with changing wound dressings and handling the disposal. In the event of an accidental exposure through a splash to the eyes or mucous membranes, flush with clean water for at least 15 minutes.

7 DRUG INTERACTIONS No drug interaction studies have been performed.

6 ADVERSE REACTIONS The most common adverse reactions (>5%) were itching, chills, redness, rash, cough, and runny nose. The most common adverse drug reactions (incidence >5%) were itching, chills, redness, rash, cough, and runny nose. (6) To report SUSPECTED ADVERSE REACTIONS, contact Krystal Biotech, Inc. at 1-844-557-9782 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflects exposure to VYJUVEK gel in a randomized, intra-patient placebo‑controlled study. A total of 31 patients with dystrophic epidermolysis bullosa (DEB), including 30 patients with autosomal recessive DEB and one patient with autosomal dominant DEB received topical administration of VYJUVEK gel to their wounds. The age of the patients ranged from 1 year to 44 years (mean age 17 years). Of the 31 patients, 19 (61%) were pediatric patients (less than 17 years of age), and 11 (36%) were females. Each patient received weekly topical application of VYJUVEK gel at one or more wound sites and placebo at a matching wound site as an intra-subject comparator. The median duration of exposure to VYJUVEK gel was 25 weeks. The most frequent adverse reactions (incidence >5%) observed in the study are summarized in Table 3. There were no discontinuations due to adverse reactions. Table 3 Adverse Reactions (incidence >5%) Following Treatment with VYJUVEK gel (n =31) Adverse Reactions Patients n (%) Itching 3 (10) Chills 3 (10) Redness 2 (6) Rash 2 (6) Cough 2 (6) Runny Nose 2 (6) In addition, the safety profile of VYJUVEK in two patients with autosomal recessive DEB (RDEB) of six and seven months of age, respectively, who received topical VYJUVEK gel weekly in an open-label study was similar to the safety profile of VYJUVEK observed in the randomized, intra-patient placebo‑controlled study described above. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflects exposure to VYJUVEK gel in a randomized, intra-patient placebo‑controlled study. A total of 31 patients with dystrophic epidermolysis bullosa (DEB), including 30 patients with autosomal recessive DEB and one patient with autosomal dominant DEB received topical administration of VYJUVEK gel to their wounds. The age of the patients ranged from 1 year to 44 years (mean age 17 years). Of the 31 patients, 19 (61%) were pediatric patients (less than 17 years of age), and 11 (36%) were females. Each patient received weekly topical application of VYJUVEK gel at one or more wound sites and placebo at a matching wound site as an intra-subject comparator. The median duration of exposure to VYJUVEK gel was 25 weeks. The most frequent adverse reactions (incidence >5%) observed in the study are summarized in Table 3. There were no discontinuations due to adverse reactions. Table 3 Adverse Reactions (incidence >5%) Following Treatment with VYJUVEK gel (n =31) Adverse Reactions Patients n (%) Itching 3 (10) Chills 3 (10) Redness 2 (6) Rash 2 (6) Cough 2 (6) Runny Nose 2 (6) In addition, the safety profile of VYJUVEK in two patients with autosomal recessive DEB (RDEB) of six and seven months of age, respectively, who received topical VYJUVEK gel weekly in an open-label study was similar to the safety profile of VYJUVEK observed in the randomized, intra-patient placebo‑controlled study described above.

8.1 Pregnancy Risk Summary There are no data with VYJUVEK gel use in pregnant women to inform a drug-associated risk. Animal developmental and reproductive toxicity studies have not been conducted with VYJUVEK. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations If the patient becomes pregnant while being administered VYJUVEK gel, the patient should be apprised of the potential hazards to the fetus and neonate. Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with VYJUVEK gel.