коллагеназа кк 250 ед

Overdose

Administration of Коллагеназа КК 250 ЕД at greater than recommended doses is expected to be associated with increased local reactions at the site of injection. Routine supportive care and symptomatic treatment must be provided in the case of overdose.

The effects of overdose of Коллагеназа КК 250 ЕД are unknown. It is possible that multiple simultaneous or excessive doses of Коллагеназа КК 250 ЕД 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.

The effects of overdose of XIAFLEX are unknown. It is possible that multiple simultaneous or excessive doses of XIAFLEX may cause more severe local effects than the recommended doses including serious adverse reactions in the injected area (e.g., tendon ruptures or corporal ruptures dependent on the injection site). Supportive care and symptomatic treatment are recommended in these circumstances.

Contraindications

Treatment of Peyronie's plaques that involve the penile urethra due to potential risk to this structure.

Коллагеназа КК 250 ЕД is contraindicated in:

• the treatment of Peyronie's plaques that involve the penile urethra due to potential risk to this structure.
• patients with a history of hypersensitivity to Коллагеназа КК 250 ЕД or to collagenase used in any other therapeutic application or application method.

XIAFLEX is contraindicated in:

• the treatment of Peyronie's plaques that involve the penile urethra due to potential risk to this structure.
• patients with a history of hypersensitivity to XIAFLEX or to collagenase used in any other therapeutic application or application method.

Undesirable effects

Dupuytren's contracture

Summary of the safety profile

The most frequently reported adverse reactions during the Коллагеназа КК 250 ЕД clinical studies (272 of 409 patients received up to three single injections of Коллагеназа КК 250 ЕД and 775 patients received two concurrent injections in the same hand) were local injection site reactions such as oedema peripheral (local to the injection site), contusion (including ecchymosis), injection site haemorrhage and injection site pain. Injection site reactions were very common, occurring in the vast majority of patients, were mostly mild to moderate in severity and generally subsided within 1-2 weeks post injection. Serious adverse reactions of tendon rupture (6 cases), tendonitis (1 case), other ligament injury (2 cases) and complex regional pain syndrome (1 case) related to the medicinal product were reported. Anaphylactic reaction was reported in a patient previously treated with Коллагеназа КК 250 ЕД (1 case).

Tabulated list of adverse reactions

Table 1 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (>1/10), common (>1/100 to <1/10), and uncommon (>1/1,000 to <1/100). Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme are those that occurred in the Phase 3 double blind placebo controlled studies for the treatment of Dupuytren's contracture in adult patients with a palpable cord (AUX-CC-857, AUX-CC-859) and the post-marketing clinical studies (AUX-CC-864, AUX-CC-867) for two concurrent injections in the same hand.

Table 1: Tabulated list of adverse reactions.

a reported with a higher incidence (very common) in patients who received two concurrent injections of Коллагеназа КК 250 ЕД in the same hand compared with subjects treated with up to three single injections in the Phase 3 placebo-controlled pivotal studies in Dupuytren's contracture.

b “skin laceration” includes “injection site laceration” and “laceration”

c “oedema peripheral” includes “injection site oedema” and “oedema”

The incidence of skin laceration (29.1%) was higher for subjects treated with two concurrent injections of Коллагеназа КК 250 ЕД in historically-controlled clinical study AUX-CC-867 compared with subjects treated with up to three single injections in the Phase 3 placebo-controlled pivotal studies in Dupuytren's contracture (CORD I and CORD II) (8.8%). The majority of the skin lacerations occurred on the manipulation day. A higher incidence of skin laceration may be attributable to more vigorous finger extension procedures in patients after receiving anaesthesia to the hand. In Study AUX-CC-867, most (85%) subjects received local anaesthesia prior to the finger extension procedure.

There were no other clinically relevant differences between two concurrent injections of Коллагеназа КК 250 ЕД in the same hand and up to three single injections of Коллагеназа КК 250 ЕД in the types of adverse events reported (i.e., most adverse events were local to the treated extremity and of mild or moderate intensity).

The overall safety profile was similar regardless of the timing of the post-injection finger extension procedure (i.e., 24 hours, 48 hours, and >72 hours after injection) among patients who received two concurrent injections of Коллагеназа КК 250 ЕД in Study AUX-CC-867.

