Collagenase clostridium histolyticum

>10%

Dupuytren contracture

• Peripheral edema (ie, swelling of injected hand) (73%)
• Contusion (70%)
• Injection site hemorrhage (38%)
• Injection site reaction (35%)
• Pain in injected extremity (35%)
• Pruritus (14%)
• Lymphadenopathy (13%)

Peyronie Disease

• Penile hematoma (65.5%)
• Penile swelling (55%)
• Penile pain (45.4%)
• Penile ecchymoses (14.5%)

1-10%

Dupuytren contracture

• Skin laceration (9%)
• Lymph node pain (8%)
• Erythema (6%)
• Axillary pain (6%)

Peyronie Disease

• Blood blister (4.5%)
• Penile blister (3.3%)
• Pruritus genital (3.1%)
• Painful erection (2.9%)
• Erectile dysfunction (1.8%)
• Procedural pain (1.6%)
• Injection site vesicles (1.3%)
• Localized edema (1.3%)
• Dyspareunia (1.1%)
• Injection site pruritus (1.1%)
• Nodule (1.1%)
• Suprapubic pain (1.1%)

<1%

Peyronie Disease

• Corporal rupture

Pregnancy Category: B

Lactation: Unknown whether distributed in breast milk, caution advised

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Intralesional Injection Preparation

Reconstitution of lyophilized powder

• Must reconstitute lyophilized powder with provided diluent prior to use
• Remove from lyophilized powder and diluent from refrigerator and allow to stand at room temperature for at least 15 min (not to exceed 60 min)
• Remove flip off cap from each vial, utilize aseptic technique and swab rubber stoppers of each vial with sterile alcohol
• Use only the supplied diluent for reconstitution (contains calcium required for activity of collagenase clostridium histolyticum
• Use 1-mL syringe with 0.01 mL gradations and 27-ga 0.5-in needle to withdraw diluent
• Inject diluent slowly into side of lyophilized powder vial, then slowly swirl solution to ensure al powder has gone into solution
• Do not invert vial or shake the solution

Sterile diluent volume for reconstitution

• MP joints: Reconstitute with 0.39 mL diluent (resulting concentration 0.58 mg/0.25 mL)
• PIP joints: Reconstitute with 0.31 mL diluent (resulting concentration

Peyronie Disease

• Using a 1 mL syringe with 0.01 mL graduations with a 27-gauge 1/2-inch needle, withdraw 0.39 mL of diluent supplied
• Inject diluent slowly along sides of vial containing the lyophilized powder; do not invert vial or shake solution; slowly swirl solution to ensure all lyophilized powder has gone into solution
• The reconstituted solution can be kept at room temperature (20-25ºC [68-77ºF]) for up to 1 hr or refrigerated at 2-8 degrees C (36-46ºF) for up to 4 hr prior to administration; if econstituted XIAFLEX solution is refrigerated, allow solution to return to room temperature for approximately 15 min before use
• Discard syringe and needle used for reconstitution and the diluent vial

Storage

Prior to reconstitution, store lyophilized powder for injection and diluent refrigerated

Reconstituted solution stable at room temperature (20-25ºC [68-77ºF]) up to 1 h, or refrigerated (2-8ºC [36-46ºF) up to 4 h before administration

Collagenase clostridium histolyticum is made from a mixture of proteins derived from a certain bacteria.

Collagenase clostridium histolyticum is used to treat Dupuytren's contracture in adults. This condition causes an abnormal thickening of the tissue in the palm of the hand. This condition may get worse over time and form a "cord" in your palm, causing a permanent bend in your finger.

Collagenase clostridium histolyticum is also used to treat a related condition called Peyronie's disease in adult men. This condition causes scar tissue or "plaque" to develop under the skin of the penis, resulting in an abnormal curving of the penis during erection.

Collagenase clostridium histolyticum is available for Peyronie's disease only from a certified pharmacy under a special program called Xiaflex REMS. You must be registered in the program and understand the risks of taking this medicine.

Collagenase clostridium histolyticum may also be used for purposes not listed in this medication guide.

Collagenase clostridium histolyticum can damage a nerve, tendon, or ligament in the hand the medicine is injected into. After the swelling from your injection goes down, call your doctor if you have numbness, tingling, increased pain, trouble bending your finger toward your wrist, or if you have new or worsened movement problems in your treated hand.

This medicine may also damage the erectile tissues inside a man's penis, which could require surgery to correct. Call your doctor right away if you have bruising and swelling of your penis, pain when you urinate, blood in the urine, sudden erection problems, or a "popping" sound or sensation in your penis during an erection.

You should not use collagenase clostridium histolyticum if you are allergic to it. This medicine should not be used to treat Peyronie's disease that affects the urethra (the tube for passing urine out of your bladder).

To make sure collagenase clostridium histolyticum is safe for you, tell your doctor if you have:

• a bleeding or blood clotting disorder, such as hemophilia; or
• if you take a blood thinner such as warfarin (Coumadin, Jantoven).

FDA pregnancy category B. Collagenase clostridium histolyticum is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether collagenase clostridium histolyticum passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; chest pain, difficult breathing; feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Collagenase clostridium histolyticum can damage a nerve, tendon, or ligament in the hand the medicine is injected into. After the swelling from your injection goes down, call your doctor if you have:

• numbness, tingling, increased pain;
• trouble bending your finger toward your wrist; or
• new or worsened movement problems in your treated hand.

