Ulcerase

Ulcerase is indicated for:

- The treatment of Dupuytren's contracture in adult patients with a palpable cord.

- 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.

Ulcerase is indicated for the treatment of adult patients with Dupuytren's contracture with a palpable cord.

Ulcerase 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 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.

Dupuytren's contracture

Ulcerase must be administered by a physician appropriately trained in the correct administration of the medicinal product and experienced in the diagnosis and management of Dupuytren's disease.

Posology

The recommended dose of Ulcerase is 0.58 mg per injection into a palpable Dupuytren's cord. The volume of solvent required and the volume of reconstituted Ulcerase to be administered into the Dupuytren's cord differs depending on the type of joint being treated.

- For cords affecting MP joints each dose is administered in an injection volume of 0.25 ml.

- For cords affecting PIP joints, each dose is administered in an injection volume of 0.20 ml.

Injections in up to two cords or two affected joints in the same hand can be administered 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. Each injection contains a 0.58 mg dose. If the disease has resulted in multiple contractures, additional cords may be treated at other treatment visits approximately 4 weeks apart.

Approximately 24-72 hours after injection, a finger extension procedure may be performed, as necessary, to facilitate cord disruption. If a satisfactory response has not been achieved, the injection and finger extension procedures may be repeated after approximately 4 weeks. Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.

Clinical study experience with Ulcerase is currently limited to up to 3 injections per cord and up to 8 injections in total.

Peyronie's disease

Ulcerase must be administered by a physician appropriately trained in the correct administration of the medicinal product and experienced in the diagnosis and treatment of male urological diseases. Patients with penile curvature >90° were not included in the clinical studies. Treatment in this group can therefore not be recommended.

Posology

The recommended dose of Ulcerase is 0.58 mg per injection administered into a Peyronie's plaque. The volume of reconstituted Ulcerase to be administered into the plaque is 0.25 ml. If more than one plaque is present, only the plaque causing the curvature deformity should be injected.

A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two Ulcerase injections and one penile modelling procedure. The second Ulcerase injection is administered 1 to 3 days after the first injection. A penile modelling procedure is performed 1 to 3 days after the second injection of each treatment cycle. The interval between treatment cycles is approximately six weeks.

Special population

Elderly

Due to the lack of quantifiable systemic exposure of Ulcerase in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Ulcerase in patients with Peyronie's disease, no dose adjustment is necessary. No overall differences in safety or effectiveness were observed between elderly and younger patients.

Hepatic impairment

Due to the lack of quantifiable systemic exposure of Ulcerase in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Ulcerase in patients with Peyronie's disease, no dose adjustment is necessary.

Renal impairment

Due to the lack of quantifiable systemic exposure of Ulcerase in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Ulcerase in patients with Peyronie's disease, no dose adjustment is necessary.

Paediatric population

There is no relevant use of Ulcerase in the paediatric population aged 0-18 years for the treatment of Dupuytren's contracture.

Peyronie's disease occurs exclusively in adult male patients and hence there is no relevant use of Ulcerase in the paediatric population aged 0-18 years for the treatment of Peyronie's disease.

Method of administration

Intralesional use.

Ulcerase must be reconstituted with the solvent provided and to the appropriate volume prior to intralesional injection.

A single-use syringe containing 0.01-ml graduations with a permanently fixed 27-gauge 12 or 13 mm needle (not supplied) should be used to withdraw the volume of reconstituted solution. There will be a small amount of reconstituted solution left in the vial.

Dupuytren's contracture

Injection procedure

Administration of a local anaesthetic medicinal product prior to injection of Ulcerase into a Dupuytren's cord is not recommended, as it may interfere with proper placement of the injection.

The joint to be treated (metacarpophalangeal [MP] or proximal interphalangeal [PIP]) should be confirmed and the volume of solvent required for reconstitution is determined by the type of joint (PIP joint requires a smaller volume for injection). The injection procedure is detailed in the package leaflet and the physician training material and must be followed.

Patients should be instructed:

- To return to see their physician approximately 24-72 hours after injection for an examination of the injected hand and a finger extension procedure to disrupt the cord.

- Not to flex or extend the fingers of the injected hand to reduce extravasation of Ulcerase out of the cord until the finger extension procedure is completed.

- Not to attempt to disrupt the injected cord by self-manipulation at any time.

- To elevate the injected hand as much as possible until the day after the finger extension procedure.

Finger extension procedure

At the follow-up visit approximately 24-72 hours after injection, it should be determined if the contracture has resolved. If a cord contracture remains, a passive finger extension procedure will be performed in an attempt to disrupt the cord. Local anaesthesia may be used, if needed, during the finger extension procedure.

While the patient's wrist is in the flexed position, a moderate stretching pressure should be applied to the injected cord by extending the finger for approximately 10 to 20 seconds. For cords affecting the PIP joint, the finger extension procedure should be performed 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. No more than 3 attempts per affected joint are recommended to disrupt a cord.

If the cord has not disrupted after 3 attempts of extension, a follow-up visit may be scheduled approximately 4 weeks after the injection. If, at that subsequent visit the contracted cord persists, an additional injection and finger extension procedure may be performed.

Following the finger extension procedure(s) and fitting patient with a splint (with treated joint in maximum extension), the patients should be instructed to:

- Not perform strenuous activity with the injected hand until advised to do so.

- Wear the splint at bedtime for up to 4 months.

- Perform a series of finger flexion and extension exercises several times a day for several months.

Peyronie's disease

Injection procedure

Administration of regional anaesthesia (penile block) or topical anaesthesia could be applied prior to Ulcerase injection when desired. In the pivotal clinical studies about 30% of the patients received penile block before injection.

The location of the target treatment area in the Peyronie's plaque is identified at the point of maximum concavity (or focal point) in the erect penis state and marked with a surgical marker. Ulcerase should be injected into the target plaque when the penis is in a flaccid state. The injection procedure is detailed in the package leaflet and the physician training material and must be followed.

Penile modelling procedure

Penile modelling helps relieve curvature deformity and straighten the penile shaft. At the follow-up visit 1 to 3 days after the second injection of each treatment cycle, the trained physician should perform a penile modelling procedure on the flaccid penis to stretch and elongate the treated plaque that Ulcerase has disrupted. Local anaesthesia may be applied before the modelling if desired. Wearing gloves the physician should grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Direct pressure on the injection site should be avoided. The target plaque is used as a fulcrum point with both hands, to firmly apply a steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient's penile curvature, with stretching to the point of moderate resistance.

