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    All Other Musculoskeletal Agents
    All Other Wound Healing Agents
    Supplemental Dietary Agents

    BOXED WARNING

    Corporal rupture

    Collagenase (Xiaflex) administration is contraindicated in the treatment of Peyronie's plaques that involve the penile urethra, due to potential risk to this structure. Of note, injection of collagenase 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). Care should be taken to properly administer collagenase into the plaque, avoiding other structures such as the urethra, nerves, blood vessels, corpora cavernosa, or other collagen-containing structures of the penis. Administration of collagenase injections for the treatment of Peyronie's disease has been associated with serious penile injury, including corporal rupture. Instruct patients to immediately report signs or symptoms indicative of penile injury. Serious injury, such as corporal rupture or severe penile hematoma, may require surgical intervention.

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    Collagenase enzymatically degrades collagen
    Topical enzyme ointment used for chemical debridement of acute or chronic wounds; subcutaneous injection (QWO) used for moderate to severe cellulite in the buttocks; intralesional injection (Xiaflex) used for Dupuytren's contracture with a palpable cord, and for Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees
    Due to the possible risk of serious penile injury, Xiaflex for the treatment of Peyronie's disease is only available through a REMS program

    COMMON BRAND NAMES

    Santyl, Xiaflex

    HOW SUPPLIED

    Santyl Topical Ointment: 1g, 250U
    Xiaflex Intralesional Inj Pwd F/Sol: 0.9mg

    DOSAGE & INDICATIONS

    For the treatment of severe partial- or full-thickness burns.
    NOTE: Removal of necrotic tissue by mechanical debridement should be considered during the initial and subsequent assessments.
    NOTE: Collagenase should only be used on wounds that have necrotic material. Antibiotic administration is paramount for infected wounds.
    NOTE: Collagenase should be discontinued as soon as the wound bed is devoid of necrotic tissue and has more than 90% granulation tissue.
    Topical dosage
    Adults, Adolescents, and Children

    Apply a thin layer to the site once daily. More frequent (e.g., twice daily) application may be needed if dressing becomes soiled.

    For the treatment of decubitus ulcer, diabetic foot ulcer, or varicose ulcer that requires debridement.
    NOTE: Removal of necrotic tissue by mechanical debridement should be considered during the initial and subsequent assessments.
    NOTE: Collagenase should only be used on wounds that have necrotic material. Stage 1 ulcers are not appropriate candidates. Antibiotic administration is paramount for infected wounds.
    NOTE: Collagenase should be discontinued as soon as the wound bed is devoid of necrotic tissue and has more than 90% granulation tissue.
    Topical dosage
    Adults, Adolescents, and Children

    Apply a thin layer to the site once daily. More frequent (e.g., twice daily) application may be needed if dressing becomes soiled. Once granulation has been firmly established, every other day application may be considered.

    For the treatment of Dupuytren's contracture with a palpable cord.
    Intralesional injection dosage (Xiaflex only)
    Adults

    0.58 mg injected into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint. If a contracture persists approximately 24 to 72 hours after injection, perform a finger extension procedure to facilitate cord disruption. Injections (0.58 mg) and finger extension procedures (24 to 72 hours later) may be administered up to 3 times per cord at approximately 4-week intervals. Up to 2 injections in the same hand may be performed during a treatment visit. Two palpable cords affecting 2 joints may be injected or 1 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 the MP or PIP joints, these cords may be injected at other treatment visits approximately 4 weeks apart.

    For the treatment of Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy.
    Intralesional injection (Xiaflex only)
    Adults males

