XIAFLEX

XIAFLEX contains purified collagenase clostridium histolyticum, consisting of two microbial collagenases in a defined mass ratio, Collagenase AUX-I and Collagenase AUX-II, which are isolated and purified from the fermentation of Clostridium histolyticum bacteria. Collagenase AUX-I is a single polypeptide chain consisting of approximately 1000 amino acids of known sequence. It has an observed molecular weight of 114 kiloDaltons (kDa). It belongs to the class I Clostridium histolyticum collagenases. Collagenase AUX-II is a single polypeptide chain consisting of approximately 1000 amino acids of deduced sequence. It has an observed molecular weight of 113 kDa. It belongs to the class II Clostridium histolyticum collagenases. XIAFLEX is supplied as a sterile lyophilized powder (white cake) intended for reconstitution with the supplied sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride) prior to intralesional injection into a Dupuytren’s cord or a Peyronie’s plaque. XIAFLEX is available in single-use, glass vials containing 0.9 mg of collagenase clostridium histolyticum. Each vial also contains 0.5 mg of hydrochloric acid, 18.5 mg of sucrose, and 1.1 mg of tromethamine.

XIAFLEX is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord. XIAFLEX is indicated for the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. XIAFLEX is a combination of bacterial collagenases indicated for: The treatment of adult patients with Dupuytren’s contracture with a palpable cord ( 1 ) The treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy ( 1 )

Dupuytren’s Contracture ( 2.1 ) XIAFLEX should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of Dupuytren’s contracture. Reconstitute XIAFLEX lyophilized powder with only the supplied diluent prior to use. Inject 0.58 mg of XIAFLEX into each palpable Dupuytren’s cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint according to the injection procedure. Up to two joints in the same hand may be treated during a treatment visit. ( 2.1 ) Approximately 24 to 72 hours following an injection, perform a finger extension procedure if a contracture persists. Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals. Inject up to two cords in the same hand at a treatment visit. If a patient has other cords with contractures, inject those cords at another treatment visit. Peyronie’s Disease ( 2.2 ) XIAFLEX should be administered by a healthcare provider experienced in the treatment of male urological diseases. Reconstitute XIAFLEX lyophilized powder with only the supplied diluent prior to use. A treatment cycle consists of two XIAFLEX injection procedures and a penile modeling procedure. Induce a penile erection. A single intracavernosal injection of 10 or 20 mcg of alprostadil may be used for this purpose. With the penis in the erect state, identify and mark the target area in the Peyronie’s plaque to be injected. The penis should be in a flaccid state before injecting XIAFLEX. Inject 0.58 mg XIAFLEX into the target plaque once on each of 2 days, 1 to 3 days apart, according to the injection procedure. Perform a penile modeling procedure 1 to 3 days after the second injection of each treatment cycle. For each plaque causing the curvature deformity, up to 4 treatment cycles may be administered. Each treatment cycle may be repeated at approximately 6-week intervals. If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if further treatment is not clinically indicated, then subsequent treatment cycles should not be administered. 2.1 Dosage and Administration for Dupuytren’s Contracture Dosing Overview for Dupuytren’s Contracture XIAFLEX should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren’s contracture. XIAFLEX, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use [see Dosage and Administration (2.1)] . The dose of XIAFLEX is 0.58 mg per injection into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint [see Dosage and Administration (2.1)] . Each vial of XIAFLEX and sterile diluent should only be used for a single injection. If two joints on the same hand are to be treated during a treatment visit, separate vials and syringes should be used for each reconstitution and injection. Table 1 displays an overview of the volumes of sterile diluent for reconstitution and the reconstituted XIAFLEX solution to be used in the intralesional injection [see Dosage and Administration (2.1)] . Approximately 24 to 72 hours after injection, perform a finger extension procedure if a contracture persists to facilitate cord disruption [see Dosage and Administration (2.1)] . Table 1. Volumes Needed for Reconstitution and Administration for Dupuytren’s Contracture For cords affecting MP joints For cords affecting PIP joints 1 The reconstituted XIAFLEX solution to be used in the intralesional injection contains 0.58 mg of XIAFLEX. Note: The entire reconstituted XIAFLEX solution contains 0.9 mg of XIAFLEX. Reconstituted XIAFLEX solution remaining in the vial after the injection should be discarded. Sterile Diluent for Reconstitution Volume 0.39 mL 0.31 mL Reconstituted XIAFLEX Solution to be Injected 1 Volume 0.25 mL 0.20 mL Four weeks after the XIAFLEX injection and finger extension procedure, if a MP or PIP contracture remains, the cord may be re-injected with a single dose of 0.58 mg of XIAFLEX and the finger extension procedure may be repeated (approximately 24 to 72 hours after injection). Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals. Perform up to two injections in the same hand according to the injection procedure during a treatment visit. Two palpable cords affecting two joints may be injected or one palpable cord affecting two joints in the same finger may be injected at two locations during a treatment visit. If patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with XIAFLEX at other treatment visits approximately 4 weeks apart. Reconstitution of the Lyophilized Powder for Dupuytren’s Contracture a) Before use, remove the vial(s) containing the lyophilized powder of XIAFLEX and the vial(s) containing the diluent for reconstitution from the refrigerator and allow the vials to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial(s) containing XIAFLEX. The cake of lyophilized powder should be intact and white in color. b) After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper and surrounding surface of the vial(s) containing XIAFLEX and the vial(s) containing the diluent for reconstitution with sterile alcohol (no other antiseptics should be used). c) Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of XIAFLEX. d) Using a 1-mL syringe that contains 0.01-mL graduations with a 27-gauge 1/2-inch needle (not supplied), withdraw a volume of the diluent supplied , as follows: 0.39 mL for cords affecting a MP joint or 0.31 mL for cords affecting a PIP joint. e) Inject the diluent slowly into the sides of the vial containing the lyophilized powder of XIAFLEX. Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. If administering two injections in the same hand during a treatment visit, use a new syringe to reconstitute a second vial of XIAFLEX with a second vial of diluent. f) The reconstituted XIAFLEX solution can be kept at room temperature (20°C to 25°C/68°F to 77°F) for up to 1 hour or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 4 hours prior to administration. If the reconstituted XIAFLEX solution is refrigerated, allow this solution to return to room temperature for approximately 15 minutes before use. g) Discard the syringe(s) and needle(s) used for reconstitution and the diluent vial(s). Preparation Prior to Injection for Dupuytren’s Contracture a) The reconstituted XIAFLEX solution should be clear. Inspect the solution visually for particulate matter and discoloration prior to administration. If the solution contains particulates, is cloudy, or is discolored, do not inject the reconstituted solution. b) Administration of a local anesthetic agent prior to injection is not recommended, as it may interfere with proper placement of the XIAFLEX injection. c) If injecting into a cord affecting the PIP joint of the fifth finger, care should be taken to inject as close to the palmar digital crease as possible (as far proximal to the digital PIP joint crease), and the needle insertion should not be more than 2 to 3 mm in depth. Tendon ruptures occurred after XIAFLEX injections near the digital PIP joint crease [see Warnings and Precautions (5.1)] . d) Reconfirm the cord(s) to be injected. The site chosen for each injection should be the area where the contracting cord is maximally separated from the underlying flexor tendons and where the skin is not intimately adhered to the cord. e) Apply an antiseptic at the site(s) of the injection(s) and allow the skin to dry. Injection Procedure for Dupuytren’s Contracture a) Using a new 1-mL hubless syringe that contains 0.01-mL graduations with a permanently fixed, 27-gauge 1/2-inch needle (not supplied), withdraw a volume of reconstituted solution (containing 0.58 mg of XIAFLEX) as follows: 0.25 mL for cords affecting a MP joint or 0.20 mL for cords affecting a PIP joint. b) With your non-dominant hand, secure the patient’s hand to be treated while simultaneously applying tension to the cord. With your dominant hand, place the needle into the cord, using caution to keep the needle within the cord. Avoid having the needle tip pass completely through the cord to help minimize the potential for injection of XIAFLEX into tissues other than the cord [see Warnings and Precautions (5.1)] . After needle placement, if there is any concern that the needle is in the flexor tendon, apply a small amount of passive motion at the distal interphalangeal (DIP) joint. If insertion of the needle into a tendon is suspected or paresthesia is noted by the patient, withdraw the needle and reposition it into the cord. c) If the needle is in the proper location, there will be some resistance noted during the injection procedure. After confirming that the needle is correctly placed in the cord, inject approximately one-third of the dose. d) Next, withdraw the needle tip from the cord and reposition it in a slightly more distal location (approximately 2 to 3 mm) to the initial injection in