collagenase Clostridium histolyticum 0.9 MG Injection [Xiaflex]

INDICATIONS AND USAGE 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 )

DOSAGE AND ADMINISTRATION 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 Pr

WARNINGS AND PRECAUTIONS Tendon rupture or serious injury to the injected finger/hand: Avoid injecting XIAFLEX into tendons, nerves, blood vessels, or other collagen-containing structure of the hand. Injection into these structures may result in possible permanent injury, such as tendon rupture, ligament damage, or skin laceration. ( 5.1 ) Corporal rupture (penile fracture) or other serious injury to the penis: Avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis. Injection into these structures may result in possible permanent injury such as corporal rupture (penile fracture). ( 5.2 ) Hypersensitivity reactions, including anaphylaxis: Healthcare providers should be prepared to address hypersensitivity reactions, including anaphylaxis, following XIAFLEX injections. ( 5.4 ) Patients with abnormal coagulation: Use with caution, including in patients who have received anticoagulant medications other than low-dose aspirin within 7 days of the injection. ( 5.5 ) Acute post-injection back pain reactions: Observe patients and provide palliative support as needed. Administer the smallest number of treatment cycles necessary to treat the patient’s curvature deformity ( 5.6 , 6.4 ) Syncope and presyncope: Make patients aware that post-injection pain can trigger syncope and presyncope. If presyncope occurs, patients should remain recumbent until symptoms resolve. ( 5.7 , 6.4 ) 5.1 Tendon Rupture or Other Serious Injury to the Injected Finger/Hand in the Treatment of Dupuytren’s Contracture In the controlled and uncontrolled portions of clinical trials in Dupuytren’s contracture, flexor tendon ruptures occurred after XIAFLEX injection [see Adverse Reactions (6.1)] . Injection of XIAFLEX into collagen-containing structures such as tendons or ligaments of the hand may result in damage to those structures and possible permanent injury such as tendon rupture or ligament damage. Therefore, XIAFLEX should be injected only into the collagen cord with a MP or PIP joint contracture, and care should be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. When injecting a cord affecting a PIP joint of the fifth finger, the needle insertion should not be more than 2 to 3 mm in depth and avoid injecting more than 4 mm distal to the palmar digital crease [see Dosage and Administration (2.1)] . Other XIAFLEX-associated serious local adverse reactions included pulley rupture, ligament injury, complex regional pain syndrome (CRPS), sensory abnormality of the hand, and skin laceration (tear). In a historically controlled post-marketing trial, the incidence of skin laceration (22%) was higher for subjects treated with two concurrent injections of XIAFLEX compared with subjects treated with up to three single injections in the placebo-controlled premarketing trials (9%). Postmarketing cases of skin laceration requiring skin graft after finger extension procedures and local skin and soft-tissue necrosis, some requiring skin grafting or, other surgical interventions including finger amputation have been reported. Signs or symptoms that may reflect serious injury to the injected finger/hand should be promptly evaluated because surgical intervention may be required. 5.2 Corporal Rupture (Penile Fracture) or Other Serious Injury to the Penis in the Treatment of Peyronie’s Disease Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX-treated patients in the controlled and uncontrolled clinical trials in Peyronie’s disease. 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 )] . In the postmarketing setting, cases of localized skin and soft tissue necrosis occurring as sequelae of penile hematoma have been reported. Some of the cases required surgical intervention. Injection of XIAFLEX into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, XIAFLEX should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis. Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to assess for corporal rupture or severe penile hematoma, which may require surgical intervention. 5.3 XIAFLEX REMS Program Because of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie’s disease, XIAFLEX is available only through the XIAFLEX REMS Program [see Warnings and Precautions (5.2)] . Required components of the XIAFLEX REMS Program include the following: Prescribers must be certified with the program by enrolling and completing training in the administration of XIAFLEX treatment for Peyronie’s disease. Healthcare sites must be certified with the program and ensure that XIAFLEX is only dispensed for use by certified prescribers. Further information is available at www.XIAFLEXREMS.com or 1-877-313-1235. 5.4 Hypersensitivity Reactions, Including Anaphylaxis In the controlled portions of the clinical trials in Dupuytren’s contracture (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of XIAFLEX-associated pruritus increased after more XIAFLEX injections in patients with Dupuytren’s contracture. In the double-blind, placebo-controlled portions of the clinical trials in Peyronie’s disease (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered. Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to XIAFLEX for the treatment of Dupuytren’s contracture. Some patients with Dupuytren’s contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive XIAFLEX injections. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. 5.5 Risk of Bleeding in Patients with Abnormal Coagulation In the XIAFLEX trials in Dupuytren’s contracture (Studies 1 and 2), 70% and 38% of XIAFLEX-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively (see Table 3). In the XIAFLEX controlled trials in Peyronie’s disease (Studies 1 and 2), 65.5% of XIAFLEX-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis (see Table 5). Patients with abnormal coagulation (except for patients taking low-dose aspirin, e.g., up to 150 mg per day) were excluded from participating in these studies. Therefore, the efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to XIAFLEX administration is not known. In addition, it is recommended to avoid use of XIAFLEX in patients with co

CONTRAINDICATIONS 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 )

Mechanism of Action Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiological conditions, resulting in lysis of collagen deposits. Injection of XIAFLEX into a Dupuytren’s cord, which is comprised mostly of collagen, may result in enzymatic disruption of the cord. The signs and symptoms of Peyronie’s disease are caused by a collagen plaque. Injection of XIAFLEX into a Peyronie’s plaque, which is comprised mostly of collagen, may result in enzymatic disruption of the plaque. Following this disruption of the plaque, penile curvature deformity and patient bother caused by Peyronie’s disease are reduced [see Clinical Studies (14.2)]. Results of in vitro studies, including those of explant tissues containing Peyronie’s plaques, suggest that XIAFLEX disrupts the predominant collagen found in plaques (Types I and III). At higher doses and longer incubation times, non-fibrillar Type IV collagen was affected causing collagen lysis in small veins, but did not cause structural damage to arteries, nerves or large veins which contain Type IV collagen in in vitro or in vivo studies. Results of in vitro studies suggest that the collagenases (AUX-I and AUX-II) worked synergistically to provide hydrolyzing activity towards collagen. However, there are no clinical data regarding the relative contributions of the individual collagenases (AUX-I or AUX-II) to the efficacy of XIAFLEX in the treatment of Dupuytren’s contracture or Peyronie’s disease. Collagen fragments generated from clostridial collagenase have been shown to generate increased vascular permeability, inflammatory responses, and regenerative changes. However, the effects of the formation of the collagen fragments derived from the collagen plaque are unknown.