Iruxol Simplex

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Iruxol Simplex uses


WARNING: CORPORAL RUPTURE 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, Iruxol Simplex is available for the treatment of Peyronie’s disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Iruxol Simplex REMS Program.

WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE’S DISEASE

See full prescribing information for complete boxed warning

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RECENT MAJOR CHANGES


1 INDICATIONS AND USAGE

Iruxol Simplex is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord.

Iruxol Simplex 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.

Iruxol Simplex is a combination of bacterial collagenases indicated for:

2 DOSAGE AND ADMINISTRATION

Dupuytren’s Contracture


Peyronie’s Disease (2.2)

2.1 Dosage and Administration for Dupuytren’s Contracture

Dosing Overview for Dupuytren’s Contracture

Iruxol Simplex should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren’s contracture.

Iruxol Simplex, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use . The dose of Iruxol Simplex is 0.58 mg per injection into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint . Each vial of Iruxol Simplex and sterile diluent should only be used for a single injection. If two joints on the same hand are to be treated during a treatment visit, separate vials and syringes should be used for each reconstitution and injection. Table 1 displays an overview of the volumes of sterile diluent for reconstitution and the reconstituted Iruxol Simplex solution to be used in the intralesional injection . Approximately 24 to 72 hours after injection, perform a finger extension procedure if a contracture persists to facilitate cord disruption .

1 The reconstituted Iruxol Simplex solution to be used in the intralesional injection contains 0.58 mg of Iruxol Simplex.

Note: The entire reconstituted Iruxol Simplex solution contains 0.9 mg of Iruxol Simplex.

Reconstituted Iruxol Simplex solution remaining in the vial after the injection should be discarded.

For cords affecting

MP joints

For cords affecting

PIP joints

Sterile Diluent for Reconstitution
Volume 0.39 mL 0.31 mL
Reconstituted Iruxol Simplex Solution to be Injected1
Volume 0.25 mL 0.20 mL

Four weeks after the Iruxol Simplex injection and finger extension procedure, if a MP or PIP contracture remains, the cord may be re-injected with a single dose of 0.58 mg of Iruxol Simplex and the finger extension procedure may be repeated (approximately 24 to 72 hours after injection). Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.

Perform up to two injections in the same hand according to the injection procedure during a treatment visit. Two palpable cords affecting two joints may be injected or one palpable cord affecting two joints in the same finger may be injected at two locations during a treatment visit. If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with Iruxol Simplex at other treatment visits approximately 4 weeks apart.

Reconstitution of the Lyophilized Powder for Dupuytren’s Contracture


Preparation Prior to Injection for Dupuytren’s Contracture


Injection Procedure for Dupuytren’s Contracture


Finger Extension Procedure for Dupuytren’s Contracture

2.2 Dosage and Administration for Peyronie’s Disease

Dosing Overview for Peyronie's Disease

Iruxol Simplex should be administered by a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of Iruxol Simplex in the treatment of Peyronie’s disease.

Iruxol Simplex, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use . The dose of Iruxol Simplex is 0.58 mg per injection administered into a Peyronie’s plaque. If more than one plaque is present, inject into the plaque causing the curvature deformity.

A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two Iruxol Simplex injection procedures and one penile modeling procedure . The second Iruxol Simplex injection procedure 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 six weeks. The treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures.

If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered.

The safety of more than one treatment course of Iruxol Simplex is not known.

Table 2 displays an overview of the volume of sterile diluent for reconstitution and the reconstituted Iruxol Simplex solution to be used in the intralesional injection .

1 The reconstituted Iruxol Simplex solution to be used in the intralesional injection contains 0.58 mg of Iruxol Simplex.
Note: The entire reconstituted Iruxol Simplex solution contains 0.9 mg of Iruxol Simplex.

Reconstituted Iruxol Simplex solution remaining in the vial after the injection should be discarded.

Sterile Diluent for Reconstitution
Volume 0.39 mL
Reconstituted Iruxol Simplex Solution to be Injected1
Volume 0.25 mL

Reconstitution of the Lyophilized Powder for Peyronie’s Disease


Identification of Treatment Area for Peyronie’s Disease


Injection Procedure for Peyronie’s Disease


Penile Modeling Procedure for Peyronie’s Disease

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 (as described below) on the flaccid penis to stretch and elongate the treated plaque:


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 as follows:

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3 DOSAGE FORMS AND STRENGTHS

Iruxol Simplex is supplied in single-use glass vials containing 0.9 mg of Iruxol Simplex 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.

Single-use glass vials containing 0.9 mg of Iruxol Simplex clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for reconstitution is also provided in a single-use glass vial. (3)

4 CONTRAINDICATIONS

Iruxol Simplex is contraindicated in:

5 WARNINGS AND PRECAUTIONS

5.1 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 Iruxol Simplex injection . Injection of Iruxol Simplex 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, Iruxol Simplex 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 .

