Corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie disease:
Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) collagenase-treated patients in clinical studies. In other collagenase-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. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) collagenase-treated patients.
Signs or symptoms that may reflect serious penile injury should be promptly evaluated to assess for corporal rupture or severe penile hematoma which may require surgical intervention.
Because of the risks of corporal rupture or other serious penile injury, collagenase is available for the treatment of Peyronie disease only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Xiaflex REMS program.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Xiaflex: 0.9 mg (1 ea)
Mechanism of Action
Collagenase clostridium histolyticum contains two forms of microbial collagenase (Collagenase AUX-I and Collagenase AUX-II) isolated and purified from the fermentation of Clostridium histolyticum bacteria; collagenase lyses collagen, leading to enzymatic disruption of contracted Dupuytren cord or Peyronie plaque (both comprised primarily of collagen).
Systemic plasma concentrations of collagenase AUX-I or collagenase AUX-II were undetectable for up to 30 days following intralesional injection into a Dupuytren cord. Low levels of collagenase AUX-I and AUX-II were quantifiable for up to 30 minutes following intralesional injection into a Peyronie plaque.
Use: Labeled Indications
Dupuytren contracture: Treatment of adults with Dupuytren contracture with a palpable cord
Peyronie disease: Treatment of adult men with Peyronie disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy
Treatment of Peyronie plaques that involve the penile urethra; history of hypersensitivity to collagenase or to collagenase used in any other therapeutic application or application method.
Dosage and Administration
Dupuytren contracture: Intralesional: Inject 0.58 mg per cord affecting a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint. If contracture persists, finger extension procedure should be performed 24 to 72 hours following injection to facilitate cord disruption. If MP or PIP contracture remains, may reinject cord with a single dose of 0.58 mg 4 weeks following initial injection; injections and finger extension procedures may be administered up to 3 times per cord separated by ~4 week intervals. Note: Up to 2 injections per hand may be used during a treatment; 2 palpable cords affecting 2 joints or 1 palpable cord affecting 2 joints in the same finger may be injected at 2 locations during a treatment. Other palpable cords with contractures of MP or PIP joints may be injected at other treatment visits ~4 weeks apart.
Peyronie disease: Intralesional: Males: Inject 0.58 mg into a Peyronie plaque; repeat injection 1 to 3 days later. A penile modeling procedure should be performed 1 to 3 days after the second injection. Administer a second treatment cycle (two 0.58 mg injections and a penile modeling procedure) in ~6 weeks if needed (maximum, 4 treatment cycles [a total of 8 injection procedures and 4 penile modeling procedures]); subsequent treatment cycles should not be administered if the curvature deformity is <15 degrees after a treatment cycle or health care provider determines further treatment is not indicated. The safety of more than 1 treatment course (ie, 4 treatment cycles) is not known. Note: If more than 1 plaque is present, inject into the plaque causing the curvature deformity.
Refer to adult dosing.
Lyophilized powder must be reconstituted with the provided diluent. Allow powder and diluent to warm to room temperature for at least 15 minutes and no longer than 60 minutes prior to reconstitution. Volume needed for reconstitution is dependent on intended site of injection. Using a 1 mL syringe with 0.01 graduations and a 27-gauge 1/2-inch needle, reconstitute powder (containing 0.9 mg collagenase clostridium histolyticum) with the following volume of diluent:
Cords affecting MP joints or Peyronie plaque: Dilute with 0.39 mL diluent; provides 0.58 mg/0.25 mL concentration; inject diluent slowly into the sides of the vial and swirl to dissolve; do not invert vial or shake
Cords affecting PIP joints: Dilute with 0.31 mL diluent; provides 0.58 mg/0.20 mL concentration; inject diluent slowly into the sides of the vial and swirl to dissolve; do not invert vial or shake
Each vial is for a single injection; if two joints on the same hand are to be treated during a treatment, use separate vials and syringes for each reconstitution and injection.
Inject intralesionally into a palpable cord or plaque using a 1 mL syringe with 0.01 mL graduations with a 27-gauge 1/2-inch needle. If reconstituted solution is refrigerated, warm to room temperature for ~15 to 60 minutes before use. Refer to product labeling for additional administration details.
Dupuytren contracture: Divide dose into 3 injections; after correct needle placement, inject 1/3 of the dose, then reposition the needle in a distal location ~2 to 3 mm from the initial injection for the second injection (1/3 of the dose), followed by the final injection (1/3 of the dose) positioned ~2 to 3 mm proximal to the initial injection. To avoid tendon rupture when injecting a cord affecting a PIP joint of the fifth finger, needle insertion should not be >2 to 3 mm in depth or >4 mm distal to the palmar digital crease. Do not administer local anesthetic agent prior to administration due to possible interference with proper needle placement. When administering two injections in the same hand during a treatment, 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).
Peyronie disease: Local anesthetic may be administered prior to injection. The penis should be in a flaccid state before injection. The first injection should be into the plaque at the point of maximum concavity (or focal point) in the bend of the penis; second injection of each treatment cycle should be made ~2 to 3 mm apart from the first injection. Inject only into the plaque; avoid injection into the urethra, nerves, blood vessels, corpora cavernosa, or other collagen-containing structures of the penis to avoid damage to these structures and possible corporal rupture. Do not advance the needle beneath the plaque or perpendicularly towards the corpora cavernosum. Withdraw the needle slowly to deposit the full dose along the needle track within the plaque.