the cord and inject another one-third of the dose. e) Again withdraw the needle tip from the cord and reposition it a third time proximal to the initial injection (approximately 2 to 3 mm) and inject the final portion of the dose into the cord. f) When administering two injections in the same hand during a treatment visit, use a new syringe and separate vial of reconstituted solution for each injection. Repeat steps a through f. g) When administering two injections in the same hand during a treatment visit, begin with the affected finger in the most medial aspect of the hand and continue toward the lateral aspect (eg, fifth finger to index finger). When administering two injections in a cord affecting two joints in the same finger, begin with the affected joint in the most proximal aspect of the finger and continue toward the distal aspect (eg, MP to PIP). h) Wrap the patient’s treated hand with a soft, bulky, gauze dressing. i) Instruct the patient to limit motion of the treated finger(s) and to keep the injected hand elevated until bedtime. j) Instruct the patient not to attempt to disrupt the injected cord(s) by self-manipulation and to return to the healthcare provider’s office the next day for follow-up and a finger extension procedure(s), if needed. k) Discard the unused portion of the reconstituted solution and diluent after injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent. Finger Extension Procedure for Dupuytren’s Contracture a) At the follow-up visit approximately 24 to 72 hours after the injection(s) , if a contracture remains, perform a passive finger extension procedure on each treated joint (as described below) to facilitate cord disruption. If two joints in one finger were treated, perform the finger extension procedure on the affected MP joint before performing the finger extension procedure on the affected PIP joint. b) Local anesthesia may be used. Avoid direct pressure on the injection site as it will likely be tender. Care should be taken during release of contracture, as some patients may experience skin splitting. If this occurs, cover the area with gauze and apply gentle pressure until bleeding stops. Standard wound care with regular dressings should be applied. c) While the patient’s wrist is in the flexed position, apply moderate stretching pressure to the injected cord by extending the finger for approximately 10 to 20 seconds. For cords affecting the PIP joint, perform the finger extension procedure when the MP joint is in the flexed position. d) If the first finger extension procedure does not result in disruption of the cord, a second and third attempt can be performed at 5- to 10-minute intervals. However, no more than 3 attempts per joint are recommended to disrupt a cord. e) If the cord has not been disrupted after 3 attempts, a follow-up visit may be scheduled in approximately 4 weeks. If, at that subsequent visit, the contracted cord persists, an additional XIAFLEX injection with finger extension procedures may be performed [see Dosage and Administration (2.1)] . f) Following the finger extension procedure(s), fit patient with a splint and provide instructions for use at bedtime for up to 4 months to maintain finger extension. Also, instruct the patient to perform finger extension and flexion exercises several times a day for several months. 2.2 Dosage and Administration for Peyronie’s Disease Dosing Overview for Peyronie's Disease XIAFLEX should be administered by a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of XIAFLEX in the treatment of Peyronie’s disease. XIAFLEX, supplied as lyophilized powder, must be reconstituted with the provided diluent prior to use [see Dosage and Administration (2.2)] . The dose of XIAFLEX is 0.58 mg per injection administered into a Peyronie’s plaque. If more than one plaque is present, inject into the plaque causing the curvature deformity. A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two XIAFLEX injection procedures [see Dosage and Administration (2.2)] and one penile modeling procedure [see Dosage and Administration (2.2)]. The second XIAFLEX injection procedure is performed 1 to 3 days after the first. The penile modeling procedure is performed 1 to 3 days after the second injection of the treatment cycle. The interval between treatment cycles is approximately 6 weeks. The treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures. If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered. The safety of more than one treatment course of XIAFLEX is not known. Table 2 displays an overview of the volume of sterile diluent for reconstitution and the reconstituted XIAFLEX solution to be used in the intralesional injection [see Dosage and Administration (2.2)] . Table 2. Volumes Needed for Reconstitution and Administration 1 The reconstituted XIAFLEX solution to be used in the intralesional injection contains 0.58 mg of XIAFLEX. Note: The entire reconstituted XIAFLEX solution contains 0.9 mg of XIAFLEX. Reconstituted XIAFLEX solution remaining in the vial after the injection should be discarded. Sterile Diluent for Reconstitution Volume 0.39 mL