    0.58 mg injected into a Peyronie's plaque. If more than 1 plaque is present, inject into the plaque causing the curvature. A treatment cycle consists of 2 injection procedures and 1 penile modeling procedure. The second of 2 injection procedures 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 6 weeks. The treatment course consists of a maximum of 8 injection procedures and 4 modeling procedures (i.e., a maximum of 4 treatment cycles). The safety of more than 1 treatment course is unknown. If the curvature deformity is less than 15 degrees after the first, second, or third treatment cycle, or if the health care provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered. The safety and effectiveness of collagenase treatment of Peyronie's disease was established in 2 randomized, double-blind, placebo-controlled studies in adult males (n = 832) with Peyronie's disease with penile curvature deformity of at least 30 degrees. Participants were given up to 4 treatment cycles of collagenase or placebo and were then followed 52 weeks. Collagenase treatment significantly reduced penile curvature deformity and related bothersome effects compared with placebo.
    NOTE: Due to the possible risk of serious penile injury, collagenase injection for the treatment of Peyronie's disease is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Treatment should be administered by a health care professional with experience in male urological diseases. The REMS requires prescribers to be certified within the program by enrolling and completing training in the administration of collagenase injection. Participating health care facilities should also be certified to ensure appropriate product distribution.

    For the treatment of moderate to severe cellulite in the buttocks of adult women.

     

    Subcutaneous dosage (QWO only)
    Adults

    0.84 mg injected subcutaneously per treatment area, repeated every 21 days for 3 treatment visits. Up to 2 areas may be treated at each visit. Each treatment area is defined as a single buttock receiving up to twelve 0.3 mL injections (total of 3.6 mL).

    MAXIMUM DOSAGE

    Adults

    For topical preparations, 2 applications per day topically. For Dupuytren's contractures, 0.58 mg per dose injected into a palpable cord (only inject 1 cord at a time). For Peyronie's disease, 0.58 mg per dose injected into penile plaque, a maximum of 8 injection procedures per treatment course. For cellulitis, 0.84 mg per treatment area subcutaneously with up to 2 treatment areas per treatment visit.

    Geriatric

    For topical preparations, 2 applications per day topically. For Dupuytren's contractures, 0.58 mg per dose injected into a palpable cord (only inject 1 cord at a time). For Peyronie's disease, 0.58 mg per dose injected into penile plaque, a maximum of 8 injection procedures per treatment course. For cellulitis, 0.84 mg per treatment area subcutaneously with up to 2 treatment areas per treatment visit.

    Adolescents

    2 applications/day topically; safety and efficacy of the injectable formulations have not been established.

    Children

    2 applications/day topically; safety and efficacy of the injectable formulations have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Due to the possible risk of serious penile injury, collagenase injection for the treatment of Peyronie's disease, is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Treatment should be administered by a health care professional with experience in male urological diseases. The REMS requires prescribers to be certified within the program by enrolling and completing training in the administration of collagenase injection. Participating health care facilities should also be certified to ensure appropriate product distribution. Further information is available at (877) 313-1235.

    Injectable Administration

    Ensure the correct injectable collagenase product is used for the correct indication.
    QWO is administered subcutaneously and is indicated to treat moderate to severe cellulite in the buttocks.
    Xiaflex is administered via intralesional injection and is indicated to treat Dupuytren's contracture and Peyronie's disease.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The reconstituted solution should be clear, colorless, and free of particulate matter. Do not use if the solution contains particulates, is cloudy, or is discolored.
    Be prepared to address severe allergic reactions. Severe reactions including anaphylaxis could occur after collagenase injections.

    Subcutaneous Administration

    QWO is the only product approved for subcutaneous administration.
     
    Reconstitution (QWO):
    Remove vials from the refrigerator and let stand at room temperature for at least 15 minutes.
    Inspect vials before reconstitution. The cake of lyophilized powder should be white in color and intact, showing no sign of erosion. The diluent should be colorless and free of particulate matter. Use only the supplied diluent to reconstitute the lyophilized powder.
    Remove the flip-off caps and swab the rubber stoppers of the vial containing lyophilized powder and the vial containing the diluent with sterile alcohol (no other antiseptic should be used).
    Using an appropriately sized syringe, withdraw the amount of supplied diluent based on the number of injection sites.
    For a single treatment area, withdraw 4 mL.
    For 2 treatment areas, withdraw 8 mL.
    Slowly inject the diluent onto the sides of the vial containing the lyophilized powder. Do not invert or shake the vial. Slowly swirl the solution to ensure all the powder has gone into solution.
    For a single treatment area, add 4 mL of diluent to a 0.92 mg vial to produce a 0.23 mg/mL solution.
    For 2 treatment areas, add 8 mL of diluent to a 1.84 mg vial to produce a 0.23 mg/mL solution.
    Storage: The reconstituted solution can be kept at room temperature at 20 to 25 degrees C (68 to 77 degrees F) for up to 8 hours or refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 72 hours. If refrigerated, allow the solution to return to room temperature for approximately 15 minutes before use.
     
