英文药名：XIAFLEX(Collagenase Clostridium histolyticum) 中文药名：胶原酶溶组织梭菌注射剂 生产厂家：Auxilium制药 药品介绍 药物名称：Xiaflex (collagenase clostridium histolyticum) 适应症：掌肌膜挛缩症 公司：Auxilium制药 批准日期：2010年2月2日 药品类型：生物制品 简要说明：用于治疗一种可影响手指伸直和正常活动的能力的掌肌膜挛缩症。该药是首个用于治疗这种疾病的药物，由位于美国宾州的Auxilium制药公司生产。 2010年2月Auxilium制药公司开发的溶组织芽胞梭菌胶原酶产品Xiaflex成为首个在美国获准用于治疗损伤手掌功能的杜普伊特伦挛缩征（Du-puytren＇s contracture）药物，FDA药物评估与研究中心的Bob Rappaport称，“在Xiaflex获准上市前，此手疾的唯一有效疗法是手术，而术后患者往往需要长时间恢复和理疗。因此，该药的成功开发是此手疾治疗研究取得的一大进展。”Auxilium公司CEO Armando Anido也称，该药获准上市是医治此手疾的重大突破”。 XIAFLEX™ (collagenase clostridium histolyticum) for injection, for intralesional use Initial U.S. Approval: 2010 DESCRIPTION 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 0.39 mL (for a MP joint) or 0.31 mL (for a PIP joint) of 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. 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. CLINICAL PHARMACOLOGY 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. 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. Pharmacokinetics Following administration of a single XIAFLEX dose of 0.58 mg into a Dupuytren’s cord in 20 patients, no quantifiable levels of XIAFLEX (AUX-I or AUX-II) were detected in plasma up to 30 days post injection INDICATIONS AND USAGE XIAFLEX is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord. CONTRAINDICATIONS None. PRECAUTIONS  WARNINGS AND PRECAUTIONS •Tendon rupture or serious injury to the injected extremity: 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 or ligament damage. •Allergic reactions: Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. •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 ADVERSE REACTIONS 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 reaction, injection site hemorrhage, and pain in the injected extremity. DOSAGE AND ADMINISTRATION Dosing Overview 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. 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. 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. Approximately 24 hours after injection, perform a finger extension procedure if a contracture persists to facilitate cord disruption Table 1. 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. 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 hours after injection). Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals. Inject only one cord at a time. If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with XIAFLEX in a sequential order. Reconstitution of the Lyophilized Powder: 1.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 two vials to stand at room temperature for at least 15 minutes and no longer than 60 minutes. 2.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). 3.Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of XIAFLEX. 4.Using a 1 mL syringe that contains 0.01 mL graduations with a 27-gauge ½-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. 5.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. 6.The reconstituted XIAFLEX solution can be kept at room temperature (20° to 25°C/68° to 77°F) for up to one hour or refrigerated at 2° to 8°C (36° 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. 7.Discard the syringe and needle used for reconstitution and the diluent vial. Preparation Prior to Injection: 1.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. 2.Administration of a local anesthetic agent prior to injection is not recommended, as it may interfere with proper placement of the XIAFLEX injection. 3.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. 4.Reconfirm the cord to be injected. The site chosen for 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. 5.Apply an antiseptic at the site of the injection and allow the skin to dry. Injection Procedure: 1.Using a new 1 mL hubless syringe that contains 0.01 mL graduations with a permanently fixed, 27-gauge half-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. 2.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. 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. 3.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. 4.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. 5.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. 6.Wrap the patient’s treated hand with a soft, bulky, gauze dressing. 7.Instruct the patient to limit motion of the treated finger and to keep the injected hand elevated until bedtime. 8.Instruct the patient not to attempt to disrupt the injected cord by self-manipulation and to return to the provider’s office the next day for follow-up and a finger extension procedure, if needed. 9.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: 1.At the follow-up visit the day after the injection, if a contracture remains, perform a passive finger extension procedure (as described below) to facilitate cord disruption. 2.Local anesthesia may be used. Avoid direct pressure on the injection site as it will likely be tender. 3.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. 4.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 are recommended to disrupt a cord. 5.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. 6.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 HOW SUPPLIED  DOSAGE FORMS AND STRENGTHS XIAFLEX is supplied in single-use glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for reconstitution is provided in the package in a single-use glass vial containing 3 mL of 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride. Storage and Stability Prior to reconstitution, the vials of XIAFLEX and diluent should be stored in a refrigerator at 2° to 8°C (36° to 46°F). Do not freeze. The reconstituted XIAFLEX solution can be kept at room temperature (20° to 25°C/68° to 77°F) for up to one hour or refrigerated at 2° to 8°C (36° to 46°F) for up to 4 hours prior to administration  Package Insert data:  Manufactured and distributed by: Auxilium Pharmaceuticals, Inc 注射用XIAFLEX(collagenase clostridium histolyticum)用于治疗掌腱膜挛缩症 美国FDA批准Auxilium制药Xiaflex（胶原酶梭菌或 CCH）一项补充生物制剂许可申请 (sBLA)，在一次单一治疗中用于同一手上两处杜普伊特伦挛缩(DC) 关节治疗。 Xiaflex在美国、欧盟、加拿大及澳大利亚被批准用于治疗带有明显胶原蛋白线的DC成人患者。 杜普伊特伦挛缩是一种侵袭性手部疾病，可表现有多条胶原蛋白线，限制手指关节活动。sBLA基于全球、多中心3b期MULTICORD试验积极结果，以及该公司早期研究 AUX-CC-861和AUX-CC-864的数据。 MULTICORD 试验还评价了药物注射后24、48或72小时后手指伸展的有效性和安全性。该公司表示，在3b期临床试验中，两种并行的 Xiaflex注射剂被安全地用于治疗多个关节受影响的一只手。 Auxilium制药首席执行官兼总裁Adams表示，该公司很高兴FDA批准Xiaflex的sBLA，扩展其标签，使其在同一手上同时治疗两处杜普伊特伦挛缩关节，手指伸展大约在药物注射后24小时至72小时内。 “我们认为这对患者及医师来说是一个重要的里程碑，因为它扩大了在一次治疗中同时治疗两处关节的治疗选择，这可能会导致更少的总体治疗时间，”Adams称。