The penile pressure should be hold for 30 seconds, thereafter released with a resting period for 30 seconds before repeating the penile modelling technique for a total of 3 modelling attempts at 30 seconds for each attempt.

In addition to the in-office penile modelling procedure, patients should be provided instructions on the appropriate technique to self-perform penile modelling activities at home each day for the 6-week period following the physician penile plaque modelling visit of each treatment cycle, according to the detailed instructions provided in the package leaflet.

If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the physician determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered.

The safety of more than one treatment course of Ulcerase for Peyronie's disease is not known.

Dosage And Administration For Dupuytren’s Contracture

Dosing Overview For Dupuytren’s Contracture

Ulcerase should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren's contracture.

Ulcerase, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use. The dose of Ulcerase is 0.58 mg per injection into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint.. Each vial of Ulcerase 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 Ulcerase solution to be used in the intralesional injection. Approximately 24 to 72 hours after injection, perform a finger extension procedure if a contracture persists to facilitate cord disruption.

Table 1: Volumes Needed for Reconstitution and Administration for Dupuytren’s Contracture

Four weeks after the Ulcerase 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 Ulcerase 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 a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with Ulcerase at other treatment visits approximately 4 weeks apart.

Reconstitution Of The Lyophilized Powder For Dupuytren’s Contracture

1. Before use, remove the vial(s) containing the lyophilized powder of Ulcerase 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 Ulcerase. The cake of lyophilized powder should be intact and white in color.
2. 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 Ulcerase and the vial(s) containing the diluent for econstitution 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 Ulcerase.
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 s upplied, 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 Ulcerase. 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 Ulcerase with a second vial of diluent.
6. The reconstituted Ulcerase 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 Ulcerase solution is refrigerated, allow this solution to return to room temperature for approximately 15 minutes before use.
7. Discard the syringe(s) and needle(s) used for reconstitution and the diluent vial(s).

Preparation Prior To Injection For Dupuytren’s Contracture

1. The reconstituted Ulcerase 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 Ulcerase 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 Ulcerase injections near the digital PIP joint crease.
4. 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.
5. Apply an antiseptic at the site(s) of the injection(s) and allow the skin to dry.

Injection Procedure For Dupuytren’s Contracture

1. 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 Ulcerase) 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 Ulcerase 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. When administering two injections in the same hand during a treatment visit, use a new syringe and separate vial of reconstituted solution for each injection. Repeat steps a through f.
7. When administering two injections in the same hand during a treatment visit, begin with the affected finger in the most medial aspect of the hand and continue toward the lateral aspect (eg, fifth finger to index finger). When administering two injections in a cord affecting two joints in the same finger, begin with the affected joint in the most proximal aspect of the finger and continue toward the distal aspect (eg, MP to PIP).
8. Wrap the patient's treated hand with a soft, bulky, gauze dressing.
9. Instruct the patient to limit motion of the treated finger(s) and to keep the injected hand elevated until bedtime.
10. Instruct the patient not to attempt to disrupt the injected cord(s) by self-manipulation and to return to the healthcare provider's office the next day for follow-up and a finger extension procedure(s), if needed.
11. 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 For Dupuytren’s Contracture

1. At the follow-up visit approximately 24 to 72 hours after the injection(s ), if a contracture remains, perform a passive finger extension procedure on each treated joint (as described below) to facilitate cord disruption. If two joints in one finger were treated, perform the finger extension procedure on the affected MP joint before performing the finger extension procedure on the affected PIP joint.
2. Local anesthesia may be used. Avoid direct pressure on the injection site as it will likely be tender. Care should be taken during release of contracture, as some patients may experience skin splitting. If this occurs, cover the area with gauze and apply gentle pressure until bleeding stops. Standard wound care with regular dressings should be applied.
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 per joint 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 Ulcerase 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.

Dosage And Administration For Peyronie’s Disease

Dosing Overview For Peyronie's Disease

Ulcerase should be administered by a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of Ulcerase in the treatment of Peyronie's disease.

Ulcerase, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use. The dose of Ulcerase is 0.58 mg per injection administered into a Peyronie's plaque. If more than one plaque is present, inject into the plaque causing the curvature deformity.

A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two Ulcerase injection procedures and one penile modeling procedure. The second Ulcerase injection procedure is performed 1 to 3 days after the first. The penile modeling procedure is performed 1 to 3 days after the second injection of the treatment cycle. The interval between treatment cycles is approximately six weeks. The treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures.

If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered.

The safety of more than one treatment course of Ulcerase is not known.

Table 2 displays an overview of the volume of sterile diluent for reconstitution and the reconstituted Ulcerase solution to be used in the intralesional injection.

Table 2: Volumes Needed for Reconstitution and Administration

Reconstituted Ulcerase solution remaining in the vial after the injection should be discarded.

Reconstitution Of The Lyophilized Powder For Peyronie’s Disease

1. Before use, remove the vial containing the lyophilized powder of Ulcerase 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. Visually inspect the vial containing Ulcerase. The cake of lyophilized powder should be intact and white in color.
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 Ulcerase 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 Ulcerase.
4. Using a 1 mL syringe with 0.01 mL graduations with a 27-gauge ½-inch needle (not supplied), withdraw a volume of 0.39 mL of the diluent supplied.
5. Inject the diluent slowly into the sides of the vial containing the lyophilized powder of Ulcerase. 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 Ulcerase 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 Ulcerase 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.

Identification Of Treatment Area For Peyronie’s Disease

1. Prior to each treatment cycle, identify the treatment area as follows:
   • Induce a penile erection. A single intracavernosal injection of 10 or 20 micrograms of alprostadil may be used for this purpose. Apply antiseptic at the site of injection and allow the skin to dry prior to the intracavernosal injection.
   • Locate the plaque at the point of maximum concavity (or focal point) in the bend of the penis.
   • Mark the point with a surgical marker. This indicates the target area in the plaque for Ulcerase deposition.

Injection Procedure For Peyronie’s Disease

1. The reconstituted Ulcerase 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. Apply antiseptic at the site of the injection and allow the skin to dry.
3. Administer suitable local anesthetic, if desired.
4. Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge ½- inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing 0.58 mg of Ulcerase).
5. The penis should be in a flaccid state before Ulcerase is injected. Place the needle tip on the side of the target plaque in alignment with the point of maximal concavity. Orient the needle so that it enters the edge of the plaque and advance the needle into the plaque itself from the side. Do not advance the needle beneath the plaque nor perpendicularly towards the corpora cavernosum.
6. Insert and advance the needle transversely through the width of the plaque, towards the opposite side of the plaque without passing completely through it. Proper needle position is tested and confirmed by carefully noting resistance to minimal depression of the syringe plunger.
7. With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly inject Ulcerase into the plaque. Withdraw the needle slowly so as to deposit the full dose along the needle track within the plaque. For plaques that are only a few millimeters in width, the distance of withdrawal of the syringe may be very minimal. The goal is always to deposit the full dose entirely within the plaque.
8. Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a dressing as necessary.
9. Discard the unused portion of the reconstituted solution and diluent after each injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.
10. The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from the first injection.

