Brand Name
Xiaflex
Generic Name
Histolyticum
View Brand Information FDA approval date: February 22, 2010
Form: Kit
What is Xiaflex (Histolyticum)?
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. XIAFLEX is a combination of bacterial collagenases indicated for: The treatment of adult patients with Dupuytren’s contracture 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
Approved To Treat
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Brand Information
XIAFLEX (collagenase clostridium histolyticum)
WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OROTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE’S DISEASE
Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX-treated patients in clinical studies. 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. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX-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, XIAFLEX is available for the treatment of Peyronie’s disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX REMS Program
1INDICATIONS AND USAGE
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.
2DOSAGE FORMS AND STRENGTHS
XIAFLEX is supplied in single-use glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for reconstitution is provided in the package in a single-use glass vial containing 3 mL of 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride.
3CONTRAINDICATIONS
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
4ADVERSE REACTIONS
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
4.1Clinical 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
In the placebo-controlled portions of Studies 1 and 2 through Day 90, 98% and 51% of XIAFLEX-treated 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).
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.
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.
4.2Clinical 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, placebo-controlled, multicenter 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 3 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.
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.
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.
4.3Immunogenicity
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 5 years more than 90% 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.
4.4Postmarketing Experience
The following adverse reactions have been identified during post-approval use of XIAFLEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Acute Lower Back Pain Reactions
Reports of acute lower back pain reactions, sometimes accompanied by radiation of pain to the lower extremities, chest and arms, muscle spasms, chest pain, paresthesias and dyspnea, have been received involving patients treated with XIAFLEX for Peyronie’s disease. Some patients have also experienced temporary gait instability and an inability to ambulate for brief periods of time post injection. These events have occurred in close temporal proximity to XIAFLEX treatments. During retreatment injections with XIAFLEX, cases of recurrent acute lower back pain reactions have been reported. These events can be mild to severe in intensity. The events typically resolved within 15 minutes, but some lasted up to 30 minutes, and one event lasted 1.5 hours. The events typically did not require intervention, but some required observation and treatment with analgesics. The events typically resolved without sequelae, but in one event, pain improved but did not resolve at the time of final report.
Skin and Soft Tissue Necrosis Events
Reports of localized skin and soft tissue necrosis, occurring as sequelae of penile hematoma, have been received in patients treated with XIAFLEX for Peyronie’s disease. Some of the cases required surgical intervention.
Syncope and Presyncope
Cases of syncope and presyncope have been reported in the postmarketing period in patients treated with XIAFLEX. Potential triggers for the syncopal events, including post-procedure pain, suggest a vasovagal mechanism. Most, but not all the cases, occurred in the immediate treatment period or within 1 to 2 days following injection. Bodily injuries, including concussion, head abrasion, and other accidental injuries, have been reported in association with the syncopal events.
5DRUG INTERACTIONS
Anticoagulant drugs: XIAFLEX should be used with caution in patients receiving concomitant anticoagulants (except for low-dose aspirin)
6OVERDOSAGE
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.
7DESCRIPTION
XIAFLEX contains purified collagenase clostridium histolyticum, consisting of two microbial collagenases in a defined mass ratio, Collagenase AUX-I and Collagenase AUX-II, which are isolated and purified from the fermentation of
Collagenase AUX-I is a single polypeptide chain consisting of approximately 1000 amino acids of known sequence. It has an observed molecular weight of 114 kiloDaltons (kDa). It belongs to the class I
Collagenase AUX-II is a single polypeptide chain consisting of approximately 1000 amino acids of deduced sequence. It has an observed molecular weight of 113 kDa. It belongs to the class II
XIAFLEX is supplied as a sterile lyophilized powder (white cake) intended for reconstitution with the supplied sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride) prior to intralesional injection into a Dupuytren’s cord or a Peyronie’s plaque.
XIAFLEX is available in single-use, glass vials containing 0.9 mg of collagenase clostridium histolyticum. Each vial also contains 0.5 mg of hydrochloric acid, 18.5 mg of sucrose, and 1.1 mg of tromethamine.
8HOW SUPPLIED/STORAGE AND HANDLING
XIAFLEX is available in single-use, glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder.
Sterile diluent for reconstitution is available in single-use, glass vials containing 3 mL of 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride.
9PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (
9.1Patient 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 1 to 3 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.
9.2Patient Counseling for Peyronie’s Disease
Advise patients of the following:
- Serious complications of XIAFLEX injection include corporal rupture, penile hematoma and skin and soft tissue necrosis related to penile hematoma, and these events may require surgery to correct the complication.
- Acute post-injection back pain reactions have been reported in patients treated with XIAFLEX. Back pain may be mild to severe and may radiate to the legs, chest and arms, may include spasms, and may make walking difficult. Events typically resolve within 15 minutes but may last longer. Patients should report post-injection back pain reactions to their healthcare provider.
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 4 weeks after the second injection of a treatment cycle before resuming sexual activity, provided pain and swelling have subsided
- To perform gentle, at home modeling activities, as recommended by their physician
- To refrain from using a vacuum erection device during treatment with XIAFLEX
- To avoid abdominal straining associated with situations, such as straining during bowel movements
Provide the patient instructions on the appropriate technique to perform penile modeling activities at home, as described in
Manufactured by:Endo USA
Rochester, MI 48307
Rochester, MI 48307
US License No. 1816
US Patent Nos. 7,811,560; RE39,941; and 6,022,539
© 2024 Endo, Inc. or one of its affiliates.
Revised: 04/2024