Reconstituted XIAFLEX Solution to be Injected 1 Volume 0.25 mL Reconstitution of the Lyophilized Powder for Peyronie’s Disease a) Before use, remove the vial containing the lyophilized powder of XIAFLEX and the vial containing the diluent for reconstitution from the refrigerator and allow the 2 vials to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial containing XIAFLEX. The cake of lyophilized powder should be intact and white in color. b) After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper and surrounding surface of the vial containing XIAFLEX and the vial containing the diluent for reconstitution with sterile alcohol (no other antiseptics should be used). c) Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of XIAFLEX. d) Using a 1-mL syringe with 0.01-mL graduations with a 27-gauge 1/2-inch needle (not supplied), withdraw a volume of 0.39 mL of the diluent supplied. e) Inject the diluent slowly into the sides of the vial containing the lyophilized powder of XIAFLEX. Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. f) The reconstituted XIAFLEX solution can be kept at room temperature (20°C to 25°C/68°F to 77°F) for up to 1 hour or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 4 hours prior to administration. If the reconstituted XIAFLEX solution is refrigerated, allow this solution to return to room temperature for approximately 15 minutes before use. g) Discard the syringe and needle used for reconstitution and the diluent vial. Identification of Treatment Area for Peyronie’s Disease a) Prior to each treatment cycle, identify the treatment area as follows: Induce a penile erection. A single intracavernosal injection of 10 or 20 mcg of alprostadil may be used for this purpose. Apply antiseptic at the site of the injection and allow the skin to dry prior to the intracavernosal injection. Locate the plaque at the point of maximum concavity (or focal point) in the bend of the penis. Mark the point with a surgical marker. This indicates the target area in the plaque for XIAFLEX deposition. Injection Procedure for Peyronie’s Disease a) The reconstituted XIAFLEX solution should be clear. Inspect the solution visually for particulate matter and discoloration prior to administration. If the solution contains particulates, is cloudy, or is discolored, do not inject the reconstituted solution. b) Apply antiseptic at the site of the injection and allow the skin to dry. c) Administer suitable local anesthetic, if desired. d) Using a new hubless syringe containing 0.01-mL graduations with a permanently fixed 27-gauge 1/2-inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing 0.58 mg of XIAFLEX). e) The penis should be in a flaccid state before XIAFLEX is injected. Place the needle tip on the side of the target plaque in alignment with the point of maximal concavity. Orient the needle so that it enters the edge of the plaque and advance the needle into the plaque itself from the side. Do not advance the needle beneath the plaque nor perpendicularly towards the corpora cavernosum. f) Insert and advance the needle transversely through the width of the plaque, towards the opposite side of the plaque without passing completely through it. Proper needle position is tested and confirmed by carefully noting resistance to minimal depression of the syringe plunger. g) With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly inject XIAFLEX into the plaque. Withdraw the needle slowly so as to deposit the full dose along the needle track within the plaque. For plaques that are only a few millimeters in width, the distance of withdrawal of the syringe may be very minimal. The goal is always to deposit the full dose entirely within the plaque. h) Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a dressing as necessary. i) Discard the unused portion of the reconstituted solution and diluent after each injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent. j) The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from the first injection. Penile Modeling Procedure for Peyronie’s Disease Penile modeling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 1 to 3 days after the second injection of each treatment cycle, perform a penile modeling procedure (as described below) on the flaccid penis to stretch and elongate the treated plaque: Administer suitable local anesthetic, if desired. Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Avoid direct pressure on the injection site. Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient’s penile curvature, with stretching to the point of moderate resistance. Hold pressure for 30 seconds then release. After a 30 second rest period, repeat the penile modeling technique for a total of 3 modeling attempts at 30 seconds for each attempt. In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle as follows: During spontaneous erections, gently attempt to straighten the penis without producing pain and hold the penis in a straightened position for 30 seconds. The flaccid penis should be gently stretched three times daily. Slow, gentle force should be used without producing pain.