    Subcutaneous injection:
    Using 1-mL syringes with removable needles, draw up 0.9 mL of the reconstituted solution into each syringe. The appropriate number of syringes needed is based on the number of injections sites.
    For a single treatment area, draw up 4 syringes with 0.9 mL each. The total injection volume in the prepared syringes is 3.6 mL. The total dose of collagenase clostridium histolyticum in the prepared syringes is 0.84 mg.
    For 2 treatment areas, draw up 8 syringes with 0.9 mL each. The total injection volume in the prepared syringes is 7.2 mL. The total dose of collagenase clostridium histolyticum in the prepared syringes is 1.68 mg.
    After the syringes are prepared, pull the solution remaining in the needles into the barrels of the syringe and replace the needles with 30-gauge 0.5-inch needles. Administer immediately; do not store the reconstituted solution in the 1-mL syringes.
    Mark the injection sites while the patient is standing. Inject the dose subcutaneously while the patient is in a prone position.
    Each injection should be administered as three 0.1 mL aliquots to positions A, B, and C (for a total injection volume of 0.3 mL). The depth of each injection should be 0.5 inches without downward pressure.
    Needle tip position A: Position the needle at a 90-degree angle perpendicular to the skin surface at the injection site and inject 0.1 mL.
    Needle tip position B: After administering at position A, withdraw the needle slightly (but not so much as to remove from the injection site) and reposition approximately 45-degrees (but not more than 45-degrees) and inject 0.1 mL (towards the head).
    Needle tip position C: After administering at position B, withdraw the needle slightly (but not so much as to remove from the injection site) and reposition approximately 45-degrees (but not more than 45-degrees) and inject 0.1 mL (toward the foot).
    Withdraw the needle from the skin completely and move to the next identified injection site.
    Each treatment area (defined as a single buttock) may receive up to 12 injections.
    After treatment, the patient should remain prone for at least 5 minutes.
    Discard any unused reconstituted solution.

    Other Injectable Administration

    Intralesional Injection Administration
    Xiaflex is the only product approved for intralesional administration.
     
    Intralesional Injection for Dupuytren's Contracture (Xiaflex)
    NOTE: Only a healthcare provider experienced in injection procedures of the hand and the treatment of patients with Dupuytren's contracture should inject collagenase intralesionally.
     
    Reconstitution:
    Remove the vial containing the collagenase lyophilized powder and the vial containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at room temperature for 15 to 60 minutes.
    Remove the flip-off cap from each vial and aseptically swab the rubber stopper and surrounding surface of each vial with sterile alcohol; do not use any other antiseptics.
    Only use the supplied diluent for reconstitution, as the diluent contains calcium that is required for the activity of collagenase. Using a 1 mL syringe that contains 0.01 mL graduations with a 27-gauge half-inch needle, withdraw 0.39 mL of diluent for cords affecting a metacarpophalangeal (MP) joint or withdraw 0.31 mL of diluent for cords affecting a proximal interphalangeal (PIP) joint.
    Inject the diluent slowly into the sides of the lyophilized powder vial. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. Do not invert the vial or shake the solution. The reconstituted solution contains 0.9 mg of collagenase.
    Discard the syringe and needle used for reconstitution.
    Storage: The reconstituted solution can be kept at room temperature at 20 to 25 degrees C (68 to 77 degrees F) for up to one hour or refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 4 hours. If refrigerated, allow the solution to return to room temperature for approximately 15 minutes before use.[38955]
     
