药物：Xiaflex（胶原酶梭菌histolyticum） 主治：Depuytren的挛缩 公司：Auxilium制药 批准日期：2月3日 2010年2月3日，Auxilium公司宣布，美国食品药品管理局(FDA)已批准注射用Xiaflex用于治疗掌腱膜挛缩症(可触及条索状结构)成人患者。根据产品标签，Xiaflex所含的纯化溶组织梭菌胶原酶为从溶组织梭菌发酵分离及纯化而来的两种微生物胶原酶。标签指出，该产品所含的胶原酶为蛋白水解酶，其作用机制在于通过溶解胶原沉积物而达到治疗目的。由于掌腱膜条索主要由胶原组成，因此通过注射Xiaflex能够酶解这种条索。 XIAFLEX - collagenase    Auxilium HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use XIAFLEX safely and effectively. See full prescribing information for XIAFLEX. XIAFLEX™ (collagenase clostridium histolyticum) for injection, for intralesional use Initial U.S. Approval: 2010   INDICATIONS AND USAGE XIAFLEX is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord. (1) DOSAGE AND ADMINISTRATION XIAFLEX should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of Dupuytren’s contracture. (2.1) Reconstitute XIAFLEX lyophilized powder with only the supplied diluent prior to use. (2.1, 2.2) Inject 0.58 mg of XIAFLEX into a palpable Dupuytren’s cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint according to the injection procedure. (2.1,2.4) Approximately 24 hours following an injection, perform a finger extension procedure if a contracture persists. (2.1,2.5) Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals. (2.1) Inject only one cord at a time. If a patient has other cords with contractures, inject each cord in sequential order. (2.1) DOSAGE FORMS AND STRENGTHS Single-use glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for reconstitution is also provided in a single-use glass vial. (3) CONTRAINDICATIONS None. (4)   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. (5.1) Allergic reactions: Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. (5.2) 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. (5.3)   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. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Auxilium Pharmaceuticals, Inc. at 1-877-663-0412 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide  FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE XIAFLEX is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord. 2 DOSAGE AND ADMINISTRATION 2.1 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[see Dosage and Administration (2.2)]. 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 (2.4)]. 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 (2.2, 2.4)]. Approximately 24 hours after injection, perform a finger extension procedure if a contracture persists to facilitate cord disruption [see Dosage and Administration (2.5)]. 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.   For cords affecting MP joints For cords affecting PIP joints Sterile Diluent for Reconstitution Volume 0.39 mL 0.31 mL Reconstituted XIAFLEX Solution to be Injected1 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 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. 2.2 Reconstitution of the Lyophilized Powder 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. 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). Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of XIAFLEX. 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. 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. 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. Discard the syringe and needle used for reconstitution and the diluent vial. 2.3 Preparation Prior to Injection 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. Administration of a local anesthetic agent prior to injection is not recommended, as it may interfere with proper placement of the XIAFLEX injection. 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)]. 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. Apply an antiseptic at the site of the injection and allow the skin to dry. 2.4 Injection Procedure Using a new 1 mL hubless syringe that contains 0.01 mL graduations with a permanently fixed, 27-gauge ½-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. 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. 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. 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. 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. Wrap the patient’s treated hand with a soft, bulky, gauze dressing. Instruct the patient to limit motion of the treated finger and to keep the injected hand elevated until bedtime. 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. 