Xiaflex

Black Box Warnings

Corporal rupture (penile fracture) was reported as adverse reaction in clinical trials

Promptly evaluate signs or symptoms reflecting serious penile injury to assess for corporal rupture or severe penile hematoma which may require surgical intervention

Because of risks of corporal rupture or other serious penile injury, available for the treatment of Peyronie’s disease only through the XIAFLEX REMS Program

Contraindications

Hypersensitivity

Plaques that involve the penile urethra

Cautions

Pruritus experienced especially after more injections

Use with caution in patients with coagulation disorders, including in patients who have received anticoagulant medications other than low- dose aspirin within 7 days of the injection

Administration in patients with abnormal coagulation may result in ecchymosis/contusion or an injection site hemorrhage

Safety and efficacy when coadministered with anticoagulants (other than low-dose aspirin up to 150 mg/day) within 7 days of administration is unknown

Dupuytren contracture

• Tendon rupture of other serious injury to the injected extremity reported in clinical trials; avoid injecting XIAFLEX into tendons, nerves, blood vessels, or other collagen-containing structure of the hand
• Healthcare providers should be prepared to address hypersensitivity reactions, including anaphylaxis, following XIAFLEX injections
• Incidence of skin laceration (22%) was higher when treating 2 concurrent injections compared with up to 3 single injections in the placebo-controlled premarketing trials (9%)

Peyronie Disease

• The patient should not have sex between first and second injections of treatment cycle; patient should wait two weeks after second injection of treatment cycle before resuming sexual activity, provided pain and swelling have subsided
• May cause corporal rupture (penile fracture) or other serious injury to penis; avoid injecting into urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis since may result in possible permanent injury (eg, corporal rupture)
• If patient experiences severe pain or swelling of the penis, severe purple bruising and swelling of the penis, difficulty urinating or blood in the urine, sudden loss of ability to maintain an erection, should contact health care provider

Yes.

The most common adverse reactions of Xiaflex are:

• fluid retention (swelling of the injected hand),
• contusion (bruising),
• injection site bleeding,
• injection site swelling,
• pain in the treated hand, and
• tenderness.

Tendon rupture or other serious injury to the injected hand may occur. Allergic reactions and development of antibodies to Xiaflex also may occur.

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.

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 [see WARNINGS AND PRECAUTIONS]

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 [see WARNINGS AND PRECAUTIONS]
• 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 [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience In Patients With Dupuytren's Contracture

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Out of 1082 patients who received 0.58 mg of XIAFLEX in the controlled and uncontrolled portions of the XIAFLEX studies (2630 XIAFLEX injections), 3 (0.3%) patients had a flexor tendon rupture of the treated finger within 7 days of the injection.

The data described below are based on two pooled randomized, double-blind, placebo-controlled trials through Day 90 in patients with Dupuytren's contracture (Studies 1 and 2). In these trials, patients were treated with up to 3 injections of 0.58 mg of XIAFLEX or placebo with approximately 4-week intervals between injections and the patients had finger extension procedures the day after injection, if needed, to facilitate disruption of the cord [see Clinical Studies]. These trials were comprised of 374 patients of whom 249 and 125 received 0.58 mg of XIAFLEX and placebo, respectively. The mean age was 63 years, 80% were male and 20% were female, and 100% were white.

In the placebo-controlled portions of Studies 1 and 2 through Day 90, 98% and 51% of XIAFLEXtreated and placebo-treated patients had an adverse reaction after up to 3 injections, respectively. Over 95% of XIAFLEX-treated patients had an adverse reaction of the injected extremity after up to 3 injections. Approximately 81% of these local reactions resolved without intervention within 4 weeks of XIAFLEX injections. The adverse reaction profile was similar for each injection, regardless of the number of injections administered. However, the incidence of pruritus increased with more injections [see WARNINGS AND PRECAUTIONS].

The most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials in patients with Dupuytren's contracture included edema peripheral (mostly swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the treated extremity. Table 3 shows the incidence of adverse reactions that were reported in greater than or equal to 5% of XIAFLEX-treated patients and at a frequency greater than placebo-treated patients after up to 3 injections in the pooled placebo-controlled trials through Day 90 (Studies 1 and 2).

Table 3: Adverse Reactions Occurring in ≥ 5% of XIAFLEX-Treated Patients with Dupuytren's Contracture and at a Greater Incidence than Placebo in the Placebo- Controlled Trials Through Day 90 After Up to 3 Injections

Some patients developed vasovagal syncope after finger extension procedures.

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

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

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

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

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

Clinical Studies Experience In Patients With Peyronie's Disease

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

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

• Corporal rupture 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 [see ADVERSE REACTIONS].