Peyronie's disease

Summary of the safety profile

The overall safety profile was similar in the two Phase 3 double-blind placebo controlled studies (832 male patients, 551 patients received Коллагеназа КК 250 ЕД) and in an open-label Phase 3 study (189 male patients) of patients who had previously received placebo in the controlled studies. In the two Phase 3 double-blind placebo controlled studies, 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%) during the Коллагеназа КК 250 ЕД controlled clinical studies were penile haematoma, penile swelling and penile pain. Severe penile haematoma including severe injection site haematoma were reported with the frequency very common.

In the controlled and uncontrolled clinical studies of Коллагеназа КК 250 ЕД in Peyronie's disease corporal rupture and other serious penile injury were reported uncommonly

A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking” and sometimes accompanied by detumescence, haematoma and/or pain, were reported in 73/551 (13.2%) Коллагеназа КК 250 ЕД-treated patients and 1/281 (0.3%) placebo-treated patients, in Studies 1 and 2 combined.

Tabulated list of adverse reactions

Table 2 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), and not known: cannot be estimated from the available data. Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme are those that occurred in the Phase 3 double-blind placebo controlled studies.

Table 2: Tabulated list of adverse reactions.

a Includes: injection site haematoma and penile haematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of patients.

b Includes: injection site swelling, penile oedema, penile swelling, local swelling, scrotal swelling, and injection site oedema.

c Includes: injection site pain, penile pain, and injection site discomfort.

d Includes: contusion, ecchymosis, penile haemorrhage, and injection site haemorrhage.

∗ reported from a post-marketing clinical study in a patient who had previous exposure to Коллагеназа КК 250 ЕД for the treatment of Dupuytren's contracture.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

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

• Tendon ruptures or other serious injury to the injected extremity

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

• Corporal rupture (penile fracture) and severe penile hematoma
• In other Коллагеназа КК 250 ЕД-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

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 Коллагеназа КК 250 ЕД in the controlled and uncontrolled portions of the Коллагеназа КК 250 ЕД studies (2630 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕДtreated and placebo-treated patients had an adverse reaction after up to 3 injections, respectively. Over 95% of Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 0.58 mg in the same hand (1450 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД-treated patients after two concurrent injections of Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД in Study 3

An observational, open label study was conducted in subjects who had participated in Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД in Study 4 were retreated (Study 5). No new safety signals were identified among subjects who were retreated with Коллагеназа КК 250 ЕД.

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 Коллагеназа КК 250 ЕД in Peyronie's disease, 1044 patients received a total of 7466 Коллагеназа КК 250 ЕД injections.

• Corporal rupture was reported as an adverse reaction after Коллагеназа КК 250 ЕД injections in 5 of 1044 (0.5%) Коллагеназа КК 250 ЕД treated patients.
• In other Коллагеназа КК 250 ЕД-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown.
• Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie's disease.

The data described below are based on two identical, pooled, randomized, double-blind, 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 Коллагеназа КК 250 ЕД and placebo, respectively. In these trials, patients were given up to 4 treatment cycles of Коллагеназа КК 250 ЕД or placebo. In each cycle, two injections of Коллагеназа КК 250 ЕД 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% Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД-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%) Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use.

Коллагеназа КК 250 ЕД was not associated with shortening of penile length in clinical trials in the treatment of Peyronie's disease.

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 Коллагеназа КК 250 ЕД (AUX-I and AUX-II).

In the Dupuytren's contracture clinical studies (Studies 1 and 2), at 30 days post the first injection of Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД, every Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД. Among patients in Study 3 who reported no prior exposure to Коллагеназа КК 250 ЕД, 97% of patients had antibodies against AUX-I and AUX-II after two concurrent doses of Коллагеназа КК 250 ЕД 0.58 mg (total dose of 1.16 mg) in the same hand. In Study 5, treatment of recurrent contractures with Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД, >99% of Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД (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.

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

• Tendon ruptures or other serious injury to the injected extremity

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

• Corporal rupture (penile fracture) and severe penile hematoma
• In other XIAFLEX-treated patients, a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded

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. 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.

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.

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.

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.

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.

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.

Preclinical safety data

Repeated dose 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 collagenase clostridium histolyticum in dogs at exposures lower than or equal to the maximum recommended human dose on a mg/m2 basis, there was no evidence of systemic toxicity.

Reproductive toxicity

When Коллагеназа КК 250 ЕД was given intravenously every other day to male and female rats before cohabitation and through mating and implantation, no effects on the oestrus cycle, tubal transport, implantation and pre-implantation development and/or on libido or epididymal sperm maturation were noted with intravenous doses up to 0.13 mg/dose (approximately 11 times the human dose on a mg/m2 basis). There were no adverse reactions on early embryonic development (indicating no evidence of teratogenicity) in rats. No systemic toxicity was observed in this study at any dose level.