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. 2.5 Finger Extension Procedure 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. Local anesthesia may be used. Avoid direct pressure on the injection site as it will likely be tender. 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. 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. 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)]. 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. 3 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. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Tendon Rupture or Other Serious Injury to the Injected Extremity In the controlled and uncontrolled portions of the clinical trials, 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 (2.3, 2.4)]. Other XIAFLEX-associated serious local adverse reactions in the controlled and uncontrolled portions of the studies included pulley rupture, ligament injury, complex regional pain syndrome (CRPS), and sensory abnormality of the hand. 5.2 Allergic Reactions In the controlled portions of the clinical trials (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. Although there were no severe allergic reactions observed in the XIAFLEX studies (e.g., those associated with respiratory compromise, hypotension, or end-organ dysfunction), severe reactions including anaphylaxis could occur following XIAFLEX injections. XIAFLEX contains foreign proteins and patients 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. 5.3 Patients with Abnormal Coagulation In the XIAFLEX trials (Studies 1 and 2), 70% and 38% of XIAFLEX-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively. 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. Therefore, XIAFLEX should be used with caution in patients with coagulation disorders including patients receiving concomitant anticoagulants (except for low-dose aspirin). 6 ADVERSE REACTIONS The following serious adverse reactions 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 most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials included edema peripheral (mostly swelling of the injected hand), contusion, injection site reaction, injection site hemorrhage, and pain in the treated extremity. 6.1 Clinical Studies Experience 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 (5.2)]. Table 2 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). 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 Some patients developed vasovagal syncope after finger extension procedures. Immunogenicity During clinical studies, patients with Dupuytren’s contracture were tested at multiple time points for antibodies to the protein components of XIAFLEX (AUX-I and AUX-II). At 30 days post the first injection of XIAFLEX 0.58 mg, 92% of patients had antibodies detected against AUX-I and 86% of patients had antibodies detected against AUX-II. After the fourth injection of XIAFLEX, every XIAFLEX-treated patient developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies to AUX-I or AUX-II, were detected in 10% and 21%, respectively, of patients treated with XIAFLEX. However, 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. 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. 7 DRUG INTERACTIONS Anticoagulant drugs: XIAFLEX should be used with caution in patients receiving concomitant anticoagulants (except for low-dose aspirin) [see Warnings and Precautions (5.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of XIAFLEX in pregnant women. Human pharmacokinetic studies showed that XIAFLEX levels were not quantifiable in the systemic circulation following injection into a Dupuytren’s cord [see Clinical Pharmacology (12.3)]. Reproduction studies have been performed in rats with intravenous doses up to 0.13 mg (approximately 45 times the human dose of XIAFLEX on a mg/kg basis, if administered intravenously) and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum. Almost all patients develop anti-product antibodies (anti-AUX-I and anti-AUX-II) after treatment with XIAFLEX, and the clinical significance of anti-product antibody formation on a developing fetus is not known [see Adverse Reactions (6.1)]. Because animal reproduction studies are not always predictive of human response, XIAFLEX should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether collagenase clostridium histolyticum is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when XIAFLEX is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of XIAFLEX in pediatric patients less than 18 years old have not been established. 