    Intralesional Injection:
    Using a new 1 mL hubless syringe that contains 0.01 ml graduations with a permanently fixed, 27-gauge, half-inch needle, withdraw 0.25 mL of reconstituted solution (containing 0.58 mg of collagenase) for cords affecting a metacarpophalangeal (MP) joint or 0.2 mL of reconstituted solution (containing 0.58 mg of collagenase) for cords affecting a proximal interphalangeal (PIP) joint. Discard any unused solution. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.
    Reconfirm the cord to be injected. The chosen injection site should be the area where the contracting cord is maximally separated from the underlying flexor tendons and where the skin is not intimately adhered to the cord.
    Apply an antiseptic at the injection site and allow the skin to dry.
    Administration of a local anesthetic agent before injection is not recommended, as the local anesthetic may interfere with proper placement of the collagenase injection.
    If injecting into a cord affecting the PIP joint of the fifth finger, take care to inject as close to the palmar digital crease as possible (as far proximal to the digital PIP joint crease); avoid injecting more than 4 mm distal to the palmar digital crease. Do not insert the needle more than 2 to 3 mm in depth.
    Secure the patient's hand to be treated with your non-dominant hand and simultaneously apply tension to the cord. With your dominant hand, place the needle into the cord and use caution to keep the needle within the cord. To help minimize the potential for injection of collagenase into tissues other than the cord, do not let the needle tip pass completely through the cord. Take care to avoid injection into tendons, nerves, blood vessels, or other collagen-containing structures of the hands.
    If there is any concern that the needle is in the flexor tendon, apply a small amount of passive motion at the distal interphalangeal joint. If insertion of the needle into a tendon is suspected or if paresthesia is noted by the patient, withdraw the needle and reposition it into the cord.
    If the needle is in the proper location, some resistance noted during the injection procedure will be noted. After confirming that the needle is correctly placed in the cord, inject approximately one-third of the dose. 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. Withdraw the needle tip from the cord and reposition it a third time proximal to the initial injection (approximately 2 to 3 mm) and inject the final portion of the dose into the cord.
    Wrap the patient's treated hand with a soft, bulky, gauze dressing. Instruct the patient to limit motion of the treated finger and to keep the injected hand elevated until bedtime. Instruct the patient not to attempt to disrupt the injected cord by self-manipulation and to return the next day for follow-up and a finger extension procedure, if needed.
    Inject only one cord at a time. If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with collagenase in a sequential order.
     
    Follow-up:
    If a contracture remains the day after the injection, perform a passive finger extension procedure to facilitate cord disruption. Put the patient's wrist is in the flexed position and apply moderate stretching pressure to the injected cord by extending the finger for approximately 10 to 20 seconds. For cords affecting the proximal interphalangeal (PIP) joint, perform the finger extension procedure when the metacarpophalangeal (MP) joint is in the flexed position. Avoid direct pressure on the injection site, as it will likely be tender. Local anesthesia may be used.
    If the first finger extension procedure does not result in cord disruption, a second and third attempt can be performed at 5 to 10-minute intervals. However, no more than 3 attempts are recommended to disrupt a cord.
    If the cord has not been disrupted after 3 attempts, a follow-up visit may be scheduled in approximately 4 weeks. If, at that subsequent visit, the contracted cord persists, an additional collagenase injection with finger extension procedures may be performed.
    After the finger extension procedure(s), fit the 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.[38955]
     
    Intralesional Injection for Peyronie's Disease (Xiaflex)
    NOTE: In accordance with XIAFLEX REMS Program, prescribers must be certified with the program by enrolling and completing training in the administration of collagenase injection treatment. Healthcare sites must also be certified with the program to ensure proper distribution of product.
     