Penile Modeling Procedure For Peyronie’s Disease

Penile modeling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 1 to 3 days after the second injection of each treatment cycle, perform a penile modeling procedure (as described below) on the flaccid penis to stretch and elongate the treated plaque:

• Administer suitable local anesthetic, if desired.
• Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Avoid direct pressure on the injection site.
• Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient's penile curvature, with stretching to the point of moderate resistance. Hold pressure for 30 seconds then release.
• After a 30 second rest period, repeat the penile modeling technique for a total of 3 modeling attempts at 30 seconds for each attempt.

In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle as follows:

• During spontaneous erections, gently attempt to straighten the penis without producing pain and hold the penis in a straightened position for 30 seconds.
• The flaccid penis should be gently stretched three times daily. Slow, gentle force should be used without producing pain.

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. 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.. 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. Approximately 24 to 72 hours after injection, perform a finger extension procedure if a contracture persists to facilitate cord disruption.

Table 1: Volumes Needed for Reconstitution and Administration for Dupuytren’s Contracture

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 a 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

1. 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.
2. 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 econstitution 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 s upplied, 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. 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.
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(s) and needle(s) used for reconstitution and the diluent vial(s).

Preparation Prior To Injection For Dupuytren’s Contracture

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(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.
5. Apply an antiseptic at the site(s) of the injection(s) and allow the skin to dry.

Injection Procedure For Dupuytren’s Contracture

1. 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.
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. When administering two injections in the same hand during a treatment visit, use a new syringe and separate vial of reconstituted solution for each injection. Repeat steps a through f.
7. When administering two injections in the same hand during a treatment visit, begin with the affected finger in the most medial aspect of the hand and continue toward the lateral aspect (eg, fifth finger to index finger). When administering two injections in a cord affecting two joints in the same finger, begin with the affected joint in the most proximal aspect of the finger and continue toward the distal aspect (eg, MP to PIP).
8. Wrap the patient's treated hand with a soft, bulky, gauze dressing.
9. Instruct the patient to limit motion of the treated finger(s) and to keep the injected hand elevated until bedtime.
10. Instruct the patient not to attempt to disrupt the injected cord(s) by self-manipulation and to return to the healthcare provider's office the next day for follow-up and a finger extension procedure(s), if needed.
11. 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 For Dupuytren’s Contracture

1. At the follow-up visit approximately 24 to 72 hours after the injection(s ), if a contracture remains, perform a passive finger extension procedure on each treated joint (as described below) to facilitate cord disruption. If two joints in one finger were treated, perform the finger extension procedure on the affected MP joint before performing the finger extension procedure on the affected PIP joint.
2. Local anesthesia may be used. Avoid direct pressure on the injection site as it will likely be tender. Care should be taken during release of contracture, as some patients may experience skin splitting. If this occurs, cover the area with gauze and apply gentle pressure until bleeding stops. Standard wound care with regular dressings should be applied.
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 per joint 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.

Dosage And Administration For Peyronie’s Disease

Dosing Overview For Peyronie's Disease

XIAFLEX should be administered by a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of XIAFLEX in the treatment of Peyronie's disease.

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 administered into a Peyronie's plaque. If more than one plaque is present, inject into the plaque causing the curvature deformity.

A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two XIAFLEX injection procedures and one penile modeling procedure. The second XIAFLEX injection procedure is performed 1 to 3 days after the first. The penile modeling procedure is performed 1 to 3 days after the second injection of the treatment cycle. The interval between treatment cycles is approximately six weeks. The treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures.

If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered.

The safety of more than one treatment course of XIAFLEX is not known.

Table 2 displays an overview of the volume of sterile diluent for reconstitution and the reconstituted XIAFLEX solution to be used in the intralesional injection.

Table 2: Volumes Needed for Reconstitution and Administration

Reconstituted XIAFLEX solution remaining in the vial after the injection should be discarded.

Reconstitution Of The Lyophilized Powder For Peyronie’s Disease

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. Visually inspect the vial containing XIAFLEX. The cake of lyophilized powder should be intact and white in color.
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 with 0.01 mL graduations with a 27-gauge ½-inch needle (not supplied), withdraw a volume of 0.39 mL of the diluent supplied.
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.

Identification Of Treatment Area For Peyronie’s Disease

1. Prior to each treatment cycle, identify the treatment area as follows:
   • Induce a penile erection. A single intracavernosal injection of 10 or 20 micrograms of alprostadil may be used for this purpose. Apply antiseptic at the site of injection and allow the skin to dry prior to the intracavernosal injection.
   • Locate the plaque at the point of maximum concavity (or focal point) in the bend of the penis.
   • Mark the point with a surgical marker. This indicates the target area in the plaque for XIAFLEX deposition.

Injection Procedure For Peyronie’s Disease

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. Apply antiseptic at the site of the injection and allow the skin to dry.
3. Administer suitable local anesthetic, if desired.
4. Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge ½- inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing 0.58 mg of XIAFLEX).
5. The penis should be in a flaccid state before XIAFLEX is injected. Place the needle tip on the side of the target plaque in alignment with the point of maximal concavity. Orient the needle so that it enters the edge of the plaque and advance the needle into the plaque itself from the side. Do not advance the needle beneath the plaque nor perpendicularly towards the corpora cavernosum.
6. Insert and advance the needle transversely through the width of the plaque, towards the opposite side of the plaque without passing completely through it. Proper needle position is tested and confirmed by carefully noting resistance to minimal depression of the syringe plunger.
7. With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly inject XIAFLEX into the plaque. Withdraw the needle slowly so as to deposit the full dose along the needle track within the plaque. For plaques that are only a few millimeters in width, the distance of withdrawal of the syringe may be very minimal. The goal is always to deposit the full dose entirely within the plaque.
8. Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a dressing as necessary.
9. Discard the unused portion of the reconstituted solution and diluent after each injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.
10. The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from the first injection.