XIAFLEX is contraindicated in: the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure. patients with a history of hypersensitivity to XIAFLEX or to collagenase used in any other therapeutic application or application method [see Warnings and Precautions (5.4)] . Peyronie’s plaques that involve the penile urethra ( 4 ) History of hypersensitivity to XIAFLEX or to collagenase used in other therapeutic applications ( 4 )

The following serious adverse reactions in patients with Dupuytren’s contracture are discussed in greater detail elsewhere in the labeling: Tendon ruptures or other serious injury to the injected extremity [see Warnings and Precautions (5.1)] The following serious adverse reactions in patients with Peyronie’s disease are discussed in greater detail elsewhere in the labeling: Corporal rupture (penile fracture) and severe penile hematoma [see Warnings and Precautions (5.2)] In other XIAFLEX-treated patients, a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded [see Warnings and Precautions (5.2)] Dupuytren’s Contracture ( 6.1 ) The most common adverse reactions reported in ≥ 25% of patients treated with XIAFLEX and at an incidence greater than placebo were edema peripheral (e.g., swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the injected extremity. Peyronie’s Disease ( 6.2 ) The most frequently reported adverse drug reactions reported with ≥ 25% of patients treated with XIAFLEX and at an incidence greater than placebo were penile hematoma, penile swelling and penile pain. To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience in Patients with Dupuytren’s Contracture Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Out of 1082 patients who received 0.58 mg of XIAFLEX in the controlled and uncontrolled portions of the XIAFLEX studies (2630 XIAFLEX injections), 3 (0.3%) patients had a flexor tendon rupture of the treated finger within 7 days of the injection. The data described below are based on two pooled randomized, double-blind, placebo-controlled trials through Day 90 in patients with Dupuytren’s contracture (Studies 1 and 2). In these trials, patients were treated with up to 3 injections of 0.58 mg of XIAFLEX or placebo with approximately 4-week intervals between injections and the patients had finger extension procedures the day after injection, if needed, to facilitate disruption of the cord [see Clinical Studies (14)] . These trials were comprised of 374 patients of whom 249 and 125 received 0.58 mg of XIAFLEX and placebo, respectively. The mean age was 63 years, 80% were male and 20% were female, and 100% were white. In the placebo-controlled portions of Studies 1 and 2 through Day 90, 98% and 51% of XIAFLEX-treated and placebo-treated patients had an adverse reaction after up to 3 injections, respectively. Over 95% of XIAFLEX-treated patients had an adverse reaction of the injected extremity after up to 3 injections. Approximately 81% of these local reactions resolved without intervention within 4 weeks of XIAFLEX injections. The adverse reaction profile was similar for each injection, regardless of the number of injections administered. However, the incidence of pruritus increased with more injections [see Warnings and Precautions (5.4)]. The most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials in patients with Dupuytren’s contracture included edema peripheral (mostly swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the treated extremity. Table 3 shows the incidence of adverse reactions that were reported in greater than or equal to 5% of XIAFLEX-treated patients and at a frequency greater than placebo-treated patients after up to 3 injections in the pooled placebo-controlled trials through Day 90 (Studies 1 and 2). Table 3. Adverse Reactions Occurring in ≥ 5% of XIAFLEX-Treated Patients with Dupuytren’s Contracture and at a Greater Incidence than Placebo in the Placebo-Controlled Trials Through Day 90 After Up to 3 Injections a Most of these events were swelling of the injected hand. b Includes the terms: contusion (any body system) and ecchymosis. c Includes the terms: injection site reaction, injection site erythema, injection site inflammation, injection site irritation, injection site pain, and injection site warmth. d Includes the terms: injection site swelling and injection site edema. e Includes the terms: pruritus and injection site pruritus. f Includes the terms: lymphadenopathy and axillary mass. Adverse Reaction XIAFLEX N=249 Placebo N=125 All Adverse Reactions 98% 51% Edema peripheral a 73% 5% Contusion b 70% 3% Injection site hemorrhage 38% 3% Injection site reaction c 35% 6% Pain in extremity 35% 4% Tenderness 24% 0% Injection site swelling d 24% 6% Pruritus e 15% 1% Lymphadenopathy f 13% 0% Skin laceration 9% 0% Lymph node pain 8% 0% Erythema 6% 0% Axillary pain 6% 0% Some patients developed vasovagal syncope after finger extension procedures. The safety of two concurrent injections of XIAFLEX 0.58 mg into Dupuytren’s cords in the same hand was