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

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

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

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

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

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

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

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

Immunogenicity

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

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

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

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

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

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to collagenase clostridium histolyticum with the incidence of antibodies to other products may be misleading.

Read the entire FDA prescribing information for Xiaflex (Collagenase Clostridium Histolyticum)

Treatment of Dupuytren’s Contracture

• Your healthcare provider will inject Xiaflex into the cord that is causing your finger to bend.
• After an injection of Xiaflex, your affected hand will be wrapped with a bandage. You should limit moving and using the treated finger after the injection.
• Do not bend or straighten the fingers of the injected hand until your healthcare provider says it is okay. This will help prevent the medicine from leaking out of the cord.
• Do not try to straighten the treated finger yourself.
• Keep the injected hand elevated until bedtime.

Call your healthcare provider right away if you have:

• signs of infection after your injection, such as fever, chills, increased redness, or swelling
• numbness or tingling in the treated finger
• trouble bending the injected finger after the swelling goes down

Return to your healthcare provider’s office as directed on the day after your injection. During this first follow-up visit, if you still have the cord, your healthcare provider may try to extend the treated finger to “break” the cord and try to straighten your finger. Your healthcare provider will provide you with a splint to wear on the treated finger.

• Wear the splint as instructed by your healthcare provider at bedtime to keep your finger straight.
• Do finger exercises each day, as instructed by your healthcare provider.
• Follow your healthcare provider’s instructions about when you can start doing your normal activities with the injected hand.

Treatment of Peyronie's Disease

A treatment course for Peyronie’s disease consists of a maximum of four treatment cycles. Each treatment cycle consists of two Xiaflex injection procedures (in which it is injected directly into the collagen-containing structure of the penis) and one penile modeling procedure performed by the health care professional.

Call your doctor for instructions if you miss an appointment for your collagenase clostridium histolyticum injection.

Use Xiaflex as ordered by your doctor. Read all information given to you. Follow all instructions closely.

For all patients taking Xiaflex (collagenase (systemic)):

• It is given as a shot.
• Your doctor will give Xiaflex.

Dupuytren's contracture:

• Do not bend or straighten the fingers of your treated hand until your doctor tells you it is okay.
• Do not try to straighten your treated finger.
• Keep your treated hand raised until bedtime on the first day.
• You will need to go back to your doctor's office the next day.
• You will be given a splint to wear on the treated finger at bedtime for up to 4 months.
• Do your finger exercises each day.
• Do not start normal actions with the treated hand until doctor tells you it is okay.

Peyronie's disease:

• Your doctor will give you a patient guide that tells you how to stretch and form your penis at home. Read it carefully.
• Follow how and when to stretch your penis after each cycle as your doctor has told you.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Tendon Rupture or Other Serious Injury to the Injected Finger/Hand in the Treatment of Dupuytren’s Contracture

In the controlled and uncontrolled portions of clinical trials in Dupuytren’s contracture, flexor tendon ruptures occurred after Xiaflex injection [see Adverse Reactions (6.1)]. Injection of Xiaflex into collagen-containing structures such as tendons or ligaments of the hand may result in damage to those structures and possible permanent injury such as tendon rupture or ligament damage. Therefore, Xiaflex should be injected only into the collagen cord with a MP or PIP joint contracture, and care should be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. When injecting a cord affecting a PIP joint of the fifth finger, the needle insertion should not be more than 2 to 3 mm in depth and avoid injecting more than 4 mm distal to the palmar digital crease [see Dosage and Administration (2.1)].

Other Xiaflex-associated serious local adverse reactions included pulley rupture, ligament injury, complex regional pain syndrome (CRPS), sensory abnormality of the hand, and skin laceration (tear). In a historically controlled post-marketing trial, the incidence of skin laceration (22%) was higher for subjects treated with two concurrent injections of Xiaflex compared with subjects treated with up to three single injections in the placebo-controlled premarketing trials (9%). Cases of skin laceration requiring skin graft after finger extension procedures have been reported post-marketing. Signs or symptoms that may reflect serious injury to the injected finger/hand should be promptly evaluated because surgical intervention may be required.

Corporal Rupture (Penile Fracture) or Other Serious Injury to the Penis in the Treatment of Peyronie’s Disease

Corporal rupture was reported as an adverse reaction after Xiaflex injections in 5 of 1044 (0.5%) Xiaflex treated patients in the controlled and uncontrolled clinical trials in Peyronie’s disease.

In other Xiaflex-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture can not be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown.

Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie’s disease [see Adverse Reactions (6)].

Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to assess for corporal rupture or severe penile hematoma, which may require surgical intervention.

Injection of Xiaflex into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, Xiaflex should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis.