Penile Modeling Procedure For Peyronie’s Disease

Penile modeling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 1 to 3 days after the second injection of each treatment cycle, perform a penile modeling procedure (as described below) on the flaccid penis to stretch and elongate the treated plaque:

• Administer suitable local anesthetic, if desired.
• Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Avoid direct pressure on the injection site.
• Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient's penile curvature, with stretching to the point of moderate resistance. Hold pressure for 30 seconds then release.
• After a 30 second rest period, repeat the penile modeling technique for a total of 3 modeling attempts at 30 seconds for each attempt.

In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle as follows:

• During spontaneous erections, gently attempt to straighten the penis without producing pain and hold the penis in a straightened position for 30 seconds.
• The flaccid penis should be gently stretched three times daily. Slow, gentle force should be used without producing pain.

Treatment of Peyronie's plaques that involve the penile urethra due to potential risk to this structure.

Ulcerase 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 Ulcerase or to collagenase used in any other therapeutic application or application method.

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.

Allergic reactions

Following Ulcerase injection, severe allergic reaction could occur, and patients should be observed for 30 minutes before leaving the clinic in order to monitor for any signs or symptoms of a serious allergic reaction, e.g. wide spread redness or rash, swelling, tightness in the throat or difficulty breathing. Patients should be instructed to consult a doctor immediately if they experience any of these signs or symptoms. Emergency medication for treatment of potential allergic reactions should be available.

An anaphylactic reaction was reported in a post-marketing clinical study in a patient who had previous exposure to Ulcerase for the treatment of Dupuytren's contracture, demonstrating that severe reactions including anaphylaxis can occur following Ulcerase injections. Some patients with Dupuytren's contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive Ulcerase injections.

In the double blind portion of the three phase 3 placebo-controlled clinical studies in Dupuytren's contracture, 17% of Ulcerase-treated patients had mild reactions (i.e. pruritus) after up to 3 injections. The incidence of Ulcerase-associated pruritus increased after more Ulcerase injections in patients with Dupuytren's contracture.

In the double-blind portion of the two phase 3 placebo-controlled clinical trials in Peyronie's disease, a greater proportion of Ulcerase-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 Ulcerase injections). The incidence of Ulcerase-associated pruritus was similar after each injection regardless of the number of injections administered.

Tendon rupture or other serious injury to the injected finger/hand in the treatment of Dupuytren's contracture

Ulcerase must only be injected into the Dupuytren's cord. Because Ulcerase lyses collagen, care must be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Injection of Ulcerase into collagen containing structures may result in damage to those structures, and possible permanent injury such as tendon rupture or ligament damage. Care should be taken when injecting Ulcerase into cords contracting the PIP joints as clinical studies indicate an increased risk of tendon rupture and ligament injury associated with treatment of PIP contractures with Ulcerase. This is particularly important for cords situated at the PIP joint of the fifth finger. When injecting a cord affecting a PIP joint of the fifth finger, the needle insertion must not be more than 2 to 3 mm in depth and not more than 4 mm distal to the palmar digital crease. Patients should be instructed to comply with the treatment instructions and to promptly contact the physician if there is trouble bending the finger after the swelling goes down (symptoms of tendon rupture).

Most patients experiencing tendon/ligament rupture or injury have gone on to have successful surgical repair. Early diagnosis and prompt evaluation and treatment are important because tendon rupture/ligament injury may potentially affect overall hand function.

Patients with Dupuytren's contractures that adhere to the skin may be at higher risk of skin lesions as a result of the pharmacological effect of Ulcerase and the finger extension procedure on the skin overlying the targeted cord.

Cases of skin laceration requiring skin graft after finger extension procedures have been reported post-marketing.).

Corporal rupture (fracture of penis) or other serious injury to the penis in the treatment of Peyronie's disease

Injection of Ulcerase 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, Ulcerase must 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.

Corporal rupture was reported as a serious adverse reaction after Ulcerase injection in 5 out of 1044 patients (0.5%) in the controlled and uncontrolled clinical trials in Peyronie's disease. In other Ulcerase-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or haematoma, 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.

Severe penile haematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical studies in Peyronie's disease.

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 haematoma, which may require surgical intervention.

Use in patients with coagulation disorders

Ulcerase must be used with caution in patients with coagulation disorders or those taking anticoagulants. In the three double-blind, placebo-controlled phase 3 studies in Dupuytren's contracture, 73% of Ulcerase-treated patients reported an ecchymosis or a contusion and 38% reported a haemorrhage at the injection site. In the two double-blind, placebo-controlled phase 3 studies in Peyronie's disease, 65.5% of Ulcerase-treated patients developed penile haematoma and 14.5% developed penile ecchymosis. The efficacy and safety of Ulcerase in patients receiving anticoagulant medicinal products other than up to 150 mg acetylsalicylic acid per day prior to Ulcerase administration is not known. Use of Ulcerase in patients who have received anticoagulants (with the exception of up to 150 mg acetylsalicylic acid daily) within 7 days prior to receiving an injection of Ulcerase is not recommended.

Immunogenicity

As with any non-human protein medicinal product, patients may develop antibodies to the therapeutic protein. During clinical studies, blood samples from patients with Dupuytren's contracture and Peyronie's disease were tested at multiple time points for antibodies to the protein components of the medicinal product (AUX-I and AUX-II).

In the Dupuytren's contracture clinical trials at 30 days post the first injection, 92% of patients had circulating antibodies detected against AUX-I and 86% of patients against AUX-II. At five years after the initial injection of Ulcerase, 92.8% and 93.4% of subjects were seropositive for anti-AUX-I and anti-AUX-II respectively.

Almost all patients had positive titers for anti-AUX-I antibodies (97.9%) and anti-AUX-II antibodies (97.5%) 60 days post two concurrent injections.

In the Peyronie's disease clinical studies, at 6 weeks after the first treatment cycle of Ulcerase, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of Ulcerase >99% of Ulcerase-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested.

In patients treated for these two indications, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions.

Since the enzymes in Ulcerase have some sequence homology with human matrix metalloproteinases (MMPs), anti-drug antibodies (ADA) could theoretically interfere with human MMPs. No safety concerns related to the inhibition of endogenous MMPs have been observed, in particular no adverse events indicating the development or exacerbation of autoimmune diseases or the development of a musculoskeletal syndrome (MSS). Whilst there is no clinical evidence from the current safety data of a musculoskeletal syndrome developing following the administration of Ulcerase, the potential for it to occur cannot be excluded. If this syndrome were to develop, it would occur progressively and is characterized by one or more of the following signs and symptoms: arthralgia, myalgia, joint stiffness, stiffness of the shoulders, hand oedema, palmar fibrosis and thickening or nodules forming in the tendons.