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 Iruxol Simplex 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.

5.2 Corporal Rupture or Other Serious Injury to the Penis in the Treatment of Peyronie’s Disease

Corporal rupture was reported as an adverse reaction after Iruxol Simplex injections in 5 of 1044 (0.5%) Iruxol Simplex 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 Iruxol Simplex 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, Iruxol Simplex 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.

5.3 Iruxol Simplex REMS Program

Because of the risks of corporal rupture or other serious penile injury in the treatment of Peyronie’s disease, Iruxol Simplex is available only through the Iruxol Simplex REMS Program .

Required components of the Iruxol Simplex REMS Program include the following:


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

5.4 Hypersensitivity Reactions, IncludingAnaphylaxis

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 Iruxol Simplex 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 Iruxol Simplex injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered.

Because Iruxol Simplex contains foreign proteins, severe allergic reactions to Iruxol Simplex can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to Iruxol Simplex 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 Iruxol Simplex injections. Healthcare providers should be prepared to address severe allergic reactions following Iruxol Simplex injections.

5.5 Risk of bleeding in Patients with Abnormal Coagulation

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

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6 ADVERSE REACTIONS

The following serious adverse reactions in patients with Dupuytren’s contracture are discussed in greater detail elsewhere in the labeling:


The following serious adverse reactions in patients with Peyronie’s disease are discussed in greater detail elsewhere in the labeling:


Dupuytren’s Contracture (6.1)

The most common adverse reactions reported in ≥ 25% of patients treated with Iruxol Simplex and at an incidence greater than placebo were edema peripheral (e.g., swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the injected extremity.

Peyronie’s Disease (6.2)

The most frequently reported adverse drug reactions reported with ≥ 25% of patients treated with Iruxol Simplex and at an incidence greater than placebo were penile hematoma, penile swelling and penile pain.

To report SUSPECTED ADVERSE REACTIONS, contact Endo Pharmaceuticals Inc. at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 Iruxol Simplex in the controlled and uncontrolled portions of the Iruxol Simplex studies (2630 Iruxol Simplex 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 Iruxol Simplex 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 . These trials were comprised of 374 patients of whom 249 and 125 received 0.58 mg of Iruxol Simplex 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 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 Iruxol Simplex 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 Iruxol Simplex 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).

a Most of these events were swelling of the injected hand.
b Includes the terms: contusion (any body system) and ecchymosis
c Includes the terms: injection site reaction, injection site erythema, injection site inflammation, injection site irritation, injection site pain, and injection site warmth
d Includes the terms: injection site swelling and injection site edema
e Includes the terms: pruritus and injection site pruritus
f Includes the terms: lymphadenopathy and axillary mass
Adverse Reaction Iruxol Simplex

N=249

Placebo

N=125

All Adverse Reactions 98% 51%
Edema Peripherala 73% 5%
Contusionb 70% 3%
Injection Site Hemorrhage 38% 3%
Injection Site Reactionc 35% 6%
Pain in Extremity 35% 4%
Tenderness 24% 0%
Injection Site Swellingd 24% 6%
Prurituse 15% 1%
Lymphadenopathyf 13% 0%
Skin Laceration 9% 0%
Lymph Node Pain 8% 0%
Erythema 6% 0%
Axillary Pain 6% 0%

Some patients developed vasovagal syncope after finger extension procedures.

The safety of two concurrent injections of Iruxol Simplex 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 Iruxol Simplex 0.58 mg in the same hand (1450 Iruxol Simplex 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 Iruxol Simplex in the same hand through Day 60 in Study 3.

Adverse Reaction Iruxol Simplex

N=715

Subjects with ≥1 adverse reaction 95%
Edema peripheral 77%
Contusion 59%
Pain in extremity 51%
Laceration 22%
Pruritus 15%
Injection site pain 14%
Lymphadenopathy 13%
Blood blister 12%
Injection site hematoma 8%
Axillary pain 7%
Injection site hemorrhage 6%
Injection site swelling 5%
Ecchymosis 5%

Safety of Retreatment of Recurrent Contractures

An observational, open label study was conducted in subjects who had participated in Iruxol Simplex 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 Iruxol Simplex in Study 4 were retreated (Study 5). No new safety signals were identified among subjects who were retreated with Iruxol Simplex.

6.2 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 Iruxol Simplex in Peyronie’s disease, 1044 patients received a total of 7466 Iruxol Simplex injections.

Corporal Rupture and Other Serious Penile Injury


The data described below are based on two identical, pooled, randomized, double-blind, placebo-controlled, 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 Iruxol Simplex and placebo, respectively. In these trials, patients were given up to 4 treatment cycles of Iruxol Simplex or placebo. In each cycle, two injections of Iruxol Simplex 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 .