Prior to use, store lyophilized powder and diluent refrigerated at 2°C to 8°C (36°F to 46°F); do not freeze. Once reconstituted, may be stored at room temperature 20°C to 25°C (68°F to 77°F) for ≤1 hour or refrigerated 2°C to 8°C (36°F to 46°F) for ≤4 hours. Discard any unused reconstituted solution.
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy
Anticoagulants: May enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy
Cardiovascular: Peripheral edema (primarily as swelling of injected hand: 73% to 77%)
Dermatologic: Pruritus (4% to 15%), hemorrhagic blister (12%)
Hematologic & oncologic: Bruise (59% to 70%), lymphadenopathy (13%)
Immunologic: Antibody development (≥86%; neutralizing antibodies: AUX-I: 10%; AUX-II: 21%)
Local: Bleeding at injection site (6% to 38%), injection site reaction (35%; includes erythema, inflammation, irritation), swelling at injection site (5% to 24%), tenderness at injection site (24%), pain at injection site (14%)
Neuromuscular & skeletal: Limb pain (35% to 51%)
Miscellaneous: Laceration (9% to 22%)
1% to 10%:
Central nervous system: Lymph node pain (8%), axillary pain (6% to 7%)
Dermatologic: Erythema (6%), ecchymoses (5%)
Local: Hematoma at injection site (8%)
<1%, postmarketing, and/or case reports: Anaphylaxis, antibody development (IgE; increased with successive injections), causalgia, ligament disorder, pulley rupture, rupture of tendon, sensory disturbance, vasodepressor syncope
Genitourinary: Penile hematoma (66%; severe: 4% to 6%), penile swelling (55%), penile pain (45%), penile ecchymoses (15%), penile popping sensation (13%)
Immunologic: Antibody development (55% to >99%; neutralizing antibodies: AUX-I: 60%; AUX-II: 52%; no correlation to clinical response or adverse reaction)
1% to 10%:
Central nervous system: Procedural pain (2%), suprapubic pain (1%)
Dermatologic: Hemorrhagic blister (5%), genital pruritus (3%), skin discoloration (2%), localized vesiculation (injection site, 1%)
Genitourinary: Blisters on penis (3%), painful erection (3%), erectile dysfunction (2%), dyspareunia (1%)
Local: Itching at injection site (1% to 4%), localized edema (1%)
Miscellaneous: Nodule (1%)
<1%, postmarketing, and/or case reports: Penile fracture, sudden penile detumescence
Concerns related to adverse effects:
- Hypersensitivity reactions: Severe allergic reactions, including anaphylaxis, may occur in response to administration of foreign proteins (ie, collagenase). Health care providers should be prepared for the immediate treatment with epinephrine for any possible severe allergic reaction.
- Bleeding disorders: Avoid use in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except low-dose aspirin).
- Corporal rupture: Peyronie disease: [U.S. Boxed Warning]: Corporal rupture (penile fracture) was reported in 0.5% of patients in clinical studies; severe penile hematoma and a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was also reported. Signs or symptoms that may reflect serious penile injury should be promptly evaluated. Careful injection technique of collagenase into the Peyronie plaque is required to avoid inadvertent injection into the urethra, nerves, blood vessels, corpora cavernosa, or other collagen-containing structures of the penis.
- Tendon rupture: Dupuytren contracture: Administration may result in tendon rupture, ligament damage, or other serious injury (eg, pulley rupture, sensory and pain abnormalities, and skin lacerations); careful injection technique of collagenase into the Dupuytren cord is required to avoid inadvertent injection into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Skin laceration requiring skin graft after finger extension procedures has been reported. Signs or symptoms of serious injury to the injected hand or finger should be immediately evaluated; surgical intervention may be necessary.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Antibody formation: IgE-anti-drug antibodies commonly developed in treated patients, with higher frequencies and titers seen in patients treated with successive injections.
- Appropriate use: Only health care providers skilled in the treatment of Dupuytren contractures or Peyronie disease and appropriate injection procedures should administer treatment. Local anesthetic is not recommended prior to Dupuytren contracture treatment due to possible interference with proper needle placement.
- REMS program: Peyronie disease: [U.S. Boxed Warning]: Because of the risks of corporal rupture or other serious penile injury, collagenase is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX REMS Program. Prescribers and healthcare sites must be certified with the program. Call 1-877-313-1235 or visit www.Xiaflexrems.com for more information.
Range of motion (Dupuytren contracture); curvature deformity (Peyronie disease).
Pregnancy Risk Factor
Adverse events have not been observed in animal reproduction studies. Pharmacokinetic studies in humans did not show quantifiable systemic levels following intralesional injection into a Dupuytren cord; however, low levels were quantifiable in the plasma following administration into the penile plaque. IgE-anti-drug antibodies commonly develop in treated patients; effects to the fetus are unknown.
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience injection site pain or irritation, bruising, enlarged lymph nodes, or mild penile pain. Have patient report immediately to prescriber pain, bruising, or swelling of the penis; blood in the urine; difficult urination; unable to keep an erection; popping sound or feeling with an erect penis; signs of infection; chest pain; severe dizziness; passing out; severe swelling or pain in hands or feet; burning or numbness feeling; bleeding; injection site skin tears; or decreased mobility in finger (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.