Post-treatment surgery

The impact of treatment with Ulcerase on subsequent surgery, if needed, is not known.

Special penile conditions/diseases not studied in clinical trials

Ulcerase treatment in patients having a calcified plaque that could have interfered with the injection technique, chordee in the presence or absence of hypospadias, thrombosis of the dorsal penile artery and/or vein, infiltration by a benign or malignant mass resulting in penile curvature, infiltration by an infectious agent, such as in lymphogranuloma venereum, ventral curvature from any cause and isolated hourglass deformity of the penis has not been studied and treatment in these patients should be avoided.

Long-term safety of Ulcerase in Peyronie's disease is not fully characterised.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially 'sodium- free'.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 Ulcerase injection. Injection of Ulcerase 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, Ulcerase 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.

Other Ulcerase-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 Ulcerase compared with subjects treated with up to three single injections in the placebo-controlled premarketing trials (9%). Cases of skin laceration requiring skin graft after finger extension procedures have been reported post-marketing. Signs or symptoms that may reflect serious injury to the injected finger/hand should be promptly evaluated because surgical intervention may be required.

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 Ulcerase injections in 5 of 1044 (0.5%) Ulcerase treated patients in the controlled and uncontrolled clinical trials in Peyronie's disease.

In other Ulcerase-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 can not 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.

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.

Injection of Ulcerase 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, Ulcerase 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.

Ulcerase REMS Program

Because of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie's disease, Ulcerase is available only through the Ulcerase REMS Program.

Required components of the Ulcerase REMS Program include the following:

• Prescribers must be certified with the program by enrolling and completing training in the administration of Ulcerase treatment for Peyronie's disease.
• Healthcare sites must be certified with the program and ensure that Ulcerase is only dispensed for use by certified prescribers.

Further information is available at www.UlceraseREMS.com or 1-877-313-1235.

Hypersensitivity Reactions, Including Anaphylaxis

In the controlled portions of the clinical trials in Dupuytren's contracture (Studies 1 and 2), a greater proportion of Ulcerase-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of Ulcerase-associated pruritus increased after more Ulcerase 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 Ulcerase-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 Ulcerase injection procedures). The incidence of Ulcerase-associated pruritus was similar after each injection regardless of the number of injections administered.

Because Ulcerase contains foreign proteins, severe allergic reactions to Ulcerase can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to Ulcerase 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 Ulcerase injections. Healthcare providers should be prepared to address severe allergic reactions following Ulcerase injections.

Risk Of bleeding In Patients With Abnormal Coagulation

In the Ulcerase trials in Dupuytren's contracture (Studies 1 and 2), 70% and 38% of Ulcerase-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively (see Table 3). In the Ulcerase controlled trials in Peyronie's disease (Studies 1 and 2), 65.5% of Ulcerase-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis (see Table 4). 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 Ulcerase in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to Ulcerase administration is not known. In addition, it is recommended to avoid use of Ulcerase in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin).

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Patient Counseling For Dupuytren’s Contracture

Advise patients of the following:

• Serious complications of Ulcerase injection include tendon rupture, serious ligament damage, or skin laceration that may result in the inability to fully bend the finger and may require surgery to correct the complication.
• Ulcerase injection is likely to result in swelling, bruising, bleeding, and/or pain of the injected site and surrounding tissue.

After the Ulcerase injections, instruct patients:

• Not to flex or extend the fingers of the injected hand to reduce extravasation of Ulcerase out of the cord(s).
• Not to attempt to disrupt the injected cord(s) 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(s), trouble bending the finger(s) after the swelling goes down (symptoms of tendon rupture), or skin laceration.
• To return to their healthcare provider's office one to three days after the injection visit for an examination of the injected hand and for possible finger extension procedure(s) 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.

Patient Counseling For Peyronie’s Disease

Advise patients of the following:

• Serious complications of Ulcerase injection include corporal rupture and penile hematoma and may require surgery to correct the complication.

After the Ulcerase injections, instruct the patient:

• That their penis may appear bruised and/or swollen
• That they may have mild-to-moderate penile pain that can be relieved by taking over-the-counter pain medications
• To promptly contact their physician if, at any time, they have severe pain or severe swelling of the penis, severe purple bruising and swelling of the penis, difficulty urinating or blood in the urine, or sudden loss of the ability to maintain an erection. These symptoms may be accompanied by a popping or cracking sound from the penis
• To return to their healthcare provider's office when directed for further injection(s) and/or penile modeling procedure(s)
• To not have sex between the first and second injections of a treatment cycle
• To wait two weeks after the second injection of a treatment cycle before resuming sexual activity, provided pain and swelling have subsided

Provide the patient instructions on the appropriate technique to perform penile modeling activities at home, as described in “What You Need to Know About Ulcerase Treatment for Peyronie's Disease: A Patient Guide”, and give the patient a copy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of collagenase clostridium histolyticum have not been conducted.

Mutagenesis

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.

Impairment Of Fertility

Collagenase clostridium histolyticum did not impair fertility and early embryonic development when administered intravenously in rats at exposures up to approximately 11 times the maximum recommended human dose (MRHD) on a mg/m² basis.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Ulcerase in pregnant women. Because animal reproduction studies are not always predictive of human response, Ulcerase should be used during pregnancy only if clearly needed.

Risk Summary

Based on animal data, Ulcerase is not predicted to increase the risk for major developmental abnormalities in humans.

Human Data

Human pharmacokinetic studies showed that Ulcerase levels were not quantifiable in the systemic circulation following injection into a Dupuytren's cord.

Low levels of Ulcerase were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of Ulcerase into the penile plaque of subjects with Peyronie's disease.

Almost all patients develop anti-product antibodies (anti-AUX-I and anti-AUX-II) after treatment with Ulcerase, and the clinical significance of anti-product antibody formation on a developing fetus is not known.

Animal Data

Reproduction studies have been performed in rats with intravenous exposures up to approximately 11 times the maximum recommended human dose (MRHD) of Ulcerase on a mg/m² basis, and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum.

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 Ulcerase is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Ulcerase in pediatric patients less than 18 years old have not been established.

Geriatric Use

Of the 249 Ulcerase-treated patients in the double-blind, placebo-controlled, clinical trials in Dupuytren's contracture (Studies 1 and 2), 104 (42%) were 65 years of age or older and 9% were 75 years of age or older. Of the 551 Ulcerase-treated patients in the double-blind, placebo-controlled, clinical trials in Peyronie's disease (Studies 1 and 2), 100 (18%) were 65 years of age or older and 5 (0.9 %) were 75 years of age or older. No overall differences in safety or effectiveness of Ulcerase were observed between these patients and younger patients.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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. 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.