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 Iruxol Simplex 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.

a Includes: injection site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of subjects.
b Includes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection site edema.
c Includes: injection site pain, penile pain, and injection site discomfort.
d Includes: contusion, ecchymoses, penile hemorrhage, and injection site hemorrhage.
Adverse Reaction Iruxol Simplex

N=551

Placebo

N=281

All Adverse Reactions 84.2% 36.3%
Penile hematomaa 65.5% 19.2%
Penile swellingb 55.0% 3.2%
Penile painc 45.4% 9.3%
Penile ecchymosesd 14.5% 6.8%
Blood blister 4.5% 0
Penile blister 3.3% 0
Pruritus genital 3.1% 0
Painful erection 2.9% 0
Erectile dysfunction 1.8% 0.4%
Skin discoloration 1.8% 0
Procedural pain 1.6% 0.7%
Injection site vesicles 1.3% 0
Localized edema 1.3% 0
Dyspareunia 1.1% 0
Injection site pruritus 1.1% 0
Nodule 1.1% 0
Suprapubic pain 1.1% 0

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.

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

Iruxol Simplex was not associated with shortening of penile length in clinical trials in the treatment of Peyronie’s disease.

6.3 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 Iruxol Simplex (AUX-I and AUX-II).

In the Dupuytren’s contracture clinical studies (Studies 1 and 2), at 30 days post the first injection of Iruxol Simplex 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 Iruxol Simplex, 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 Iruxol Simplex. Among patients in Study 3 who reported no prior exposure to Iruxol Simplex, 97% of patients had antibodies against AUX-I and AUX-II after two concurrent doses of Iruxol Simplex 0.58 mg (total dose of 1.16 mg) in the same hand. In Study 5, treatment of recurrent contractures with Iruxol Simplex 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 Iruxol Simplex 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 Iruxol Simplex, >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 Iruxol Simplex (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 Iruxol Simplex clostridium histolyticum with the incidence of antibodies to other products may be misleading.

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7 DRUG INTERACTIONS

Anticoagulant drugs: Iruxol Simplex should be used with caution in patients receiving concomitant anticoagulants (except for low-dose aspirin) .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Iruxol Simplex in pregnant women. Because animal reproduction studies are not always predictive of human response, Iruxol Simplex should be used during pregnancy only if clearly needed.

Risk Summary

Based on animal data, Iruxol Simplex is not predicted to increase the risk for major developmental abnormalities in humans.

Human Data

Human pharmacokinetic studies showed that Iruxol Simplex levels were not quantifiable in the systemic circulation following injection into a Dupuytren’s cord.

Low levels of Iruxol Simplex were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of Iruxol Simplex into the penile plaque of subjects with Peyronie’s disease .

Almost all patients develop anti-product antibodies (anti-AUX-I and anti-AUX-II) after treatment with Iruxol Simplex, and the clinical significance of anti-product antibody formation on a developing fetus is not known .

Animal Data

Reproduction studies have been performed in rats with intravenous exposures up to approximately 11 times the maximum recommended human dose (MRHD) of Iruxol Simplex on a mg/m2 basis, and have revealed no evidence of impaired fertility or harm to the fetus due to Iruxol Simplex clostridium histolyticum.

8.3 Nursing Mothers

It is not known whether Iruxol Simplex clostridium histolyticum is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Iruxol Simplex is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of Iruxol Simplex in pediatric patients less than 18 years old have not been established.

8.5 Geriatric Use

Of the 249 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials in Dupuytren’s contracture (Studies 1 and 2), 104 (42%) were 65 years of age or older and 9% were 75 years of age or older. Of the 551 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials in Peyronie’s disease (Studies 1 and 2), 100 (18%) were 65 years of age or older and 5 (0.9 %) were 75 years of age or older. No overall differences in safety or effectiveness of Iruxol Simplex were observed between these patients and younger patients.

10 OVERDOSAGE

The effects of overdose of Iruxol Simplex are unknown. It is possible that multiple simultaneous or excessive doses of Iruxol Simplex 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.

11 DESCRIPTION

Iruxol Simplex contains purified Iruxol Simplex clostridium histolyticum, consisting of two microbial collagenases in a defined mass ratio, Iruxol Simplex AUX-I and Iruxol Simplex AUX-II, which are isolated and purified from the fermentation of Clostridium histolyticum bacteria.

Iruxol Simplex 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 Clostridium histolyticum collagenases.

Iruxol Simplex 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 Clostridium histolyticum collagenases.

Iruxol Simplex 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.

Iruxol Simplex is available in single-use, glass vials containing 0.9 mg of Iruxol Simplex clostridium histolyticum. Each vial also contains 0.5 mg of hydrochloric acid, 18.5 mg of sucrose, and 1.1 mg of tromethamine.