Collagenase clostridium histolyticum may also damage the erectile tissues inside a man's penis, which could require surgery to correct. Call your doctor right away if you have:

• bruising and swelling of your penis;
• pain when you urinate, blood in the urine;
• sudden erection problems; or
• a "popping" sound or sensation in your penis during an erection.

Also call your doctor at once if you have:

• signs of infection such as fever, chills, redness or swelling;
• severe pain, itching, or other irritation; or
• feeling like you might pass out (even while lying down).

Common side effects may include:

• swelling, bruising, bleeding, pain, or tenderness where the medicine was injected;
• swollen glands in your elbow or underarm;
• itching, redness, or warmth of the skin;
• cracked skin;
• underarm pain;
• mild pain or tenderness in your treated hand;
• bruising of the penis or scrotum, erection problems; or
• discoloration of the skin on your penis, bruising or blisters where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Collagenase clostridium histolyticum can cause serious side effects, including:

1. Tendon rupture or ligament damage. Receiving an injection of collagenase clostridium histolyticum may cause damage to a tendon or ligament in your hand and cause it to break or weaken. This could require surgery to fix the damaged tendon or ligament. Call your healthcare provider right away if you have trouble bending your injected finger (towards the wrist) after the swelling goes down or you have problems using your treated hand after your follow-up visit.
2. Nerve injury or other serious injury of the hand. Call your healthcare provider right away if you get numbness, tingling, or increased pain in your treated finger or hand after your injection or after your follow-up visit.
3. Allergic Reactions. Allergic reactions can happen in people who take collagenase clostridium histolyticum because it contains foreign proteins.

Call your healthcare provider right away if you have any of these symptoms of an allergic reaction after an injection of collagenase clostridium histolyticum:

• hives
• swollen face
• breathing trouble
• chest pain

Treatment of Peyronie's Disease

When prescribed for the treatment of Peyronie’s disease, collagenase clostridium histolyticum is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) because of the risks of serious adverse reactions, including penile fracture (rupture of one of the penile bodies within the penile shaft, also known as corporal rupture) and other serious penile injury.

Collagenase clostridium histolyticum for the treatment of Peyronie’s disease should be administered by a health care professional who is experienced in the treatment of male urological diseases. The REMS requires participating health care professionals to be certified within the program by enrolling and completing training in the administration of collagenase clostridium histolyticum treatment for Peyronie’s disease. The REMS also requires health care facilities to be certified within the program and ensure that collagenase clostridium histolyticum is dispensed only for use by certified health care professionals.

Usual Adult Dose for Dupuytren's Contracture:

0.58 mg injected into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint

Comments:
-This drug should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren's contracture.
-Up to 2 joints in the same hand may be treated during a treatment visit. Two palpable cords affecting 2 joints may be injected or one palpable cord affecting 2 joints in the same finger may be injected at 2 locations during a treatment visit. If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected at other treatment visits approximately 4 weeks apart.
-Approximately 24 to 72 hours following an injection, a finger extension procedure should be performed if a contracture persists. Consult manufacturer product information or local protocol for information on the finger extension procedure.
-Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.
-Up to 2 cords in the same hand may be injected at a treatment visit. If a patient has other cords with contractures, those cords should be injected at another treatment visit.
-Vital signs should be monitored and appropriate equipment should be available to address any severe local or systemic reactions including the potential for anaphylaxis that may occur following injection.

Use: The treatment of adult patients with Dupuytren's contracture with a palpable cord

Usual Adult Dose for Peyronie's Disease:

0.58 mg injected into the target plaque once on each of two days, 1 to 3 days apart

Comments:
-This drug should be administered by a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of this drug in the treatment of Peyronie's disease.
-A treatment cycle consists of 2 injection procedures and a penile modeling procedure.
-For each plaque causing the curvature deformity, up to 4 treatment cycles may be administered. Each treatment cycle may be repeated at approximately 6 week intervals. If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if further treatment is not indicated, then subsequent treatment cycles should not be administered.
-The safety of more than one treatment course for Peyronie's disease is not known.

Use: 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

Other drugs may interact with collagenase clostridium histolyticum, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Dupuytren’s Contracture

Treatment of Dupuytren’s contracture in adults having a palpable collagen cord.1 2 7 8 10 12 13 Designated an orphan drug by FDA for the treatment of advanced Dupuytren’s disease.3

Dupuytren’s disease is a progressive fibroproliferative condition of the palmar fascia in the hand.2 7 Abnormal collagen deposition results in nodule and cord formation; may eventually limit hand movement by causing the affected fingers to chronically bend toward the palm with loss of ability to straighten these fingers resulting in contracture.2 7

May be a useful alternative to surgery, particularly in patients reluctant to have surgical intervention or who desire minimal recovery time.8 10 12 13

• Enzymatic agent isolated and purified from fermentation of Clostridium histolyticum.1 2 7

• Mixture of 2 microbial collagenases, collagenase AUX-I (clostridial type I collagenase) and collagenase AUX-II (clostridial type II collagenase), in a fixed ratio.1 2 7

• Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiologic conditions resulting in lysis of collagen deposits.1 7

• Injection may result in enzymatic disruption of Dupuytren’s cord (comprised mostly of collagen).1 8 10

• In vitro data suggest that collagenases AUX-I and AUX-II work synergistically to hydrolyze collagen.1

• No clinical data available regarding relative contribution of collagenase AUX-I or AUX-II to overall efficacy of the drug for Dupuytren’s contracture.1