Mutagenicity

Collagenase clostridium histolyticum was not mutagenic in Salmonella typhimurium (AMES test) and was not clastogenic in both an in vivo mouse micronucleus assay and an in vitro chromosomal aberration assay in human lymphocytes.

Carcinogenicity

Standard two-year rodent bioassays have not been performed with Коллагеназа КК 250 ЕД. Thus, the carcinogenic risk is unknown.

Therapeutic indications

Коллагеназа КК 250 ЕД is indicated for:

- The treatment of Dupuytren's contracture in adult patients with a palpable cord.

- The treatment of adult men with Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy.

Коллагеназа КК 250 ЕД is indicated for the treatment of adult patients with Dupuytren's contracture with a palpable cord.

Коллагеназа КК 250 ЕД is indicated for the treatment of adult men with Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy.

XIAFLEX is 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.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Other Drugs For Disorders of the Musculo-Skeletal System - Enzymes, ATC code: M09AB02

Коллагеназа КК 250 ЕД is a lyophilized product for parenteral administration containing collagenase clostridium histolyticum which is comprised of two collagenases in a defined mass ratio. These collagenases, referred to as AUX-I and AUX-II, are representative of the two major collagenase classes (Class I and Class II) produced by Clostridium histolyticum. AUX-I and AUX-II are single polypeptide chains consisting of approximately 1000 amino acids of known sequence with a molecular weight of 114 kDa and 113 kDa respectively as determined by mass spectrometry. The two polypeptides are purified by chromatographic steps customary for the separation and isolation of biotherapeutic proteins to yield a consistent, well characterized and controlled mixture of two collagenase enzymes.

Because the collagen lysis process following Коллагеназа КК 250 ЕД administration is localized and does not require or result in quantifiable systemic levels of AUX-I and AUX-II, the primary pharmacodynamic activity of Коллагеназа КК 250 ЕД cannot be evaluated in subjects and therefore, such studies have not been undertaken.

Mechanism of action

Collagenases are proteinases that hydrolyze collagen under physiological conditions. Коллагеназа КК 250 ЕД is comprised of a mixture of Class I (AUX-I) and Class II (AUX-II) clostridial collagenases in a defined mass ratio. The two classes of collagenases have similar but complementary substrate specificity. Both collagenases effectively cleave interstitial collagen but at different sites on the molecule; additionally, they prefer different conformations (triple helical versus denatured or cleaved). These differences account for the ability of the two classes of enzymes to digest collagen in a complementary manner. Class I collagenases (α, β, γ, and η) are the products of the colG gene, they initiate collagen hydrolysis near the amino and carboxy termini of triple helical domains, and generate large proteolytic fragments. In contrast, the Class II collagenases (δ, ε, and ζ,) are products of colH gene, their initial cleavage sites are located within the interior of the collagen molecule, and generate smaller collagen fragments. Both classes of collagenases readily hydrolyze gelatin (denatured collagen) and small collagen peptides, whereas Class II has higher affinity for small collagen fragments. Class I cleaves insoluble triple helical collagen with higher affinity than Class II collagenase. Together, these collagenases work to provide broad hydrolytic activity towards collagen.

Dupuytren's contracture

Injection of Коллагеназа КК 250 ЕД into a Dupuytren's cord, which is comprised mostly of interstitial collagen types I and III, results in enzymatic disruption of the cord.

Peyronie's disease

The signs and symptoms of Peyronie's disease are caused by a collagen plaque. Injection of Коллагеназа КК 250 ЕД 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.

Clinical efficacy and safety

Dupuytren's contracture

The efficacy of Коллагеназа КК 250 ЕД 0.58 mg was evaluated in two pivotal randomized, double-blind, placebo-controlled studies, CORD I (AUX-CC-857) and CORD II (AUX-CC-859), in adult patients with Dupuytren's contracture. The double-blind study population comprised 409 patients of whom 272 received Коллагеназа КК 250 ЕД 0.58 mg and 137 received placebo. The mean age was 63 years (range 33 to 89 years) and 80% of patients were male. At study entry, patients in the clinical studies 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 MP joint or 20° to 80° in 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. The cord affecting a selected primary joint received up to 3 injections of 0.58 mg of Коллагеназа КК 250 ЕД or placebo. A finger extension procedure was performed if needed, approximately 24 hours after injection to facilitate disruption of the cord. Each injection was separated by approximately 4 weeks.