12 CLINICAL PHARMACOLOGY

12.1 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 Iruxol Simplex 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 Iruxol Simplex 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 .

Results of in vitro studies, including those of explant tissues containing Peyronie’s plaques, suggest that Iruxol Simplex 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 Iruxol Simplex in the treatment of Dupuytren’s contracture or Peyronie’s disease.

Collagen fragments generated from clostridial Iruxol Simplex 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.

12.3 Pharmacokinetics

Following administration of either a single injection of Iruxol Simplex 0.58 mg into a Dupuytren’s cord in 20 patients or two concurrent injections of Iruxol Simplex 0.58 mg into Dupuytren’s cords of 12 patients, no quantifiable levels of Iruxol Simplex (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 Iruxol Simplex 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 Iruxol Simplex 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).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of Iruxol Simplex clostridium histolyticum have not been conducted.

Mutagenesis

Purified Iruxol Simplex clostridium histolyticum was not mutagenic in Salmonella typhimurium and was not clastogenic in both an in vivo mouse micronucleus assay and an in vitro chromosomal aberration assay in human lymphocytes.

Impairment of Fertility

Iruxol Simplex clostridium histolyticum did not impair fertility and early embryonic development when administered intravenously in rats at exposures up to approximately 11 times the maximum recommended human dose (MRHD) on a mg/m2 basis.

13.2 Animal Toxicology and/or Pharmacology

Single or repeat-dose intravenous studies of Iruxol Simplex clostridium histolyticum in rats were conducted to evaluate the toxicological impact of injection of Iruxol Simplex clostridium histolyticum directly into the systemic circulation. Dose-dependent liver toxicity was noted at exposures greater than or equal to approximately 11 times the MRHD on a mg/m2 basis as characterized by elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, increased liver weights, mild regenerative anemia with secondary changes in the spleen and histologic findings of chronic active inflammation, hemorrhage/hematoma, fibrosis, bile duct hyperplasia and/or hepatocellular necrosis. The histologic findings remained unresolved following a 2-week recovery period, while the other findings resolved completely. Animals that were found dead or prematurely euthanized had histopathological findings of hemorrhage and necrosis in the liver and extramedullary hematopoiesis in the liver and/or spleen. Death occurred at approximately 25 times the MRHD on a mg/m2 basis between study days 7 and 15 following 8 repeat intravenous administrations of Iruxol Simplex clostridium histolyticum over 16 days or after single intravenous doses at approximately 40 times the MRHD on a mg/m2 basis.

In intermittent 13-week subcutaneous repeat-dose studies in rats or dogs administered doses up to approximately 3 times the MRHD on a mg/m2 basis, respectively, there was no evidence of systemic toxicity. In a single-dose phase or 61-day repeat-dose phase (3 times a week every 3 weeks for 3 cycles) study of intrapenile administration of Iruxol Simplex clostridium histolyticum in dogs at exposures lower than or equal to the MRHD on a mg/m2 basis, there was no evidence of systemic toxicity.

14 CLINICAL STUDIES

14.1 Dupuytren’s Contracture

The efficacy of 0.58 mg of Iruxol Simplex was evaluated in two randomized, double-blind, placebo-controlled, multi-centered trials in 374 adult patients with Dupuytren’s contracture. At study entry, patients must have had: (1) a finger flexion contracture with a palpable cord of at least one finger (other than the thumb) of 20° to 100° in a metacarpophalangeal (MP) joint or 20° to 80° in a proximal interphalangeal (PIP) joint and (2) a positive “table top test” defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. Patients could not have received a surgical treatment (e.g., fasciectomy, fasciotomy) on the selected primary joint within 90 days before the first injection of study medication and patients could not have received anticoagulation medication (except for up to 150 mg of aspirin per day) within 7 days before the first injection of study medication.

The cord affecting the selected primary joint received up to 3 injections of 0.58 mg of Iruxol Simplex or placebo on Days 0, 30, and 60. About 24 hours after each injection of study medication, if needed, the investigator manipulated (extended) the treated finger in an attempt to facilitate rupture of the cord (finger extension procedure). Following manipulation, patients were fitted with a splint, instructed to wear the splint at bedtime for up to 4 months, and instructed to perform a series of finger flexion and extension exercises each day.

Table 6 shows the baseline disease characteristics of patients with Dupuytren’s contracture in Studies 1 and 2.