evaluated in a historically-controlled, open-label multi-center trial in 715 adult subjects with Dupuytren’s contracture (Study 3). In Study 3, finger extension procedures were performed approximately 24 to 72 hours after injection. The patient demographics were similar to Studies 1 and 2. Out of 715 patients who received two concurrent injections of XIAFLEX 0.58 mg in the same hand (1450 XIAFLEX injections) in Study 3, one (0.1%) patient experienced a tendon rupture of the treated finger within 3 days of the injection. Table 4 shows the incidence of adverse reactions that were reported in greater than or equal to 5% of XIAFLEX-treated patients after two concurrent injections of XIAFLEX in the same hand through Day 60 in Study 3. Table 4. Adverse Reactions Occurring in ≥5.0% of Subjects Who Received Two Concurrent Injections of XIAFLEX in Study 3 Adverse Reaction XIAFLEX N=715 Subjects with ≥1 adverse reaction 95% Edema peripheral 77% Contusion 59% Pain in extremity 51% Laceration 22% Pruritus 15% Injection site pain 14% Lymphadenopathy 13% Blood blister 12% Injection site hematoma 8% Axillary pain 7% Injection site hemorrhage 6% Injection site swelling 5% Ecchymosis 5% Safety of Retreatment of Recurrent Contractures An observational, open-label study was conducted in subjects who had participated in XIAFLEX clinical trials for Dupuytren’s contracture (Study 4). A subset of patients who had recurrence of contracture in a joint that was previously successfully treated with XIAFLEX in Study 4 were retreated (Study 5). No new safety signals were identified among subjects who were retreated with XIAFLEX. 6.2 Clinical Studies Experience in Patients with Peyronie’s Disease Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In the controlled and uncontrolled clinical studies of XIAFLEX in Peyronie’s disease, 1044 patients received a total of 7466 XIAFLEX injections. Corporal Rupture and Other Serious Penile Injury Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX treated patients. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie’s disease [see Adverse Reactions (6)]. The data described below are based on two identical, pooled, randomized, double-blind, placebo-controlled, multicenter trials through Day 365 in patients with Peyronie’s disease (Studies 1 and 2). These trials included 832 patients of whom 551 and 281 received XIAFLEX and placebo, respectively. In these trials, patients were given up to 4 treatment cycles of XIAFLEX or placebo. In each cycle, two injections of XIAFLEX or two injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed at the study site on patients 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately 6-week intervals up to 3 additional times, for a maximum of 8 total injection procedures and 4 total modeling procedures [see Clinical Studies (14.2)]. The majority of Peyronie’s patients experienced at least one adverse reaction (92% XIAFLEX-treated patients, 61% placebo-treated). Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered. The most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials in patients with Peyronie’s disease were penile hematoma, penile swelling, and penile pain. Table 5 shows the incidence of adverse reactions that were reported in greater than or equal to 1% of XIAFLEX-treated patients and at a frequency greater than placebo-treated patients after up to 8 injections in the pooled placebo-controlled trials through Day 365. Table 5. Adverse Reactions Occurring in ≥ 1% of XIAFLEX-Treated Patients with Peyronie’s disease and at a Greater Incidence than Placebo After Up to Four Treatment Cycles in Studies 1 and 2 Combined a Includes: injection site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of subjects. b Includes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection site edema. c Includes: injection site pain, penile pain, and injection site discomfort. d Includes: contusion, ecchymoses, penile hemorrhage, and injection site hemorrhage. Adverse Reaction XIAFLEX N=551 Placebo N=281 All Adverse Reactions 84.2% 36.3% Penile hematoma a 65.5% 19.2% Penile swelling b 55.0% 3.2% Penile pain c 45.4% 9.3% Penile ecchymoses d 14.5% 6.8% Blood blister 4.5% 0 Penile blister 3.3% 0 Pruritus genital 3.1% 0 Painful erection 2.9% 0 Erectile dysfunction 1.8% 0.4% Skin discoloration 1.8% 0 Procedural pain 1.6% 0.7% Injection site vesicles 1.3% 0 Localized edema 1.3% 0 Dyspareunia 1.1% 0 Injection site pruritus 1.1% 0 Nodule 1.1% 0 Suprapubic pain 1.1% 0 Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of XIAFLEX-treated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined. Reports of penile “popping” sounds or sensations A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking”, and sometimes accompanied by detumescence, hematoma and/or pain, were reported in 73/551 (13.2%) XIAFLEX-treated patients and 1/281 (0.3%) placebo-treated patients. There were no clinically meaningful differences in the incidence of adverse events following treatment with XIAFLEX based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use. XIAFLEX was not associated with shortening of penile length in clinical trials in the treatment of Peyronie’s disease. 