XIAFLEX™ (collagenase clostridium histolyticum)

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.

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.

• 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.

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

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

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.

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

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