1 Prior surgery for Dupuytren’s contracture included fasciotomy and fasciectomy
Study 1 Study 2
Proportion of patients with prior surgery for Dupuytren’s contracture1 38% 53%
Proportion of patients with prior surgery for Dupuytren’s contracture on the same finger as the primary joint1 8% 18%
Mean number of affected joints 3.0 3.3

In Studies 1 and 2, the primary endpoint was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to within 0° to 5° of normal, 30 days after the last injection of that joint on Days 30, 60, or 90 (after up to 3 injections). As shown in Table 7, a greater proportion of XIAFLEX-treated patients compared to placebo-treated patients achieved the primary endpoint.

a Patients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90).
b For XIAFLEX-treated patients, the mean (±SD) number of injections given to the cord associated with the contracture was 1.7 (±0.8) in the 90-day controlled period in each trial.
c MP joints are metacarpophalangeal joints
d PIP joints are proximal interphalangeal joints
e 95% confidence interval
Treated Joint Study 1 Study 2
Iruxol Simplexb Placebo Iruxol Simplexb Placebo
All Joints (MP and PIP)c,d

Difference (CIe)

N=203 N=103 N=45 N=21
64%

57% (47%, 67%)

7%

-

44%

40% (14%, 62%)

5%

-

MP Jointsc

Difference (CIe)

N=133 N=69 N=20 N=11
77%

69% (57%, 79%)

7%

-

65%

56% (19%, 83%)

9%

-

PIP Jointsd

Difference (CIe)

N=70 N=34 N=25 N=10
40%

34% (14%, 52%)

6%

-

28%

28% (-10%, 61%)

0%

-


The proportion of patients who achieved a contracture reduction of the primary joint to 0° to 5° after the first injection was 39% and 1% in Study 1 and 27% and 5% in Study 2 in the Iruxol Simplex and placebo groups respectively.

XIAFLEX-treated patients, compared to placebo-treated patients, showed a greater increase from baseline in the range of motion of MP and PIP joints.

aPatients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90). Baseline and final range of motion degree values are expressed in mean (SD).
bMP = Metacarpophalangeal joint
cPIP = Proximal interphalangeal joint
Range of Motion = Degrees of Full Flexion minus Degrees of Fixed Extension
Not all patients had range of motion values at both time points.
Treated Joint Study 1 Study 2
Iruxol Simplex Placebo Iruxol Simplex Placebo
All Joints b,c N=196 N=102 N=45 N=21
Baseline 44 (20) 45 (19) 40 (15) 44 (16)
Final 80 (20) 50 (22) 76 (18) 52 (20)
Increase 36 (21) 4 (15) 35 (18) 8 (15)
MP Joints b N=129 N=68 N=20 N=11
Baseline 43 (20) 46 (19) 40 (12) 41 (21)
Final 83 (16) 50 (21) 80 (11) 50 (22)
Increase 41 (20) 4 (13) 40 (13) 9 (15)
PIP Joints c N=67 N=34 N=25 N=10
Baseline 46 (20) 44 (18) 41 (18) 47 (10)
Final 75 (24) 49 (24) 73 (21) 54 (18)
Increase 28 (22) 5 (19) 32 (20) 7 (16)

Recurrence

A long term, observational, Year 2 to Year 5 follow-up study (Study 4) was undertaken to evaluate recurrence of contracture and long-term safety in subjects who received up to 8 single injections of Iruxol Simplex 0.58mg in a previous Phase 3 open-label or double-blind with open-label extension study. Of the 950 patients eligible for Study 4, only 645 patients enrolled. Of the 645 patients enrolled, 30% discontinued the study. Recurrence was assessed in successfully treated joints (i.e., subjects had a reduction in contracture to 5° or less at the Day 30 evaluation after the last injection of Iruxol Simplex in a previous study) and was defined as an increase in joint contracture by at least 20° in the presence of a palpable cord, or the joint underwent medical or surgical intervention primarily to correct a new or worsening Dupuytren’s contracture in that joint. Data on remaining recurrence free following successful treatment with Iruxol Simplex are provided in Figure 1.

Figure 1. Kaplan-Meier Plot Displaying Estimated Probability of Remaining Recurrence-Free over Time in the Observational Study 4 among Joints that were Successfully Treated in a Previous Study


Retreatment of Recurrent Contractures

Study 5 retreated a subset of patients from Study 4 for a joint that was previously successfully treated but had recurrence. Patients in Study 5 received up to 3 injections of Iruxol Simplex (0.58 mg). Of the 91patients eligible for Study 5, 52 patients enrolled. In Study 5, 65% of recurrent MP joints and 45% of recurrent PIP joints achieved clinical success after retreatment with up to three injections of Iruxol Simplex. There was no control group for comparison in Study 5.

Figure 1. Kaplan-Meier Plot Displaying Estimated Probability of Remaining Recurrence-Free over Time in the Observational Study 4 among Joints that were Successfully Treated in a Previous Study

14.2 Peyronie’s Disease

The efficacy of Iruxol Simplex was evaluated in two randomized, double-blind, placebo-controlled, multi-centered trials in 832 adult males with Peyronie’s disease (Studies 1 and 2). At study entry, patients must have had penile curvature deformity of at least 30 degrees in the stable phase of Peyronie’s disease. Patients were excluded if they had a ventral curvature deformity, an isolated hourglass deformity or a calcified plaque that could have interfered with the injection technique. At baseline, penile pain was either not present or was mild in most (98%) patients.