The primary endpoint of each study was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to 5° or less of normal, approximately 4 weeks after the last injection of that joint. Other endpoints included >50% reduction from baseline in degree of contracture, percent change from baseline in degree of contracture, change from baseline in range of motion, subject global assessment of treatment satisfaction and physician global assessment of severity.

Коллагеназа КК 250 ЕД demonstrated a clinically significant benefit compared to placebo in the proportion of patients achieving the primary endpoint of a reduction in the contracture of all joints treated to 5° or less, approximately 4 weeks after the last injection (MP plus PIP, MP only, PIP only). For patients who achieved a contracture of the selected joint to 5° or less, the mean number of injections required to achieve this was 1.5 in the 2 studies. Коллагеназа КК 250 ЕД also demonstrated a clinically significant benefit compared to placebo in decreasing the degree of contracture and increasing both the range of motion from baseline for all joints treated (MP plus PIP, MP only, PIP only) and the subject global assessment of treatment satisfaction.

Table 3 provides demographic and baseline characteristics for the study population and Tables 4-5 provide the results of the major efficacy endpoints measured in the 2 double-blind placebo controlled studies CORD I (AUX-CC-857) and CORD II (AUX-CC-859).

Table 3.

Demographic and baseline characteristics

Phase 3 Double-Blind, Placebo controlled studies (CORD I, CORD II)

Table 4.

Percentage of patients who achieved reduction in contracture to 5° or less

(Last injection)

Table 5.

Mean increase in range of motion from baseline

(Last injection)

Physician-rated change in contracture severity was reported as very much improved or much improved in 86% and 80% of the subjects in the Коллагеназа КК 250 ЕД group compared to 3% and 5% of subjects in the placebo group for the CORD I and CORD II studies, respectively (p<0.001). Based on the Patient Global Assessment of Treatment Satisfaction, more than 85% of subjects in the CORD I and CORD II studies reported either being quite satisfied or very satisfied with their treatment with Коллагеназа КК 250 ЕД versus approximately 30% treated with placebo (p<0.001). Greater patient satisfaction was correlated with improved range of motion (r=0.51, p<0.001).

Treatment of two concurrent injections

The administration of two concurrent Коллагеназа КК 250 ЕД injections into Dupuytren's cords in the same hand was evaluated in clinical study AUX-CC-867, a historically-controlled, open-label multi-centre trial in 715 adult subjects (1450 Коллагеназа КК 250 ЕД injections) with Dupuytren's contracture. The finger extension procedures were performed approximately 24 to 72 hours after injection.

Primary efficacy endpoint was fixed flexion contracture in the treated joint pair subgroup. A significant mean improvement (74.4%) from baseline to Day 31 was observed overall in fixed flexion contracture following administration of two concurrent injections of Коллагеназа КК 250 ЕД 0.58 mg (one injection per joint) in the same hand, see Table 6.

Improvement was observed regardless of joint type or finger involvement (range: 60.5% to 83.9%). Improvement of the total fixed flexion contracture was also observed irrespectively of the time of finger extension, 24, 48 or 72 hours after injection, with a mean improvement at Day 31 of 75.2% 74.8% and 72.4% respectively. An improvement from baseline was also seen in range of motion at Day 31 for all the treated joint pair subgroups, see Table 6.

Clinical success (a reduction of contracture to ≤5° within 30 days) after two concurrent injections of Коллагеназа КК 250 ЕД (one per joint) in the same hand was achieved for the majority of MP joints (64.6%) compared with 28.6% of PIP joints following a single injection per affected joint. Time of finger extension after injection had no impact on the rate of clinical success for either MP or PIP joints. Clinically meaningful improvement in hand function as determined by the URAM (Unite´ Rhumatologique des Affections de la Main) score was observed at Day 31 (-11.3) and Day 61 (-12.3).

Long-term efficacy and safety

A long term, non-treatment, Year 2 to Year 5 follow-up study (AUX-CC-860) was undertaken to evaluate recurrence of contracture and long-term safety in subjects who received up to 8 single injections of Коллагеназа КК 250 ЕД 0.58 mg in a previous Phase 3 open-label or double-blind with open-label extension study. No new safety signals were identified among subjects who were followed for 5 years after their initial injection of Коллагеназа КК 250 ЕД in a previous clinical study. The majority of adverse events reported during the long-term follow-up period were non-serious, mild or moderate in intensity, and were not related to the local administration of Коллагеназа КК 250 ЕД. These data support the long term safety profile of Коллагеназа КК 250 ЕД confirming that no new safety risks were identified during the 5 year follow-up period.

