collagenase Clostridium histolyticum

1 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 )

12.1 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.

2 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 F

6 ADVERSE REACTIONS 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 wit

5 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 unknow

4 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 )

10 OVERDOSAGE The effects of overdose of XIAFLEX are unknown. It is possible that multiple simultaneous or excessive doses of XIAFLEX may cause more severe local effects than the recommended doses including serious adverse reactions in the injected area (e.g., tendon ruptures or corporal ruptures dependent on the injection site). Supportive care and symptomatic treatment are recommended in these circumstances.