8.5 Geriatric Use Of the 249 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials (Studies 1 and 2), 104 (42%) were 65 years of age or older and 9% were 75 years of age or older. No overall differences in safety or effectiveness of XIAFLEX were observed between these patients and younger patients. 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 including serious adverse reactions (e.g., tendon ruptures) than the recommended doses. Supportive care and symptomatic treatment are recommended in these circumstances. 11 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. 12 CLINICAL PHARMACOLOGY 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. 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. 12.3 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. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term animal studies to evaluate the carcinogenic potential of collagenase clostridium histolyticum have not been conducted. Purified collagenase clostridium histolyticum was not mutagenic in Salmonella typhimurium (AMES test) and was not clastogenic in both an in vivo mouse micronucleus assay and an in vitro chromosomal aberration assay in human lymphocytes. Collagenase clostridium histolyticum did not impair fertility and early embryonic development when administered intravenously in rats at doses up to 0.13 mg/dose (approximately 45 times the human dose on a mg/kg basis). 14 CLINICAL STUDIES The efficacy of 0.58 mg of XIAFLEX was evaluated in two randomized, double-blind, placebo-controlled, multi-centered trials in 374 adult patients with Dupuytren’s contracture (Studies 1 and 2). At study entry, patients must have had: (1) a finger flexion contracture with a palpable cord of at least one finger (other than the thumb) of 20° to 100° in a metacarpophalangeal (MP) joint or 20° to 80° in a proximal interphalangeal (PIP) joint and (2) a positive “table top test” defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. Patients could not have received a surgical treatment (e.g., fasciectomy, fasciotomy) on the selected primary joint within 90 days before the first injection of study medication and patients could not have received anticoagulation medication (except for up to 150 mg of aspirin per day) within 7 days before the first injection of study medication. The cord affecting the selected primary joint received up to 3 injections of 0.58 mg of XIAFLEX or placebo on Days 0, 30, and 60. About 24 hours after each injection of study medication, if needed, the investigator manipulated (extended) the treated finger in an attempt to facilitate rupture of the cord (finger extension procedure). Following manipulation, patients were fitted with a splint, instructed to wear the splint at bedtime for up to 4 months, and instructed to perform a series of finger flexion and extension exercises each day. See Table 3 for the baseline disease characteristics of patients with Dupuytren’s contracture in Studies 1 and 2. Prior surgery for Dupuytren’s contracture included fasciotomy and fasciectomy In Studies 1 and 2, the primary endpoint was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to within 0° to 5° of normal, 30 days after the last injection of that joint on Days 30, 60, or 90 (after up to 3 injections). A greater proportion of XIAFLEX-treated patients compared to placebo-treated patients achieved the primary endpoint (see Table 4). a Patients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90). b For XIAFLEX-treated patients, the mean (±SD) number of injections given to the cord associated with the contracture was 1.7 (±0.8) in the 90-day controlled period in each trial. c MP joints are metacarpophalangeal joints d PIP joints are proximal interphalangeal joints e 95% confidence interval The proportion of patients who achieved a contracture reduction of the primary joint to 0° to 5° after the first injection was 39% and 1% in Study 1 and 27% and 5% in Study 2 in the XIAFLEX and placebo groups respectively. XIAFLEX-treated patients, compared to placebo-treated patients, showed a greater increase from baseline in the range of motion of MP and PIP joints (see Table 5). a Patients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90). Baseline and final range of motion degree values are expressed in mean (SD). b MP = Metacarpophalangeal joint c PIP = Proximal interphalangeal joint Range of Motion = Degrees of Full Flexion minus Degrees of Fixed Extension Not all patients had range of motion values at both time points. 