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 Коллагеназа КК 250 ЕД 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 the long term recurrence rates following successful treatment with Коллагеназа КК 250 ЕД are provided in Table 7.

Table 7.

Long Term Recurrence Rates for Joints Treated Successfully with Коллагеназа КК 250 ЕД

Retreatment of recurrent contractures

A study AUX-CC-862 was conducted in patients with Dupuytren's contracture who had recurrence of contracture in a joint that was effectively treated with Коллагеназа КК 250 ЕД in a previous clinical study. No new safety signals were identified among subjects who were retreated with Коллагеназа КК 250 ЕД. Most adverse events were non-serious, mild or moderate in intensity, and related to the local administration of Коллагеназа КК 250 ЕД or to the finger extension procedure to facilitate cord disruption. The clinical efficacy in study AUX-CC-862 was similar to that reported in studies CORD I and CORD II. In study AUX-CC-862, 64.5% of recurrent MP joints and 45.0% of recurrent PIP joints achieved clinical success after retreatment with up to three injections of Коллагеназа КК 250 ЕД.

In the retreatment study AUX-CC-862, 150 anti-AUX-I antibody positive samples and 149 anti-AUX-II antibody positive samples were assessed for potential cross-reactivity with human MMPs-1, -2, -3, -8, and -13. Results showed no cross-reactivity with any of the five MMPs tested.

Paediatric population

).

Peyronie's disease

The efficacy of Коллагеназа КК 250 ЕД was evaluated in two randomized, double-blind, placebo-controlled studies, Study 1 (AUX-CC-803) and Study 2 (AUX-CC-804), in adult males with Peyronie's disease. The double-blind study population comprised 832 male patients of whom 551 patients received Коллагеназа КК 250 ЕД and 281 received placebo. The median age was 58 years (range 23 to 84 years). 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 studies, patients were given up to 4 treatment cycles of Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 0.58 mg or two injections of placebo were administered 1 to 3 days apart. A penile modelling 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 modelling procedures. In addition, patients were instructed to perform penile modelling at home for six weeks after each treatment cycle.

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

- the percent change from baseline to Week 52 in penile curvature deformity and

- the change from baseline to Week 52 in the Bother domain of the Peyronie's Disease Questionnaire (PDQ)

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.

Коллагеназа КК 250 ЕД treatment significantly improved penile curvature deformity in patients with Peyronie's disease compared with placebo (Table 9). The improvement in curvature deformity was numerically similar among patients with baseline deformity from 30 to 60 degrees and those with curvature deformity from 61 to 90 degrees.

Коллагеназа КК 250 ЕД significantly reduced patient-reported bother associated with Peyronie's disease compared with placebo (Table 10). 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).

Table 8 provides the baseline disease characteristics for the study population and Tables 9 -10 provide the results of the co-primary efficacy endpoints measured in the 2 double-blind placebo-controlled studies AUX-CC-803 and AUX-CC-804.

Pharmacokinetic properties

Absorption

Following administration of either a single dose of 0.58 mg of Коллагеназа КК 250 ЕД to 16 patients with Dupuytren's contracture, or two concurrent injections of 0.58 mg of Коллагеназа КК 250 ЕД in the same hand in 12 patients with Dupuytren's contracture, no quantifiable levels of Коллагеназа КК 250 ЕД were detected in plasma from 5 minutes to 30 days post injection.

Following each of two intralesional administrations, separated by 24 hours, of Коллагеназа КК 250 ЕД 0.58 mg into the penile plaque of 19 patients with Peyronie's disease, plasma levels of AUX-I and AUX-II in patients with quantifiable levels (82% and 40% for AUX-I and AUX-II, respectively) were minimal and short-lived. The maximal individual plasma concentrations of AUX-I and AUX-II were <29 ng/mL and <71 ng/mL, respectively. 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 Коллагеназа КК 250 ЕД administered 24 hours apart. No patients had quantifiable plasma levels 15 minutes after modelling of plaque on Day 3 (i.e., 24 hours after Injection 2 on Day 2).