    Reconstitution:
    Remove the vial containing the collagenase lyophilized powder and the vial containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at room temperature for 15 to 60 minutes.
    Remove the flip-off cap from each vial and aseptically swab the rubber stopper and surrounding surface of each vial with sterile alcohol; do not use any other antiseptics.
    Only use the supplied diluent for reconstitution, as the diluent contains calcium that is required for the activity of collagenase. Using a 1 ml syringe that contains 0.01 ml graduations with a 27-gauge half-inch needle, withdraw 0.39 ml of diluent.
    Inject the diluent slowly into the sides of the lyophilized powder vial. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. Do not invert the vial or shake the solution. The reconstituted solution contains 0.9 mg of collagenase.
    Discard the syringe and needle used for reconstitution.
    Storage: The reconstituted solution can be kept at room temperature at 20 to 25 degrees C (68 to 77 degrees F) for up to one hour or refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 4 hours. If refrigerated, allow the solution to return to room temperature for approximately 15 minutes before use.[38955]
     
    Intralesional Injection:
    If the reconstituted solution is refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 4 hours before administration, allow this solution to return to room temperature for approximately 15 minutes before use.
    Prior to each treatment cycle, identify the treatment area by inducing a penile erection. A single intracavernosal injection of 10 or 20 mcg 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 intralesional injection.
    Before intralesional injection, apply an antiseptic at the injection site and allow the skin to dry. Administer suitable local anesthetic, if desired.
    Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge half-inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing 0.58 mg of collagenase).
    The penis should be in a flaccid state before intralesional injection. 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.
    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.
    With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly inject collagenase 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.
    Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a dressing as necessary.
    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.
    The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from the first injection.
     
    Follow-up:
    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 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. 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.
    Of note, injection of collagenase 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, collagenase 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.[38955]

    Topical Administration

    Collagenase is only for use on necrotic skin tissue.
     
    Site preparation:
    Assess the need for pain control during wound manipulation. Enzyme application is usually not pain-inducing because tissue is not removed mechanically as with surgical debridement or wet-to-dry dressings. The process of washing and rinsing the wound could cause discomfort.
    There is no need to remove all collagenase ointment from the wound, if it has been applied previously. Gently wash the site with a normal saline soaked sterile gauze pad. Do not scrub the site. Wash several times if povidone iodine, acidic detergents, or cleansers with heavy metal ions (e.g., mercury, silver) have been used previously on the site. Examples of such items include silver sulfadiazine, silver nitrate, aluminum acetate, Burow's solution, and povidone-iodine. Hydrogen peroxide and Dakin's solution do not interact with collagenase. After the wash, rinse the wound with normal saline.
    If appropriate, remove loose necrotic debris with forceps and scissors.
    If clinically indicated, thick eschar may be crosshatched using a #10 blade to expose more surface area to collagenase.
    If an infection is present, surgical debridement may be needed initially; systemic antibiotics are of limited value for necrotic tissue, as it is avascular. If a topical antibiotic is applied to the site, the antibiotic is applied before collagenase. Antibiotic therapy should be chosen based on culture results. If the infection does not resolve, collagenase ointment should be withheld until culture results show infection resolution.

    Cream/Ointment/Lotion Formulations

    Apply the ointment within the boundaries of the wound. Application may be direct to the site or to a sterile gauze pad that it secured to the site. Do not touch the tip of the tube to any surface, including a finger, the wound, or sterile gauze pad. Application to normal skin may cause some irritation.
    Once daily application is usually sufficient; however, if the dressing becomes soiled, wound cleansing and collagenase reapplication may be appropriate.
    Cessation of collagenase use is needed when necrotic tissue debridement is complete and granulation tissue is well-established.

    STORAGE

    Generic:
    - Protect from extreme heat
    - Protect from light
    - Protect from moisture
    - Store in a cool, dry place
    Santyl:
    - Store at 77 degrees F
    Xiaflex:
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store reconstituted product in accordance with package insert instructions
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Bone marrow suppression, hyperglycemia, immunosuppression, infection, malnutrition

    Treatment with subcutaneous collagenase (QWO) is contraindicated if an infection is present at the injection sites. The use of topical collagenase may increase the risk of bacteremia in at-risk patients; the presence of eschar or necrotic tissue is a good medium to support bacterial growth. Wounds of patients with immunosuppression need to be monitored vigilantly for signs and symptoms of infection. Patients who are elderly or patients with hyperglycemia, malnutrition, immunosuppressant use, bone marrow suppression, or certain cancers may be at greater risk for wound infection due to immunosuppression. Patients with malnutrition may have inadequate intake of nutrients, protein, and calories necessary for proper wound repair. Infection at the wound site may lead to a systemic infection (sepsis). Patients with a fever, chills, elevated white blood count, hypotension, confusion, purulent wound exudate, or odiferous wounds may need appropriate antimicrobial therapy.