16 HOW SUPPLIED/STORAGE AND HANDLING Each single-use vial of XIAFLEX is packaged with a single-use vial of sterile diluent in an outer carton. The National Drug Code is: NDC 66887-003-01 XIAFLEX is available in single-use, glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder. Sterile diluent for reconstitution is available in single-use, glass vials 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) [see Dosage and Administration (2.2)]. 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 [see Dosage and Administration (2.2)]. 17 PATIENT COUNSELING INFORMATION See Medication Guide Advise patients of the following: Serious complications of XIAFLEX injection include tendon rupture or serious ligament damage that may result in the inability to fully bend the finger and may require surgery to correct the complication. XIAFLEX injection is likely to result in swelling, bruising, bleeding, and/or pain of the injected site and surrounding tissue. After the XIAFLEX injections, instruct patients: Not to flex or extend the fingers of the injected hand to reduce extravasation of XIAFLEX out of the cord. Not to attempt to disrupt the injected cord by self manipulation. To elevate the injected hand until bedtime. To promptly contact their physician if there is evidence of infection (e.g., fever, chills, increasing redness or edema), sensory changes in the treated finger, or trouble bending the finger after the swelling goes down (symptoms of tendon rupture). To return to their healthcare provider’s office the next day for an examination of the injected hand and for a possible finger extension procedure to disrupt the cord. Following the finger extension procedure(s) and fitting patient with a splint, instruct patients: Not to perform strenuous activity with the injected hand until advised to do so. To wear the splint at bedtime for up to 4 months. To perform a series of finger flexion and extension exercises each day. Manufactured and distributed by: Auxilium Pharmaceuticals, Inc. Malvern, PA 19355 USA US License No. 1816 PL-0108-001.a MEDICATION GUIDE XIAFLEX™ (Zī a flex) (collagenase clostridium histolyticum) Read this Medication Guide before you receive XIAFLEX and each time you get an injection. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information I should know about XIAFLEX? XIAFLEX can cause serious side effects, including: Tendon or ligament damage. Receiving an injection of XIAFLEX may cause damage to a tendon or ligament in your hand and cause it to break or weaken. This could require surgery to fix the damaged tendon or ligament. Call your healthcare provider right away if you have trouble bending your injected finger (towards the wrist) after the swelling goes down or you have problems using your treated hand after your follow-up visit. Nerve injury or other serious injury of the hand. Call your healthcare provider if you get numbness, tingling, or increased pain in your treated finger or hand after your injection or after your follow-up visit. Allergic Reactions. Allergic reactions can happen in people who take XIAFLEX because it contains foreign proteins. Call your healthcare provider right away if you have any of these symptoms of an allergic reaction after an injection of XIAFLEX: ➢ hives ➢ swollen face ➢ breathing trouble ➢ chest pain What is XIAFLEX? XIAFLEX is a prescription medicine used to treat adults with Dupuytren’s contracture when a “cord” can be felt. In people with Dupuytren’s contracture, there is thickening of the skin and tissue in the palm of your hand that is not normal. Over time, this thickened tissue can form a cord in your palm. This causes one or more of your fingers to bend toward the palm, so you can not straighten them. XIAFLEX should be injected into a cord by a healthcare provider who is skilled in injection procedures of the hand and treating people with Dupuytren’s contracture. The proteins in XIAFLEX help to “break” the cord of