In these trials, patients were given up to 4 treatment cycles of Iruxol Simplex or placebo (weeks 0, 6, 12, 18), and were followed in a non-treatment follow-up period (weeks 24 -52). In each treatment cycle, two injections of Iruxol Simplex or two injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed on patients at the study site 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately six-week intervals for up to three additional times, for a maximum of 8 total injection procedures and 4 total modeling procedures. In addition, patients were instructed to perform penile modeling at home for six weeks after each treatment cycle .

Table 9 shows the baseline disease characteristics of patients with Peyronie’s disease in Studies 1 and 2.

a Subjects were from ITT population and received at least one dose of study drug in Study 1 or 2
b Each PDQ assessment required subjects to have had vaginal intercourse in the 3 months prior to completion
c Higher scores represent worse symptoms
Study 1 Study 2
Iruxol Simplex

N=277

Placebo

N=140

Iruxol Simplex

N=274

Placebo

N=141

Mean age (years) (Min-Max) 57.9

(28 - 79)

58.2

(30 - 81)

57.3

(23 - 84)

57.6

(33 - 78)

Mean duration of PD (years) (Min-Max) 3.9

(1.0 - 35.9)

4.8

(1.0 - 50.8)

4.2

(1.1 - 30.9)

3.4

(1.1 - 47.1)

Mean Penile Curvature Deformity (degrees) (Min-Max) 48.8

(30-90)

49.0

(30-89)

51.3

(30-90)

49.6

(30-85)

Peyronie’s Disease Questionnaire (PDQ) b, – Mean Patient-Reported PD Bother Score (range: 0-16) c 7.5 7.4 7.4 8.4
History of Erectile Dysfunction N (%) 128 (46.2) 75 (53.6) 134 (48.9) 76 (53.9)

Before the first dose of study drug was administered, eligible subjects were stratified by the degree of curvature deformity (30 to 60 degrees, and 61 to 90 degrees) and then randomized into two treatment groups to receive either Iruxol Simplex or placebo in a 2:1 ratio. The efficacy population (modified intent-to-treat (mITT) population) comprised a total of 612 intent-to-treat subjects who had both a curvature deformity measurement and a PDQ assessment at baseline, and at one or more subsequent time points in Studies 1 and 2, and had engaged in vaginal intercourse within 3 months prior to each PDQ assessment.

In Studies 1 and 2, the co-primary endpoints were:


The Bother domain score is a composite of the following patient-reported items: concern about erection pain, erection appearance, and the impact of Peyronie’s disease on intercourse and on frequency of intercourse.

Penile curvature deformity (co-primary endpoint)

Iruxol Simplex treatment significantly improved penile curvature deformity in patients with Peyronie’s disease compared with placebo. The improvement in curvature deformity was numerically similar among subjects with baseline curvature deformity from 30 to 60 degrees and those with curvature deformity from 61 to 90 degrees.

a Mean percent change, treatment difference, 95% CI, and p-value were based on an ANOVA model with factors for treatment, stratum of baseline penile curvature, and their interaction and using last observation carried forward (LOCF) in the modified intent-to-treat (mITT) population. The mITT population was defined as all randomized subjects who had both a penile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.
b p-value < 0.01
Study 1 Study 2
Iruxol Simplex

N=199

Placebo

N=104

Iruxol Simplex

N=202

Placebo

N=107

Baseline Mean (degrees) 48.8° 49.0° 51.3° 49.6°
Mean Percent Change a -35.0% -17.8% -33.2% -21.8%
Treatment Difference (95% CI) -17.2%b

(-26.7%, -7.6%)

-11.4% b

(-19.5%, -3.3%)


Figure 2. Mean Percent Change in Penile Curvature Deformity – Study 1

ANOVA model –adjusted values with factors for treatment, stratum of baseline penile curvature, and their interaction and using last observation carried forward (LOCF) in the modified intent-to-treat (mITT) population.

Figure 3. Mean Percent Change in Penile Curvature Deformity – Study 2

ANOVA model –adjusted values with factors for treatment, stratum of baseline penile curvature, and their interaction and using last observation carried forward (LOCF) in the modified intent-to-treat (mITT) population.