Distribution

There has been no evidence of systemic toxicity to date in the clinical studies conducted with Коллагеназа КК 250 ЕД administered through localized injection into the Dupuytren's cord or into the Peyronie's plaque.

Biotransformation

Because Коллагеназа КК 250 ЕД is not a substrate for cytochrome P450 or other medicinal product metabolizing enzyme pathways, and because no active metabolites are expected, no metabolism studies have been performed.

Elimination

No formal studies on elimination have been performed. There is no quantifiable systemic exposure following a single injection of Коллагеназа КК 250 ЕД in patients with Dupuytren's contracture and only minimal and short-lived systemic exposure in patients with Peyronie's disease.

Special population

No dose adjustment is necessary in any special patient groups e.g., Elderly, Renally or Hepatically Impaired, by Gender or Race.

Paediatric population

Коллагеназа КК 250 ЕД has not been studied in children and adolescents aged 0-18 years and hence no pharmacokinetic data are available.

Following administration of either a single injection of Коллагеназа КК 250 ЕД 0.58 mg into a Dupuytren's cord in 20 patients or two concurrent injections of Коллагеназа КК 250 ЕД 0.58 mg into Dupuytren's cords of 12 patients, no quantifiable levels of Коллагеназа КК 250 ЕД (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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 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).

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).

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Allergic reactions

Following Коллагеназа КК 250 ЕД injection, severe allergic reaction could occur, and patients should be observed for 30 minutes before leaving the clinic in order to monitor for any signs or symptoms of a serious allergic reaction, e.g. wide spread redness or rash, swelling, tightness in the throat or difficulty breathing. Patients should be instructed to consult a doctor immediately if they experience any of these signs or symptoms. Emergency medication for treatment of potential allergic reactions should be available.

An anaphylactic reaction was reported in a post-marketing clinical study in a patient who had previous exposure to Коллагеназа КК 250 ЕД for the treatment of Dupuytren's contracture, demonstrating that severe reactions including anaphylaxis can occur following Коллагеназа КК 250 ЕД injections. Some patients with Dupuytren's contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive Коллагеназа КК 250 ЕД injections.

In the double blind portion of the three phase 3 placebo-controlled clinical studies in Dupuytren's contracture, 17% of Коллагеназа КК 250 ЕД-treated patients had mild reactions (i.e. pruritus) after up to 3 injections. The incidence of Коллагеназа КК 250 ЕД-associated pruritus increased after more Коллагеназа КК 250 ЕД injections in patients with Dupuytren's contracture.

In the double-blind portion of the two phase 3 placebo-controlled clinical trials in Peyronie's disease, a greater proportion of Коллагеназа КК 250 ЕД-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 Коллагеназа КК 250 ЕД injections). The incidence of Коллагеназа КК 250 ЕД-associated pruritus was similar after each injection regardless of the number of injections administered.

Tendon rupture or other serious injury to the injected finger/hand in the treatment of Dupuytren's contracture

Коллагеназа КК 250 ЕД must only be injected into the Dupuytren's cord. Because Коллагеназа КК 250 ЕД lyses collagen, care must be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Injection of Коллагеназа КК 250 ЕД into collagen containing structures may result in damage to those structures, and possible permanent injury such as tendon rupture or ligament damage. Care should be taken when injecting Коллагеназа КК 250 ЕД into cords contracting the PIP joints as clinical studies indicate an increased risk of tendon rupture and ligament injury associated with treatment of PIP contractures with Коллагеназа КК 250 ЕД. This is particularly important for cords situated at the PIP joint of the fifth finger. When injecting a cord affecting a PIP joint of the fifth finger, the needle insertion must not be more than 2 to 3 mm in depth and not more than 4 mm distal to the palmar digital crease. Patients should be instructed to comply with the treatment instructions and to promptly contact the physician if there is trouble bending the finger after the swelling goes down (symptoms of tendon rupture).

Most patients experiencing tendon/ligament rupture or injury have gone on to have successful surgical repair. Early diagnosis and prompt evaluation and treatment are important because tendon rupture/ligament injury may potentially affect overall hand function.

Patients with Dupuytren's contractures that adhere to the skin may be at higher risk of skin lesions as a result of the pharmacological effect of Коллагеназа КК 250 ЕД and the finger extension procedure on the skin overlying the targeted cord.

Cases of skin laceration requiring skin graft after finger extension procedures have been reported post-marketing.).