6.3 Immunogenicity During clinical studies in Dupuytren’s contracture and Peyronie’s disease, patients were tested at multiple time points for antibodies to the protein components of XIAFLEX (AUX-I and AUX-II). In the Dupuytren’s contracture clinical studies (Studies 1 and 2), at 30 days post the first injection of XIAFLEX 0.58 mg, 92% of patients had antibodies against AUX-I detected and 86% of patients had antibodies against AUX-II detected. After the fourth injection of XIAFLEX, every XIAFLEX-treated patient developed high titers of antibodies to both AUX-I and AUX-II. After 5 years more than 90% of patients remained seropositive for anti-AUX-I and anti-AUX-II antibody (Study 4). Neutralizing antibodies were assayed for all patients (204) in Study 1. Neutralizing antibodies to AUX-I or AUX-II, were detected in 10% and 21%, respectively, of patients treated with XIAFLEX. Among patients in Study 3 who reported no prior exposure to XIAFLEX, 97% of patients had antibodies against AUX-I and AUX-II after two concurrent doses of XIAFLEX 0.58 mg (total dose of 1.16 mg) in the same hand. In Study 5, treatment of recurrent contractures with XIAFLEX resulted in similar immunogenicity results as seen in Studies 1 and 2. In the Peyronie’s disease clinical studies, at 6 weeks after the first treatment cycle of XIAFLEX 0.58 mg, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of XIAFLEX, >99% of XIAFLEX-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at Week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested. In patients treated for these two indications, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions. Since the protein components in XIAFLEX (AUX-I and AUX-II) have some sequence homology with human matrix metalloproteinases (MMPs), anti-product antibodies could theoretically interfere with human MMPs. In vitro studies showed no evidence of cross-reactivity between anti-drug-antibody positive patient sera and a series of relevant MMPs. In addition, no clinical safety concerns related to the inhibition of endogenous MMPs have been observed. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to collagenase clostridium histolyticum with the incidence of antibodies to other products may be misleading. 6.4 Postmarketing Experience The following adverse reactions have been identified during post-approval use of XIAFLEX. 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. Acute Lower Back Pain Reactions Reports of acute lower back pain reactions, sometimes accompanied by radiation of pain to the lower extremities, chest and arms, muscle spasms, chest pain, paresthesias and dyspnea, have been received involving patients treated with XIAFLEX for Peyronie’s disease. Some patients have also experienced temporary gait instability and an inability to ambulate for brief periods of time post injection. These events have occurred in close temporal proximity to XIAFLEX treatments. During retreatment injections with XIAFLEX, cases of recurrent acute lower back pain reactions have been reported. These events can be mild to severe in intensity. The events typically resolved within 15 minutes, but some lasted up to 30 minutes, and one event lasted 1.5 hours. The events typically did not require intervention, but some required observation and treatment with analgesics. The events typically resolved without sequelae, but in one event, pain improved but did not resolve at the time of final report. Skin and Soft Tissue Necrosis Events Reports of localized skin and soft tissue necrosis, occurring as sequelae of penile hematoma, have been received in patients treated with XIAFLEX for Peyronie’s disease. Some of the cases required surgical intervention. Syncope and Presyncope Cases of syncope and presyncope have been reported in the postmarketing period in patients treated with XIAFLEX. Potential triggers for the syncopal events, including post-procedure pain, suggest a vasovagal mechanism. Most, but not all the cases, occurred in the immediate treatment period or within 1 to 2 days following injection. Bodily injuries, including concussion, head abrasion, and other accidental injuries, have been reported in association with the syncopal events.

Anticoagulant drugs: XIAFLEX should be used with caution in patients receiving concomitant anticoagulants (except for low-dose aspirin) [see Warnings and Precautions (5.5)] .

Storage and Stability Prior to reconstitution, the vials of XIAFLEX and diluent should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F). [ see Dosage and Administration (2.1 , 2.2 )] . Do not freeze. The reconstituted XIAFLEX solution can be kept at room temperature (20°C to 25°C/68°F to 77°F) for up to 1 hour or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 4 hours prior to administration [ see Dosage and Administration (2.1 , 2.2 )] .