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%). Cases of skin laceration requiring skin graft after finger extension procedures have been reported post-marketing. Signs or symptoms that may reflect serious injury to the injected finger/hand should be promptly evaluated because surgical intervention may be required.

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 can not 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.

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.

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.

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.

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.

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.

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 4). 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 coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin).

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Patient Counseling For Dupuytren’s Contracture

Advise patients of the following:

• Serious complications of XIAFLEX injection include tendon rupture, serious ligament damage, or skin laceration 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(s).
• Not to attempt to disrupt the injected cord(s) 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(s), trouble bending the finger(s) after the swelling goes down (symptoms of tendon rupture), or skin laceration.
• To return to their healthcare provider's office one to three days after the injection visit for an examination of the injected hand and for possible finger extension procedure(s) 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.

Patient Counseling For Peyronie’s Disease

Advise patients of the following:

• Serious complications of XIAFLEX injection include corporal rupture and penile hematoma and may require surgery to correct the complication.

After the XIAFLEX injections, instruct the patient:

• That their penis may appear bruised and/or swollen
• That they may have mild-to-moderate penile pain that can be relieved by taking over-the-counter pain medications
• To promptly contact their physician if, at any time, they have severe pain or severe swelling of the penis, severe purple bruising and swelling of the penis, difficulty urinating or blood in the urine, or sudden loss of the ability to maintain an erection. These symptoms may be accompanied by a popping or cracking sound from the penis
• To return to their healthcare provider's office when directed for further injection(s) and/or penile modeling procedure(s)
• To not have sex between the first and second injections of a treatment cycle
• To wait two weeks after the second injection of a treatment cycle before resuming sexual activity, provided pain and swelling have subsided

Provide the patient instructions on the appropriate technique to perform penile modeling activities at home, as described in “What You Need to Know About XIAFLEX Treatment for Peyronie's Disease: A Patient Guide”, and give the patient a copy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of collagenase clostridium histolyticum have not been conducted.

Mutagenesis

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.

Impairment Of Fertility

Collagenase clostridium histolyticum did not impair fertility and early embryonic development when administered intravenously in rats at exposures up to approximately 11 times the maximum recommended human dose (MRHD) on a mg/m² basis.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of XIAFLEX in pregnant women. Because animal reproduction studies are not always predictive of human response, XIAFLEX should be used during pregnancy only if clearly needed.

Risk Summary

Based on animal data, XIAFLEX is not predicted to increase the risk for major developmental abnormalities in humans.

Human Data

Human pharmacokinetic studies showed that XIAFLEX levels were not quantifiable in the systemic circulation following injection into a Dupuytren's cord.

Low levels of XIAFLEX were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of XIAFLEX into the penile plaque of subjects with Peyronie's disease.

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.

Animal Data

Reproduction studies have been performed in rats with intravenous exposures up to approximately 11 times the maximum recommended human dose (MRHD) of XIAFLEX on a mg/m² basis, and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum.

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.

Pediatric Use

The safety and effectiveness of XIAFLEX in pediatric patients less than 18 years old have not been established.

Geriatric Use

Of the 249 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials in Dupuytren's contracture (Studies 1 and 2), 104 (42%) were 65 years of age or older and 9% were 75 years of age or older. Of the 551 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials in Peyronie's disease (Studies 1 and 2), 100 (18%) were 65 years of age or older and 5 (0.9 %) were 75 years of age or older. No overall differences in safety or effectiveness of XIAFLEX were observed between these patients and younger patients.

Dupuytren's contracture

Summary of the safety profile

The most frequently reported adverse reactions during the Ulcerase clinical studies (272 of 409 patients received up to three single injections of Ulcerase and 775 patients received two concurrent injections in the same hand) were local injection site reactions such as oedema peripheral (local to the injection site), contusion (including ecchymosis), injection site haemorrhage and injection site pain. Injection site reactions were very common, occurring in the vast majority of patients, were mostly mild to moderate in severity and generally subsided within 1-2 weeks post injection. Serious adverse reactions of tendon rupture (6 cases), tendonitis (1 case), other ligament injury (2 cases) and complex regional pain syndrome (1 case) related to the medicinal product were reported. Anaphylactic reaction was reported in a patient previously treated with Ulcerase (1 case).

Tabulated list of adverse reactions

Table 1 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (>1/10), common (>1/100 to <1/10), and uncommon (>1/1,000 to <1/100). Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme are those that occurred in the Phase 3 double blind placebo controlled studies for the treatment of Dupuytren's contracture in adult patients with a palpable cord (AUX-CC-857, AUX-CC-859) and the post-marketing clinical studies (AUX-CC-864, AUX-CC-867) for two concurrent injections in the same hand.

Table 1: Tabulated list of adverse reactions.

a reported with a higher incidence (very common) in patients who received two concurrent injections of Ulcerase in the same hand compared with subjects treated with up to three single injections in the Phase 3 placebo-controlled pivotal studies in Dupuytren's contracture.

b “skin laceration” includes “injection site laceration” and “laceration”

c “oedema peripheral” includes “injection site oedema” and “oedema”

The incidence of skin laceration (29.1%) was higher for subjects treated with two concurrent injections of Ulcerase in historically-controlled clinical study AUX-CC-867 compared with subjects treated with up to three single injections in the Phase 3 placebo-controlled pivotal studies in Dupuytren's contracture (CORD I and CORD II) (8.8%). The majority of the skin lacerations occurred on the manipulation day. A higher incidence of skin laceration may be attributable to more vigorous finger extension procedures in patients after receiving anaesthesia to the hand. In Study AUX-CC-867, most (85%) subjects received local anaesthesia prior to the finger extension procedure.

There were no other clinically relevant differences between two concurrent injections of Ulcerase in the same hand and up to three single injections of Ulcerase in the types of adverse events reported (i.e., most adverse events were local to the treated extremity and of mild or moderate intensity).

The overall safety profile was similar regardless of the timing of the post-injection finger extension procedure (i.e., 24 hours, 48 hours, and >72 hours after injection) among patients who received two concurrent injections of Ulcerase in Study AUX-CC-867.