Peyronie’s Disease Questionnaire Bother domain score (co-primary endpoint)

Iruxol Simplex significantly reduced patient-reported bother associated with Peyronie’s disease compared with placebo. The reduction in the bother domain score was numerically similar between patient groups stratified by degree of baseline curvature deformity (30 to 60 degrees, and 61 to 90 degrees).

a Mean change, treatment difference, 95% CI, and p-value all based on an ANOVA model with factors for treatment, stratum of baseline penile curvature, and their interaction and using last observation carried forward (LOCF) in the modified intent-to-treat (mITT) population. The mITT population was defined as all randomized subjects who had both a penile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.
b p-value < 0.05.
Study 1 Study 2
Iruxol Simplex

N=199

Placebo

N=104

Iruxol Simplex

N=202

Placebo

N=107

Baseline Mean 7.5 7.4 7.4 8.2
Mean Change a -2.8 -1.6 -2.6 -1.5
Treatment Difference

(95% CI)

-1.2b

(-2.4, -0.03)

-1.1b

(-2.1, -0.002)


Figure 4. Mean Change in Patient-Reported Peyronie’s Disease Bother Domain Score – Study 1

ANOVA model –adjusted values with factors for treatment, stratum of baseline penile curvature, and their interaction and using last observation carried forward (LOCF) in the modified intent-to-treat (mITT) population.

Figure 5. Mean Change in Patient-Reported Peyronie’s Disease Bother Domain Score – Study 2

ANOVA model –adjusted values with factors for treatment, stratum of baseline penile curvature, and their interaction and using last observation carried forward (LOCF) in the modified intent-to-treat (mITT) population.

There were no clinically meaningful differences in the mean percent improvement in curvature deformity or mean reduction in the bother domain score following treatment with Iruxol Simplex based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use.

Figure 2. Mean Percent Change in Penile Curvature Deformity – Study 1 Figure 3. Mean Percent Change in Penile Curvature Deformity – Study 2 Figure 4. Mean Change in Patient-Reported Peyronie’s Disease Bother Domain Score – Study 1 Figure 5. Mean Change in Patient-Reported Peyronie’s Disease Bother Domain Score – Study 2

16 HOW SUPPLIED/STORAGE AND HANDLING

Iruxol Simplex is available in single-use, glass vials containing 0.9 mg of Iruxol Simplex 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.

NDC Number Package Size
66887-003-01 Single-use package:

1 carton containing a single-use vial of Iruxol Simplex and a single-use vial of sterile diluent

66887-003-02 Dual-Pack (two single-use packages):

1 box containing 2 cartons, each containing a single-use vial of Iruxol Simplex and a single-use vial of sterile diluent


Storage and Stability

Prior to reconstitution, the vials of Iruxol Simplex and diluent should be stored in a refrigerator at 2° to 8°C (36° to 46°F) . Do not freeze.

The reconstituted Iruxol Simplex 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 .

17 PATIENT COUNSELING INFORMATION

17.1 Patient Counseling for Dupuytren’s Contracture

Advise patients of the following:


After the Iruxol Simplex injections, instruct patients:


Following the finger extension procedure(s) and fitting patient with a splint, instruct patients:

17.2 Patient Counseling for Peyronie’s Disease

Advise patients of the following:


After the Iruxol Simplex injections, instruct the patient:


Provide the patient instructions on the appropriate technique to perform penile modeling activities at home, as described in “What You Need to Know About Iruxol Simplex Treatment for Peyronie's Disease: A Patient Guide”, and give the patient a copy.

Distributed by:

Endo Pharmaceuticals Inc.

Malvern, PA 19355

US License No. 1816

US Patent Nos. 7,811,560; RE39,941; and 6,022,539

118323

Medication Guide

XIAFLEX® (Zī a flex)

(collagenase clostridium histolyticum)

For injection, for intralesional use

Iruxol Simplex is approved for two uses: Dupuytren's contracture and Peyronie's disease. Information is provided separately for each use. Use for treating Dupuytren's contracture is described first, followed by use for treating Peyronie's disease.

Read this Medication Guide before you receive Iruxol Simplex for the treatment of Dupuytren’s contracture and each time you get an injection. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Iruxol Simplex for the treatment of Dupuytren’s contracture?

Iruxol Simplex can cause serious side effects, including:


Call your healthcare provider right away if you have any of these symptoms of an allergic reaction after an injection of Iruxol Simplex:


What is Iruxol Simplex?

Iruxol Simplex is a prescription medicine used to treat adults with Dupuytren’s contracture when a “cord” can be felt.

It is not known if Iruxol Simplex is safe and effective in children under the age of 18.

Who should not receive Iruxol Simplex?

Do not receive Iruxol Simplex if you:


Talk to your healthcare provider before receiving this medicine if you have any of these conditions.

What should I tell my healthcare provider before receiving Iruxol Simplex?

Before receiving Iruxol Simplex, tell your healthcare provider if you:


Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Using Iruxol Simplex with certain other medicines can cause serious side effects.

Especially tell your healthcare provider if you take:


Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How will I receive Iruxol Simplex?


What are the possible side effects of Iruxol Simplex?