    Arteriosclerosis, diabetes mellitus, peripheral vascular disease

    Certain wounds of patients with peripheral vascular disease, diabetes mellitus, or arteriosclerosis may have insufficient vascular supply. Wound beds need adequate blood supply to facilitate nutrition delivery, infection control, and waste removal. Topical collagenase application to a wound bed with inadequate blood perfusion may be moot. Steps to optimize circulation, such as external compression, surgery, exercise, and medication optimization may be considered, as appropriate.

    Anticoagulant therapy, coagulopathy, hemophilia, thrombocytopenia, vitamin K deficiency

    Cautious use of injectable collagenase is warranted for patients with coagulopathy, hemophilia, vitamin K deficiency, thrombocytopenia, or on anticoagulant therapy (except low-dose aspirin). In clinical trials, 70% of patients receiving intralesional injections developed an ecchymosis or contusion, and 38% developed an injection site hemorrhage. For subcutaneously administered collagenase, 84% of drug recipients experienced injection site hemorrhage. The efficacy and safety of injectable collagenase in patients receiving anticoagulant medications (other than aspirin up to 150 mg per day) within 7 days of injectable collagenase administration are unknown.

    Serious hypersensitivity reactions or anaphylaxis

    Collagenase is contraindicated for use in patients with a history of collagenase hypersensitivity. Serious hypersensitivity reactions or anaphylaxis have been reported with the use of injectable collagenase. If a hypersensitivity reaction occurs, discontinue any further injections and institute appropriate medical therapy.

    Pregnancy

    There are no data available regarding the use of collagenase injections in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. However, pharmacokinetic studies showed that collagenase concentrations are not quantifiable in the systemic circulation following subcutaneous or intralesional injections. Almost all patients develop anti-AUX-I and anti-AUX-II after injectable collagenase treatment; the clinical significance of anti-product antibody formation on a developing fetus is unknown. In animal studies, intravenous doses of collagenase (up to 43-times the human equivalent dose) administered to pregnant rats during organogenesis revealed no evidence of harm to the fetus. Human collagenase also plays a role in cervical ripening during labor, and the effects on labor or obstetric delivery are not completely understood. There is no information regarding the systemic absorption of topical collagenase ointment; theoretically, systemic absorption would be influenced by application site size and other factors; use as directed rarely results in systemic adverse effects to the person to whom it is applied. Case reports describe topical collagenase ointment use for wound care during pregnancy within the medical literature, and use is generally considered compatible when clearly needed for proper wound care.

    Breast-feeding

    Topical collagenase ointment has no specific precautions for use in breast-feeding women. For the injectable products, there are no data on the presence of collagenase in human milk, the effects on the breast-fed infant, or the effects on milk product; however, human pharmacokinetic studies showed that collagenase concentrations were not quantifiable in the systemic circulation following subcutaneous or intralesional injections.  Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Corporal rupture

    Collagenase (Xiaflex) administration is contraindicated in the treatment of Peyronie's plaques that involve the penile urethra, due to potential risk to this structure. Of note, injection of collagenase 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). Care should be taken to properly administer collagenase into the plaque, avoiding other structures such as the urethra, nerves, blood vessels, corpora cavernosa, or other collagen-containing structures of the penis. Administration of collagenase injections for the treatment of Peyronie's disease has been associated with serious penile injury, including corporal rupture. Instruct patients to immediately report signs or symptoms indicative of penile injury. Serious injury, such as corporal rupture or severe penile hematoma, may require surgical intervention.

    Requires an experienced clinician

    Collagenase injection (Xiaflex) requires an experienced clinician in the treatment of patients with Dupuytren's contracture and injection procedures of the hand. Additionally, Xiaflex should be administered by a health care provider experienced in the treatment of male urological diseases, who has completed the required training for use of the drug in the treatment of Peyronie's disease.