Peyronie's disease

Summary of the safety profile

The overall safety profile was similar in the two Phase 3 double-blind placebo controlled studies (832 male patients, 551 patients received Ulcerase) and in an open-label Phase 3 study (189 male patients) of patients who had previously received placebo in the controlled studies. In the two Phase 3 double-blind placebo controlled studies, most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered. The most frequently reported adverse drug reactions (>25%) during the Ulcerase controlled clinical studies were penile haematoma, penile swelling and penile pain. Severe penile haematoma including severe injection site haematoma were reported with the frequency very common.

In the controlled and uncontrolled clinical studies of Ulcerase in Peyronie's disease corporal rupture and other serious penile injury were reported uncommonly

A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking” and sometimes accompanied by detumescence, haematoma and/or pain, were reported in 73/551 (13.2%) Ulcerase-treated patients and 1/281 (0.3%) placebo-treated patients, in Studies 1 and 2 combined.

Tabulated list of adverse reactions

Table 2 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), and not known: cannot be estimated from the available data. Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme are those that occurred in the Phase 3 double-blind placebo controlled studies.

Table 2: Tabulated list of adverse reactions.

a Includes: injection site haematoma and penile haematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of patients.

b Includes: injection site swelling, penile oedema, penile swelling, local swelling, scrotal swelling, and injection site oedema.

c Includes: injection site pain, penile pain, and injection site discomfort.

d Includes: contusion, ecchymosis, penile haemorrhage, and injection site haemorrhage.

∗ reported from a post-marketing clinical study in a patient who had previous exposure to Ulcerase for the treatment of Dupuytren's contracture.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

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

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
• In other Ulcerase-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

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 Ulcerase in the controlled and uncontrolled portions of the Ulcerase studies (2630 Ulcerase 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 Ulcerase 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. These trials were comprised of 374 patients of whom 249 and 125 received 0.58 mg of Ulcerase 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 Ulcerasetreated and placebo-treated patients had an adverse reaction after up to 3 injections, respectively. Over 95% of Ulcerase-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 Ulcerase 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.

The most frequently reported adverse drug reactions (≥ 25%) in the Ulcerase 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 Ulcerase-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 Ulcerase-Treated Patients with Dupuytren’s Contracture and at a Greater Incidence than Placebo in the Placebo- Controlled Trials Through Day 90 After Up to 3 Injections

Some patients developed vasovagal syncope after finger extension procedures.

The safety of two concurrent injections of Ulcerase 0.58 mg into Dupuytren's cords in the same hand was evaluated in a historically-controlled, open-label multi-center trial in 715 adult subjects with Dupuytren's contracture (Study 3). In Study 3, finger extension procedures were performed approximately 24 to 72 hours after injection. The patient demographics were similar to Studies 1 and 2.

Out of 715 patients who received two concurrent injections of Ulcerase 0.58 mg in the same hand (1450 Ulcerase injections) in Study 3, one (0.1%) patient experienced a tendon rupture of the treated finger within 3 days of the injection.

Table 4 shows the incidence of adverse reactions that were reported in greater than or equal to 5% of Ulcerase-treated patients after two concurrent injections of Ulcerase in the same hand through Day 60 in Study 3.

Table 4: Adverse Reactions Occurring in ≥ 5.0% of Subjects Who Received Two Concurrent Injections of Ulcerase in Study 3

Safety Of Retreatment Of Recurrent Contractures

An observational, open label study was conducted in subjects who had participated in Ulcerase clinical trials for Dupuytren's contracture (Study 4). A subset of patients who had recurrence of contracture in a joint that was previously successfully treated with Ulcerase in Study 4 were retreated (Study 5). No new safety signals were identified among subjects who were retreated with Ulcerase.

Clinical Studies Experience In Patients With Peyronie’s Disease

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.

In the controlled and uncontrolled clinical studies of Ulcerase in Peyronie's disease, 1044 patients received a total of 7466 Ulcerase injections.

Corporal Rupture And Other Serious Penile Injury

• Corporal rupture was reported as an adverse reaction after Ulcerase injections in 5 of 1044 (0.5%) Ulcerase treated patients.
• In other Ulcerase-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.

The data described below are based on two identical, pooled, randomized, double-blind, placebocontrolled, multi-center trials through Day 365 in patients with Peyronie's disease (Studies 1 and 2). These trials included 832 patients of whom 551 and 281 received Ulcerase and placebo, respectively. In these trials, patients were given up to 4 treatment cycles of Ulcerase or placebo. In each cycle, two injections of Ulcerase or two injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed at the study site on patients 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately 6-week intervals up to three additional times, for a maximum of 8 total injection procedures and 4 total modeling procedures.

The majority of Peyronie's patients experienced at least one adverse reaction (92% Ulcerase-treated patients, 61% placebo-treated). Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered.

The most frequently reported adverse drug reactions (≥ 25%) in the Ulcerase clinical trials in patients with Peyronie's disease were penile hematoma, penile swelling, and penile pain. Table 5 shows the incidence of adverse reactions that were reported in greater than or equal to 1% of Ulcerase-treated patients and at a frequency greater than placebo-treated patients after up to 8 injections in the pooled placebo-controlled trials through Day 365.

Table 5: Adverse Reactions Occurring in ≥ 1% of Ulcerase-Treated Patients with Peyronie’s disease and at a Greater Incidence than Placebo After Up to Four Treatment Cycles in Studies 1 and 2 Combined

Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of Ulcerase-treated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined.

Reports Of Penile “Popping” Sounds Or Sensations

A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking”, and sometimes accompanied by detumescence, hematoma and/or pain, were reported in 73/551 (13.2%) Ulcerase-treated patients and 1/281 (0.3%) placebo-treated patients.

There were no clinically meaningful differences in the incidence of adverse events following treatment with Ulcerase based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use.

Ulcerase was not associated with shortening of penile length in clinical trials in the treatment of Peyronie's disease.

Immunogenicity

During clinical studies in Dupuytren's contracture and Peyronie's disease, patients were tested at multiple time points for antibodies to the protein components of Ulcerase (AUX-I and AUX-II).

In the Dupuytren's contracture clinical studies (Studies 1 and 2), at 30 days post the first injection of Ulcerase 0.58 mg, 92% of patients had antibodies against AUX-I detected and 86% of patients had antibodies against AUX-II detected. After the fourth injection of Ulcerase, every Ulcerase-treated patient developed high titers of antibodies to both AUX-I and AUX-II. After five years more than 90 percent of patients remained seropositive for anti-AUX-I and anti-AUX-II antibody (Study 4). Neutralizing antibodies were assayed for all patients (204) in Study 1. Neutralizing antibodies to AUX-I or AUX-II, were detected in 10% and 21%, respectively, of patients treated with Ulcerase. Among patients in Study 3 who reported no prior exposure to Ulcerase, 97% of patients had antibodies against AUX-I and AUX-II after two concurrent doses of Ulcerase 0.58 mg (total dose of 1.16 mg) in the same hand. In Study 5, treatment of recurrent contractures with Ulcerase resulted in similar immunogenicity results as seen in Studies 1 and 2.