Corporal rupture (fracture of penis) or other serious injury to the penis in the treatment of Peyronie's disease

Injection of Коллагеназа КК 250 ЕД 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, Коллагеназа КК 250 ЕД must 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.

Corporal rupture was reported as a serious adverse reaction after Коллагеназа КК 250 ЕД injection in 5 out of 1044 patients (0.5%) in the controlled and uncontrolled clinical trials in Peyronie's disease. In other Коллагеназа КК 250 ЕД-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or haematoma, 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 haematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical studies in Peyronie's disease.

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 haematoma, which may require surgical intervention.

Use in patients with coagulation disorders

Коллагеназа КК 250 ЕД must be used with caution in patients with coagulation disorders or those taking anticoagulants. In the three double-blind, placebo-controlled phase 3 studies in Dupuytren's contracture, 73% of Коллагеназа КК 250 ЕД-treated patients reported an ecchymosis or a contusion and 38% reported a haemorrhage at the injection site. In the two double-blind, placebo-controlled phase 3 studies in Peyronie's disease, 65.5% of Коллагеназа КК 250 ЕД-treated patients developed penile haematoma and 14.5% developed penile ecchymosis. The efficacy and safety of Коллагеназа КК 250 ЕД in patients receiving anticoagulant medicinal products other than up to 150 mg acetylsalicylic acid per day prior to Коллагеназа КК 250 ЕД administration is not known. Use of Коллагеназа КК 250 ЕД in patients who have received anticoagulants (with the exception of up to 150 mg acetylsalicylic acid daily) within 7 days prior to receiving an injection of Коллагеназа КК 250 ЕД is not recommended.

Immunogenicity

As with any non-human protein medicinal product, patients may develop antibodies to the therapeutic protein. During clinical studies, blood samples from patients with Dupuytren's contracture and Peyronie's disease were tested at multiple time points for antibodies to the protein components of the medicinal product (AUX-I and AUX-II).

In the Dupuytren's contracture clinical trials at 30 days post the first injection, 92% of patients had circulating antibodies detected against AUX-I and 86% of patients against AUX-II. At five years after the initial injection of Коллагеназа КК 250 ЕД, 92.8% and 93.4% of subjects were seropositive for anti-AUX-I and anti-AUX-II respectively.

Almost all patients had positive titers for anti-AUX-I antibodies (97.9%) and anti-AUX-II antibodies (97.5%) 60 days post two concurrent injections.

In the Peyronie's disease clinical studies, at 6 weeks after the first treatment cycle of Коллагеназа КК 250 ЕД, 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 Коллагеназа КК 250 ЕД >99% of Коллагеназа КК 250 ЕД-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 enzymes in Коллагеназа КК 250 ЕД have some sequence homology with human matrix metalloproteinases (MMPs), anti-drug antibodies (ADA) could theoretically interfere with human MMPs. No safety concerns related to the inhibition of endogenous MMPs have been observed, in particular no adverse events indicating the development or exacerbation of autoimmune diseases or the development of a musculoskeletal syndrome (MSS). Whilst there is no clinical evidence from the current safety data of a musculoskeletal syndrome developing following the administration of Коллагеназа КК 250 ЕД, the potential for it to occur cannot be excluded. If this syndrome were to develop, it would occur progressively and is characterized by one or more of the following signs and symptoms: arthralgia, myalgia, joint stiffness, stiffness of the shoulders, hand oedema, palmar fibrosis and thickening or nodules forming in the tendons.

Post-treatment surgery

The impact of treatment with Коллагеназа КК 250 ЕД on subsequent surgery, if needed, is not known.

Special penile conditions/diseases not studied in clinical trials

Коллагеназа КК 250 ЕД treatment in patients having a calcified plaque that could have interfered with the injection technique, chordee in the presence or absence of hypospadias, thrombosis of the dorsal penile artery and/or vein, infiltration by a benign or malignant mass resulting in penile curvature, infiltration by an infectious agent, such as in lymphogranuloma venereum, ventral curvature from any cause and isolated hourglass deformity of the penis has not been studied and treatment in these patients should be avoided.

Long-term safety of Коллагеназа КК 250 ЕД in Peyronie's disease is not fully characterised.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially 'sodium- free'.

Included as part of the PRECAUTIONS section.