tissue that is causing the finger to be bent. It is not known if XIAFLEX is safe and effective in children under the age of 18. What should I tell my healthcare provider before starting treatment with XIAFLEX? XIAFLEX may not be right for you. Before receiving XIAFLEX, tell your healthcare provider if you: have had an allergic reaction to a previous XIAFLEX injection. have a bleeding problem. have any other medical conditions. are pregnant or plan to become pregnant. It is not known if XIAFLEX will harm your unborn baby. are breastfeeding. It is not known if XIAFLEX passes into your breast-milk. Talk to healthcare provider about the best way to feed your baby if you receive XIAFLEX. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you use: ➢ a blood thinner medicine such as aspirin, clopidogrel (PLAVIX®), prasugrel hydrochloride (EFFIENT®), or warfarin sodium (COUMADIN®). If you are told to stop taking a blood thinner before your XIAFLEX injection, your healthcare provider should tell you when to restart the blood thinner. How will I receive XIAFLEX? Your healthcare provider will inject XIAFLEX into the cord that is causing your finger to bend. After an injection of XIAFLEX, your affected hand will be wrapped with a bandage. You should limit moving and using the treated finger after the injection. ➢ Do not bend or straighten the fingers of the injected hand until your healthcare provider says it is okay. This will help prevent the medicine from leaking out of the cord. ➢ Do not try to straighten the treated finger yourself. Keep the injected hand elevated until bedtime. Call your healthcare provider right away if you have ➢ signs of infection after your injection, such as fever, chills, increased redness, or swelling ➢ numbness or tingling in the treated finger ➢ trouble bending the injected finger after the swelling goes down Return to your healthcare provider’s office as directed on the day after your injection. During this first follow-up visit, if you still have the cord, your healthcare provider may try to extend the treated finger to “break” the cord and try to straighten your finger. Your healthcare provider will provide you with a splint to wear on the treated finger. Wear the splint as instructed by your healthcare provider at bedtime to keep your finger straight. Do finger exercises each day, as instructed by your healthcare provider. Follow your healthcare provider’s instructions about when you can start doing your normal activities with the injected hand. What are the possible side effects of XIAFLEX? XIAFLEX can cause serious side effects. See “What is the most important information I should know about XIAFLEX?”. Common side effects with XIAFLEX include: swelling of the injection site or the hand bleeding or bruising at the injection site pain or tenderness of the injection site or the hand swelling of the lymph nodes (glands) in the elbow or underarm itching breaks in the skin redness or warmth of the skin pain in the underarm These are not all of the possible side effects with XIAFLEX. Tell your healthcare provider about any side effect that bothers you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. General information about XIAFLEX Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide summarizes the most important information about XIAFLEX. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider for information about XIAFLEX that is written for health professionals. For more information visit. What are the ingredients in XIAFLEX? Active ingredient: collagenase clostridium histolyticum. Ingredients: hydrochloric acid, sucrose, and tromethamine. The diluent contains: calcium chloride dihydrate in 0.9% sodium chloride. Manufactured and distributed by: Auxilium Pharmaceuticals, Inc. Malvern, PA 19355 USA Revised February 2010 This Medication Guide has been approved by the U.S. Food and Drug Administration. US License No. 1816 PL-1109-001.a Package Label - Principal Display Panel – 3 mL Vial, Sterile Diluent 美国FDA核准一种生物制剂治疗令人衰弱的手部疾病        美国食品药物管理局（FDA）的核准溶组织芽胞梭菌胶原酵素注射剂（商品名Xiaflex，Auxilium制药药厂）用于一种渐进性手部疾病，迪皮特朗氏孪缩症（腱膜挛缩症）的治疗，该公司预计在2010年3月底发售此类别中的第一种罕见疾病生物制剂。    迪皮特朗氏孪缩症是一种手掌和手连结组织中之胶原异常建立而引起的令人衰弱的状况，形成厚绳状的韧带而使得手指卷曲。随着挛缩程度增加，而难以使用这些发病的手指抓取物品，在欧美，约有24.0万人受到此状况影响，其中以白人与50岁以上男性较常见。    FDA的疾病评估与研究中心麻醉，止痛和风湿制剂小组主任鲍勃拉帕波特医师在该局的新闻稿中表示，在美国FDA核准Xiaflex之前，这种手部疾病的唯一有效治疗方式就是手术，有时候需要很长的恢复期，病患也需要物理治疗。