    ADVERSE REACTIONS

    Severe

    penile edema / Early / 55.0-55.0
    tendon rupture / Delayed / 0-1.0
    corporal rupture / Delayed / 0.5-0.5
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    bleeding / Early / 6.0-84.0
    peripheral edema / Delayed / 73.0-77.0
    hematoma / Early / 3.7-65.5
    edema / Delayed / 8.0-55.0
    penile pain / Rapid / 45.4-45.4
    skin laceration / Delayed / 9.0-22.0
    lymphadenopathy / Delayed / 13.0-13.0
    erythema / Early / 6.0-9.0
    impotence (erectile dysfunction) / Delayed / 1.8-1.8
    penile irritation / Rapid / 1.1-1.1
    dyspareunia / Delayed / 1.1-1.1
    dyspnea / Early / Incidence not known
    antibody formation / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known

    Mild

    injection site reaction / Rapid / 5.0-84.0
    ecchymosis / Delayed / 5.0-70.0
    pruritus / Rapid / 4.0-15.0
    skin discoloration / Delayed / 1.8-8.0
    pelvic pain / Delayed / 1.1-1.1
    rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    skin irritation / Early / Incidence not known
    infection / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    headache / Early / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Anagrelide: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Anticoagulants: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Antithrombin III: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Apixaban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Argatroban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Caffeine: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Carisoprodol: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Dipyridamole: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Omeprazole: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Oxycodone: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA; Pravastatin: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Betrixaban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Bivalirudin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Cilostazol: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Clopidogrel: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Dabigatran: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Dalteparin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Danaparoid: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Desirudin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Dipyridamole: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Edoxaban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Enoxaparin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Eptifibatide: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Fondaparinux: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Heparin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Lepirudin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Pentosan: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Platelet Inhibitors: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Povidone-Iodine: (Contraindicated) Collagenase can interact with other topically-applied medication products. Povidone-iodine inactivates collagenase and concurrent use should be avoided.
    Prasugrel: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Rivaroxaban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Silver Nitrate: (Contraindicated) Topical collagenase can interact with other topically-applied medication products. Care should be taken to avoid topical antimicrobials, such as silver nitrate. Silver ions and agents with a low pH (< 6) inhibit the enzymatic activity of collagenase.
    Silver Sulfadiazine: (Contraindicated) Silver sulfadiazine should not be used with the proteolytic enzymes collagenase, papain, or sutilains because heavy metals such as silver inactivate these enzymes.
    Ticagrelor: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Ticlopidine: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Tinzaparin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Tirofiban: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Vorapaxar: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Warfarin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data available regarding the use of collagenase injections in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. However, pharmacokinetic studies showed that collagenase concentrations are not quantifiable in the systemic circulation following subcutaneous or intralesional injections. Almost all patients develop anti-AUX-I and anti-AUX-II after injectable collagenase treatment; the clinical significance of anti-product antibody formation on a developing fetus is unknown. In animal studies, intravenous doses of collagenase (up to 43-times the human equivalent dose) administered to pregnant rats during organogenesis revealed no evidence of harm to the fetus. Human collagenase also plays a role in cervical ripening during labor, and the effects on labor or obstetric delivery are not completely understood. There is no information regarding the systemic absorption of topical collagenase ointment; theoretically, systemic absorption would be influenced by application site size and other factors; use as directed rarely results in systemic adverse effects to the person to whom it is applied. Case reports describe topical collagenase ointment use for wound care during pregnancy within the medical literature, and use is generally considered compatible when clearly needed for proper wound care.