Xiaflex REMS Program

Because of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie’s disease, Xiaflex is available only through the Xiaflex REMS Program [see Warnings and Precautions (5.2)].

Required components of the Xiaflex REMS Program include the following:

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

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

Hypersensitivity Reactions, Including Anaphylaxis

In the controlled portions of the clinical trials in Dupuytren’s contracture (Studies 1 and 2), a greater proportion of Xiaflex-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of Xiaflex-associated pruritus increased after more Xiaflex injections in patients with Dupuytren’s contracture.

In the double-blind, placebo-controlled portions of the clinical trials in Peyronie’s disease (Studies 1 and 2), a greater proportion of Xiaflex-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 Xiaflex injection procedures). The incidence of Xiaflex-associated pruritus was similar after each injection regardless of the number of injections administered.

Because Xiaflex contains foreign proteins, severe allergic reactions to Xiaflex can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to Xiaflex for the treatment of Dupuytren’s contracture. Some patients with Dupuytren’s contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive Xiaflex injections. Healthcare providers should be prepared to address severe allergic reactions following Xiaflex injections.

Risk of bleeding in Patients with Abnormal Coagulation

In the Xiaflex trials in Dupuytren’s contracture (Studies 1 and 2), 70% and 38% of Xiaflex-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively (see Table 3). In the Xiaflex controlled trials in Peyronie’s disease (Studies 1 and 2), 65.5% of Xiaflex-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis (see Table 4). Patients with abnormal coagulation (except for patients taking low-dose aspirin, e.g., up to 150 mg per day) were excluded from participating in these studies.

Therefore, the efficacy and safety of Xiaflex in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to Xiaflex administration is not known. In addition, it is recommended to avoid use of Xiaflex in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin).

Mechanism of Action

Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiological conditions, resulting in lysis of collagen deposits.

Injection of Xiaflex into a Dupuytren’s cord, which is comprised mostly of collagen, may result in enzymatic disruption of the cord.

The signs and symptoms of Peyronie’s disease are caused by a collagen plaque. Injection of Xiaflex into a Peyronie’s plaque, which is comprised mostly of collagen, may result in enzymatic disruption of the plaque. Following this disruption of the plaque, penile curvature deformity and patient bother caused by Peyronie’s disease are reduced [see Clinical Studies (14.2)].

Results of in vitro studies, including those of explant tissues containing Peyronie’s plaques, suggest that Xiaflex disrupts the predominant collagen found in plaques (Types I and III). At higher doses and longer incubation times, non-fibrillar Type IV collagen was affected causing collagen lysis in small veins, but did not cause structural damage to arteries, nerves or large veins which contain Type IV collagen in in vitro or in vivo studies.

Results of in vitro studies suggest that the collagenases (AUX-I and AUX-II) worked synergistically to provide hydrolyzing activity towards collagen. However, there are no clinical data regarding the relative contributions of the individual collagenases (AUX-I or AUX-II) to the efficacy of Xiaflex in the treatment of Dupuytren’s contracture or Peyronie’s disease.

Collagen fragments generated from clostridial collagenase have been shown to generate increased vascular permeability, inflammatory responses, and regenerative changes. However, the effects of the formation of the collagen fragments derived from the collagen plaque are unknown.

Pharmacokinetics

Following administration of either a single injection of Xiaflex 0.58 mg into a Dupuytren’s cord in 20 patients or two concurrent injections of Xiaflex 0.58 mg into Dupuytren’s cords of 12 patients, no quantifiable levels of Xiaflex (AUX-I or AUX-II) were detected in plasma up to 30 days post injection.

Following each of two intralesional administrations, separated by 24 hours, of Xiaflex 0.58 mg into the penile plaque of 19 subjects with Peyronie’s disease, plasma levels 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 <29 ng/mL and <71 ng/mL, respectively, and were observed approximately within 10 minutes after injection. All plasma levels were below the limits of quantification within 30 minutes following dosing. There was no evidence of accumulation following two sequential injections of Xiaflex administered 24 hours apart. No subject had quantifiable plasma levels 15 minutes after modeling of plaque on Day 3 (i.e., 24 hours after Injection 2 on Day 2).

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.

Storage and Stability
Prior to reconstitution, the vials of Xiaflex and diluent should be stored in a refrigerator at 2° to 8°C (36° to 46°F) [see Dosage and Administration (2.1, 2.2)]. Do not freeze.

The reconstituted Xiaflex solution can be kept at room temperature (20° to 25°C/68° to 77°F) for up to one hour or refrigerated at 2° to 8°C (36° to 46°F) for up to 4 hours prior to administration [see Dosage and Administration (2.1, 2.2)].