因为迪皮特朗氏孪缩症没有其他非手术的替代治疗方式，Xiaflex将是此一失能状况之处置的重要进步。    该产品包括了衍生自溶组织芽胞梭菌的两个微生物胶原酵素，注射入手之患部病灶内，软化与分解这些韧带，重建弹性。     这项核准是根据一个有306名病患之研究的部份资料，显示那些以这个生物制剂治疗的病患有64％达到手指可动，使用安慰剂者只有7％。在比较小型的研究中（ 66例人），成功率为44％（安慰剂组为5％）。    这些研究中，最常报告的副作用（发生率≧25％），包括周边水肿，挫伤，注射部位反应，注射部位出血，注射四肢疼痛。虽然没有观察到严重的过敏反应，出现外来蛋白质仍有可能引起免疫反应的风险。    纽约州立大学石溪校区骨科部主任拉里赫斯特医师在药厂的新闻稿中表示，经过多个临床试验显示Xiaflex的安全性和效果，医师们现在可以使用Xiaflex来治疗迪皮特朗氏孪缩症病患之任何有症状的韧带。我相信，Xiaflex这种新的非手术治疗方式，可以变成迪皮特朗氏孪缩症的标准照护。    因为可能会造成肌腱破裂，美国FDA要求进行风险评估以及缓解策略计画，告知医师们有关如何适当进行注射以及手指伸展。仅限有受过完整训练计画的医师们使用胶原酵素制剂，    FDA批准Xiaflex（溶组织梭菌胶原酶）成为首个治疗掌腱膜挛缩症的药物。掌腱膜挛缩症会对患者的伸指功能及手指适用产生不良影响，患者手掌皮肤下胶原组织增生，形成阻碍手指正常伸展的组织条索。该疾病在年龄大于50岁的白种人中最为常见。Xiaflex是一种生物制剂，通过溶解手掌胶原沉积物而达到治疗目的。           在一项涉及66例患者的研究中，Xiaflex治疗者有44%症状缓解，安慰剂组患者仅为5%。在另一项涉及306例患者的研究中，Xiaflex的治疗有效率高达64%，安慰剂仅为7%。           在该药被批准前，手术是治疗掌腱膜挛缩症的唯一有效方法，但手术治疗恢复时间较长并且有时需行理疗。Xiaflex的出现将显著推进该致残性疾病的非手术性治疗。           由于Xiaflex可能导致肌腱断裂，所以应由专业人士进行注射。Xiaflex的常见不良反应包括肿胀、出血及注射部位疼痛。尽管目前尚未观察到药物严重过敏反应，但由于该药物是一种可引发免疫系统反应的异种蛋白，所以不能排除相关可能性。 XIAFLEX® (collagenase clostridium histolyticum) is indicated for the treatment of adult patients with Dupytren's contracture with a palpable cord. IMPORTANT SAFETY INFORMATION In the controlled and uncontrolled portions of clinical trials, flexor tendon ruptures occurred after XIAFLEX injection. 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, insert the needle no more than 2 to 3 mm in depth, and avoid injecting more than 4 mm distal to the palmar digital crease. Other serious local adverse reactions in clinical trials include: pulley rupture, ligament injury, complex regional pain syndrome (CRPS), and sensory abnormality of the hand. In the controlled portions of the clinical trials (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. Although there were no severe allergic reactions observed in the XIAFLEX studies (e.g., those associated with respiratory compromise, hypotension, or end-organ dysfunction), severe reactions including anaphylaxis could occur following XIAFLEX injections. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. In the XIAFLEX trials (Studies 1 and 2), 70% and 38% of XIAFLEX-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively. The efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than low-dose aspirin) within 7 days prior to XIAFLEX administration is not known. Therefore, use with caution in patients with coagulation disorders including patients receiving concomitant anticoagulants (except for low-dose aspirin). The most frequently reported adverse drug reactions (≥ 5%) in the XIAFLEX clinical trials and at an incidence greater than placebo included: edema peripheral, contusion, injection site hemorrhage, injection site reaction, pain in extremity, tenderness, injection site swelling, pruritus, lymphadenopathy, skin laceration, lymph node pain, erythema, and axillary pain. Xiaflex(溶组织梭菌胶原酶）治疗阴茎硬结症 Xiaflex(溶组织梭菌胶原酶collagenase clostridium histolyticum) 批准日期：2010年2月 3日；公司：BioSpecifics Technologies Corp. 欧盟宣布讨论持正面支持上市意见。 FDA药物评价和研究中心的麻醉、镇痛和风湿部主任医学博士Bob Rappaport说“FDA批准Xiaflex前，唯一有效治疗方法是手术，有时需长期恢复和物理治疗。对杜普征氏掌挛缩尚无其它可取代非手术方法，Xiaflex将是处理这类残疾的重要进展”。 摘自：https://www.xiaflex.com/docs/pi_medguide_combo.pdf 2.2.1.1.一般描述： XIAFLEX含纯制的溶组织梭菌胶原酶(collagenase clostridium histolyticum)，由确定质量比的两种微生物胶原酶组成，胶原酶AUX-I和胶原酶AUX-II，是从溶组织梭菌(Clostridium histolyticum bacteria)发酵液中分离和和纯制。胶原酶AUX-I是一个多肽单链有由约1000个已知序列的氨基酸组成。观察分子量114 千道尔顿(kDa)。属于I类溶组织梭菌胶原酶。胶原酶AUX-II是一多肽单链由约1000个推论氨基酸序列组成，观察分子量113 kDa。属于II类溶组织梭菌胶原酶。 2.2.1.2.适应症： XIAFLEX适用于治疗有触诊摸到条索的成年杜普征氏掌挛缩患者。         2.2.1.3.剂量和给药方法： （1）应由专业对手注射方法和杜普征氏掌挛缩治疗有经验医疗人员进行给予XIAFLEX。用前只能用提供的稀释液配制XIAFLEX冻干粉。 （2）按照注射方法掌指(MP)关节或近端指间(PIP)关节中注入0.58mgXIAFLEX至可触摸到的杜普征氏条索病变。 （3）如持续挛缩，注射后约24小时进行手指延伸步骤。 （4）间隔约4-周每条条索病变可注射和手指延伸步骤3次。 （5）每次仅注射一个条索病变。如患者挛缩有其它条索，按顺序依次注射每个条索病变。 2.2.1.4.剂型和规格： 为重新配制单次使用小瓶含0.9 mg溶组织梭菌胶原酶，消毒(灭菌和病毒)，冻干粉。单次使用小瓶提供为配制用灭菌稀释液。 2.2.1.5.禁忌证：无。         2.2.1.6.警告和注意事项： （1）肌腱断裂或对这是肢体严重损伤：避免注射的XIAFLEX进入肌腱，神经，血管，或手的其它含胶原结构。注射进入这些结构可能导致永久损伤可能性，例如肌腱断裂或韧带损伤。 （2）过敏反应：注射XIAFLEX后医疗保健人员应准备面对严重过敏反应。 （3）有凝血异常患者：慎用，包括注射7天内已接受除低剂量阿司匹林以外抗凝药物患者。         2.2.1.7.不良反应： 用XIAFLEX治疗25%患者报道最常见及发生率高于安慰剂的不良反应是外周水肿(如注射手肿胀)、挫伤、注射部位反应、注射部位出血和注射肢体疼痛。         2.2.1.8.作用机制： 在生理学条件下胶原酶是水解天然三重螺旋构象胶原的蛋白水解酶胶原酶，导致胶原沉积溶解。注射XIAFLEX入杜普征氏条索病变导致条索破坏。         体外探究结果提示胶原酶(AUX-I和AUX-II)协同作用向胶原提供水解活性。但是，没有各个胶原酶(AUX-I或AUX-II)在治疗杜普征氏条索相对贡献的临床资料.