In the Peyronie's disease clinical studies, at 6 weeks after the first treatment cycle of Ulcerase 0.58 mg, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of Ulcerase, >99% of Ulcerase-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested.

In patients treated for these two indications, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions.

Since the protein components in Ulcerase (AUX-I and AUX-II) have some sequence homology with human matrix metalloproteinases (MMPs), anti-product antibodies could theoretically interfere with human MMPs. In vitro studies showed no evidence of cross-reactivity between anti-drug-antibody positive patient sera and a series of relevant MMPs. In addition, no clinical safety concerns related to the inhibition of endogenous MMPs have been observed.

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.

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

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
• 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

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. 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 XIAFLEXtreated 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.

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 with Dupuytren’s Contracture and at a Greater Incidence than Placebo in the Placebo- Controlled Trials Through Day 90 After Up to 3 Injections

Some patients developed vasovagal syncope after finger extension procedures.

The safety of two concurrent injections of XIAFLEX 0.58 mg into Dupuytren's cords in the same hand was evaluated in a historically-controlled, open-label multi-center trial in 715 adult subjects with Dupuytren's contracture (Study 3). In Study 3, finger extension procedures were performed approximately 24 to 72 hours after injection. The patient demographics were similar to Studies 1 and 2.

Out of 715 patients who received two concurrent injections of XIAFLEX 0.58 mg in the same hand (1450 XIAFLEX injections) in Study 3, one (0.1%) patient experienced a tendon rupture of the treated finger within 3 days of the injection.

Table 4 shows the incidence of adverse reactions that were reported in greater than or equal to 5% of XIAFLEX-treated patients after two concurrent injections of XIAFLEX in the same hand through Day 60 in Study 3.

Table 4: Adverse Reactions Occurring in ≥ 5.0% of Subjects Who Received Two Concurrent Injections of XIAFLEX in Study 3

Safety Of Retreatment Of Recurrent Contractures

An observational, open label study was conducted in subjects who had participated in XIAFLEX clinical trials for Dupuytren's contracture (Study 4). A subset of patients who had recurrence of contracture in a joint that was previously successfully treated with XIAFLEX in Study 4 were retreated (Study 5). No new safety signals were identified among subjects who were retreated with XIAFLEX.

Clinical Studies Experience In Patients With Peyronie’s Disease

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.

In the controlled and uncontrolled clinical studies of XIAFLEX in Peyronie's disease, 1044 patients received a total of 7466 XIAFLEX injections.

Corporal Rupture And Other Serious Penile Injury

• Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX treated patients.
• 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.

The data described below are based on two identical, pooled, randomized, double-blind, placebocontrolled, multi-center trials through Day 365 in patients with Peyronie's disease (Studies 1 and 2). These trials included 832 patients of whom 551 and 281 received XIAFLEX and placebo, respectively. In these trials, patients were given up to 4 treatment cycles of XIAFLEX or placebo. In each cycle, two injections of XIAFLEX or two injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed at the study site on patients 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately 6-week intervals up to three additional times, for a maximum of 8 total injection procedures and 4 total modeling procedures.

The majority of Peyronie's patients experienced at least one adverse reaction (92% XIAFLEX-treated patients, 61% placebo-treated). Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered.

The most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials in patients with Peyronie's disease were penile hematoma, penile swelling, and penile pain. Table 5 shows the incidence of adverse reactions that were reported in greater than or equal to 1% of XIAFLEX-treated patients and at a frequency greater than placebo-treated patients after up to 8 injections in the pooled placebo-controlled trials through Day 365.

Table 5: Adverse Reactions Occurring in ≥ 1% of XIAFLEX-Treated Patients with Peyronie’s disease and at a Greater Incidence than Placebo After Up to Four Treatment Cycles in Studies 1 and 2 Combined

Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of XIAFLEX-treated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined.

Reports Of Penile “Popping” Sounds Or Sensations

A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking”, and sometimes accompanied by detumescence, hematoma and/or pain, were reported in 73/551 (13.2%) XIAFLEX-treated patients and 1/281 (0.3%) placebo-treated patients.

There were no clinically meaningful differences in the incidence of adverse events following treatment with XIAFLEX based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use.

XIAFLEX was not associated with shortening of penile length in clinical trials in the treatment of Peyronie's disease.

Immunogenicity

During clinical studies in Dupuytren's contracture and Peyronie's disease, patients were tested at multiple time points for antibodies to the protein components of XIAFLEX (AUX-I and AUX-II).

In the Dupuytren's contracture clinical studies (Studies 1 and 2), at 30 days post the first injection of XIAFLEX 0.58 mg, 92% of patients had antibodies against AUX-I detected and 86% of patients had antibodies against AUX-II detected. After the fourth injection of XIAFLEX, every XIAFLEX-treated patient developed high titers of antibodies to both AUX-I and AUX-II. After five years more than 90 percent of patients remained seropositive for anti-AUX-I and anti-AUX-II antibody (Study 4). Neutralizing antibodies were assayed for all patients (204) in Study 1. Neutralizing antibodies to AUX-I or AUX-II, were detected in 10% and 21%, respectively, of patients treated with XIAFLEX. Among patients in Study 3 who reported no prior exposure to XIAFLEX, 97% of patients had antibodies against AUX-I and AUX-II after two concurrent doses of XIAFLEX 0.58 mg (total dose of 1.16 mg) in the same hand. In Study 5, treatment of recurrent contractures with XIAFLEX resulted in similar immunogenicity results as seen in Studies 1 and 2.

In the Peyronie's disease clinical studies, at 6 weeks after the first treatment cycle of XIAFLEX 0.58 mg, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of XIAFLEX, >99% of XIAFLEX-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested.

In patients treated for these two indications, 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. In vitro studies showed no evidence of cross-reactivity between anti-drug-antibody positive patient sera and a series of relevant MMPs. In addition, no clinical safety concerns related to the inhibition of endogenous MMPs have been observed.

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.

Administration of Ulcerase at greater than recommended doses is expected to be associated with increased local reactions at the site of injection. Routine supportive care and symptomatic treatment must be provided in the case of overdose.

The effects of overdose of Ulcerase are unknown. It is possible that multiple simultaneous or excessive doses of Ulcerase 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.

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.