    Topical collagenase ointment has no specific precautions for use in breast-feeding women. For the injectable products, there are no data on the presence of collagenase in human milk, the effects on the breast-fed infant, or the effects on milk product; however, human pharmacokinetic studies showed that collagenase concentrations were not quantifiable in the systemic circulation following subcutaneous or intralesional injections.  Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Collagenase digests collagen in collagen deposits. Lysis of collagen deposits occurs, as collagenases hydrolyze collagen in its native triple-helical conformation under physiological conditions. The exact mechanism by which collagenase treats moderate to severe cellulite is unknown.[65680]
     
    A Dupuytren's cord is comprised mostly of collagen, and injection of collagenase into the cord may result in enzymatic disruption of the cord. In vitro data suggest that the AUX-I and AUX-II collagenases work synergistically to provide hydrolyzing activity towards collagen. The relative contributions of the individual collagenases (AUX-I or AUX-II) to the efficacy of collagenase in the treatment of Dupuytren's contracture are unknown.[38955]
     
    The curvature deformity of Peyronie's disease is caused by a collagen plaque. Intralesional injection of collagenase into the penile plaque may enzymatically disrupt the plaque and reduce signs and symptoms. In vitro data suggest collagenase targets Types I and III collagen found in explanted tissues containing Peyronie's plaques. At higher doses and longer incubation times, non-fibrillar Type IV collagen is affected causing collagen lysis in small veins. However, in vitro and in vivo studies have not demonstrated structural damage to arteries, nerves, or large veins that contain Type IV collagen. In addition, collagen fragments derived from plaque disruption have been shown to generate increased vascular permeability, inflammatory responses, and regenerative changes; however, the effects of these changes have not been studied.[38955]
     
    Collagenase also digests collagen in necrotic tissue. Moist, necrotic tissue provides a medium for infection, initiates an inflammatory response, places a phagocytic demand on the wound, and retards wound healing. As collagen composes roughly 75% of dry tissue weight and provides the framework to hold necrotic cells to the tissue bed, collagen removal by collagenase facilitates granulation tissue formation. Granulation is necessary for proper epithelialization. Human collagenases are produced by macrophages, fibroblasts, and keratinocytes, which are all necessary for wound healing. Unlike mammalian collagenase, Clostridial collagenase is secreted as an active enzyme and splits collagen into small peptides. The small peptides appear to enhance chemotaxis of macrophages, monocytes, fibroblasts, neutrophils, and keratinocytes. In vitro data suggest that Clostridial collagenase and the small peptides promote epithelization by enhancing keratinocyte migration to the wound.[27507]

    PHARMACOKINETICS

    Collagenase is applied topically or is injected intralesionally into palpable cords in patients with Dupuytren's contractures.

    Subcutaneous Route

    The pharmacokinetics of collagenase clostridium histolyticum has been evaluated in 140 females with cellulite. Following administration of a single subcutaneous dose (up to 3.36 mg distributed across 4 treatment areas; 0.84 mg per treatment area), all drug recipients had clostridium type 1 collagenase (AUX-1) and clostridium type II collagenase (AUX-II) plasma concentrations that were below the lower limit of quantitation (5 ng/mL and 25 ng/mL, respectively).

    Topical Route

    Collagenase is applied topically directly to the wound bed. The optimal pH for enzymatic activity of collagenase is between 6 and 8. No information is available regarding the absorption, distribution, metabolism, or excretion of topically applied collagenase.

    Other Route(s)

    Intralesional Route
    No quantifiable concentrations of either microbial collagenase (AUX-I or AUX-II) were detected in plasma up to 30 days after injection of either a single collagenase dose of 0.58 mg into a Dupuytren's cord in 20 patients or 2 concurrent injections of 0.58 mg into Dupuytren's cords of 12 patients.
     
    Following each of 2 intralesional administrations (0.58 mg collagenase, separated by 24 hours) into the penile plaque of 19 subjects with Peyronie's disease, plasma concentrations of AUX-I and AUX-II in subjects with quantifiable levels (79% and 40% for AUX-I and AUX-II, respectively) were minimal and short-lived. The maximal plasma concentrations of AUX-I and AUX-II were less than 29 ng/mL and less than 71 ng/mL, respectively, and were observed within approximately 10 minutes after injection. Within 30 minutes following dosing, all plasma concentrations were below the limits of quantification. No evidence of accumulation was evident following 2 sequential injections. No subject had quantifiable plasma levels 15 minutes after modeling of plaque on Day 3 (i.e., 24 hours after the second injection on Day 2).