Iruxol Simplex may cause serious side effects, including:


The most common side effects with Iruxol Simplex for the treatment of Dupuytren’s contracture include:


Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects with Iruxol Simplex. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Iruxol Simplex.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about Iruxol Simplex. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about Iruxol Simplex that is written for health professionals.

For more information, go to www. XIAFLEX.com or call 1-800-462-3636.

What are the ingredients in Iruxol Simplex?

Active ingredient: Iruxol Simplex clostridium histolyticum

Inactive ingredients: hydrochloric acid, sucrose, and tromethamine. The diluent contains: calcium chloride dihydrate in 0.9% sodium chloride

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Endo Pharmaceuticals Inc.

Malvern, PA 19355

US License No. 1816

US Patent Nos. 7,811,560 and RE39,941

118324

Approved: 07/2017

Medication Guide

Iruxol Simplex®(Zī a flex)

(collagenase clostridium histolyticum)

For injection, for intralesional use

Iruxol Simplex is approved for two uses: Dupuytren's contracture and Peyronie's disease. Information is provided separately for each use. Use for treating Dupuytren's contracture is described on the previous pages, and use for treating Peyronie's disease is described below.

Read this Medication Guide before you receive Iruxol Simplex for the treatment of Peyronie’s disease and each time you get an injection. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment.

Your healthcare provider will also talk to you about receiving Iruxol Simplex for the treatment of Peyronie’s disease using the “What You Need to Know About Iruxol Simplex Treatment for Peyronie’s Disease: A Patient Guide”. You can ask your healthcare provider for a copy of the Patient Guide.

What is the most important information I should know about Iruxol Simplex for the treatment of Peyronie’s disease?

Iruxol Simplex can cause serious side effects, including:


What is Iruxol Simplex?

Iruxol Simplex is a prescription medicine used to treat adult men with Peyronie’s disease who have a “plaque” that can be felt and a curve in their penis greater than 30 degrees when treatment is started.

It is not known if Iruxol Simplex is safe and effective in children under the age of 18.

Who should not receive Iruxol Simplex?

Do not receive Iruxol Simplex if you:


Talk to your healthcare provider before receiving this medicine if you have any of these conditions.

What should I tell my healthcare provider before receiving Iruxol Simplex?

Before receiving Iruxol Simplex, tell your healthcare provider if you:


Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Using Iruxol Simplex with certain other medicines can cause side effects.

Especially tell your healthcare provider if you take:


Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How will I receive Iruxol Simplex?


Tell your healthcare provider right away if you have trouble stretching or straightening your penis, or if you have pain or other concerns.

How to gently stretch your penis:

Gently stretch your penis 3 times a day. Only stretch your penis if your penis is not hard (erect).


(Figure A)

How to gently straighten your penis:

Gently straighten your penis 1 time a day. Only straighten your penis if you have an erection that happens without any sexual activity (spontaneous erection). Bending your penis should not cause any pain or discomfort.


(Figure B)

What are the possible side effects of Iruxol Simplex?

Iruxol Simplex can cause serious side effects, including:

See “What is the most important information I should know about Iruxol Simplex?”


The most common side effects with Iruxol Simplex for the treatment of Peyronie’s disease include:


Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects with Iruxol Simplex. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Iruxol Simplex.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about Iruxol Simplex. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider for information about Iruxol Simplex that is written for health professionals.

For more information, go to www. XIAFLEX.com or call 1-800-462-3636.

What are the ingredients in Iruxol Simplex?

Active ingredient: Iruxol Simplex clostridium histolyticum

Inactive ingredients: hydrochloric acid, sucrose, and tromethamine. The diluent contains: calcium chloride dihydrate in 0.9% sodium chloride

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Endo Pharmaceuticals Inc.

Malvern, PA 19355

US License No. 1816

US Patent Nos. 7,811,560 and 6,022,539

118324

Approved: 07/2017

Figure A Figure B

Package Label - Principal Display Panel – 3 mL Vial, Sterile Diluent


Sterile Diluent Vial Image

Package Label - Principal Display Panel – 0.9 mg Vial, Iruxol Simplex for Injection


Drug Product Vial Image

Package Label - Principal Display Panel – Single-Pack Carton


Carton Image

Iruxol Simplex pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Iruxol Simplex available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Iruxol Simplex destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Iruxol Simplex Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Iruxol Simplex pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. "Collagenase". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
  2. "Collagenase clostridium histolyticum - DrugBank". http://www.drugbank.ca/drugs/DB0004... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Iruxol Simplex?

Depending on the reaction of the Iruxol Simplex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Iruxol Simplex not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Iruxol Simplex addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Iruxol Simplex, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Iruxol Simplex consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

Two visitors reported doses

What is the dose of Iruxol Simplex drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 11-50mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
11-50mg2
100.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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