In the controlled and uncontrolled portions of clinical trials in Dupuytren's contracture, flexor tendon ruptures occurred after Коллагеназа КК 250 ЕД injection. Injection of Коллагеназа КК 250 ЕД 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, Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД 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 was reported as an adverse reaction after Коллагеназа КК 250 ЕД injections in 5 of 1044 (0.5%) Коллагеназа КК 250 ЕД treated patients in the controlled and uncontrolled clinical trials in Peyronie's disease.

In other Коллагеназа КК 250 ЕД-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.

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 Коллагеназа КК 250 ЕД 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, Коллагеназа КК 250 ЕД 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.

Because of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie's disease, Коллагеназа КК 250 ЕД is available only through the Коллагеназа КК 250 ЕД REMS Program.

Required components of the Коллагеназа КК 250 ЕД REMS Program include the following:

• Prescribers must be certified with the program by enrolling and completing training in the administration of Коллагеназа КК 250 ЕД treatment for Peyronie's disease.
• Healthcare sites must be certified with the program and ensure that Коллагеназа КК 250 ЕД is only dispensed for use by certified prescribers.

Further information is available at www.Коллагеназа КК 250 ЕДREMS.com or 1-877-313-1235.

In the controlled portions of the clinical trials in Dupuytren's contracture (Studies 1 and 2), a greater proportion of Коллагеназа КК 250 ЕД-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of Коллагеназа КК 250 ЕД-associated pruritus increased after more Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 Коллагеназа КК 250 ЕД injection procedures). The incidence of Коллагеназа КК 250 ЕД-associated pruritus was similar after each injection regardless of the number of injections administered.

Because Коллагеназа КК 250 ЕД contains foreign proteins, severe allergic reactions to Коллагеназа КК 250 ЕД can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД injections. Healthcare providers should be prepared to address severe allergic reactions following Коллагеназа КК 250 ЕД injections.

In the Коллагеназа КК 250 ЕД trials in Dupuytren's contracture (Studies 1 and 2), 70% and 38% of Коллагеназа КК 250 ЕД-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively (see Table 3). In the Коллагеназа КК 250 ЕД controlled trials in Peyronie's disease (Studies 1 and 2), 65.5% of Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to Коллагеназа КК 250 ЕД administration is not known. In addition, it is recommended to avoid use of Коллагеназа КК 250 ЕД in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin).

See FDA-approved patient labeling (Medication Guide).

Advise patients of the following:

• Serious complications of Коллагеназа КК 250 ЕД injection include tendon rupture, serious ligament damage, or skin laceration that may result in the inability to fully bend the finger and may require surgery to correct the complication.
• Коллагеназа КК 250 ЕД injection is likely to result in swelling, bruising, bleeding, and/or pain of the injected site and surrounding tissue.

After the Коллагеназа КК 250 ЕД injections, instruct patients:

• Not to flex or extend the fingers of the injected hand to reduce extravasation of Коллагеназа КК 250 ЕД out of the cord(s).
• Not to attempt to disrupt the injected cord(s) by self-manipulation.
• To elevate the injected hand until bedtime.
• To promptly contact their physician if there is evidence of infection (e.g., fever, chills, increasing redness or edema), sensory changes in the treated finger(s), trouble bending the finger(s) after the swelling goes down (symptoms of tendon rupture), or skin laceration.
• To return to their healthcare provider's office one to three days after the injection visit for an examination of the injected hand and for possible finger extension procedure(s) to disrupt the cord.

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

• Not to perform strenuous activity with the injected hand until advised to do so.
• To wear the splint at bedtime for up to 4 months.
• To perform a series of finger flexion and extension exercises each day.

Advise patients of the following:

• Serious complications of Коллагеназа КК 250 ЕД injection include corporal rupture and penile hematoma and may require surgery to correct the complication.

After the Коллагеназа КК 250 ЕД injections, instruct the patient:

• That their penis may appear bruised and/or swollen
• That they may have mild-to-moderate penile pain that can be relieved by taking over-the-counter pain medications
• To promptly contact their physician if, at any time, they have severe pain or severe swelling of the penis, severe purple bruising and swelling of the penis, difficulty urinating or blood in the urine, or sudden loss of the ability to maintain an erection. These symptoms may be accompanied by a popping or cracking sound from the penis
• To return to their healthcare provider's office when directed for further injection(s) and/or penile modeling procedure(s)
• To not have sex between the first and second injections of a treatment cycle
• To wait two weeks after the second injection of a treatment cycle before resuming sexual activity, provided pain and swelling have subsided

Provide the patient instructions on the appropriate technique to perform penile modeling activities at home, as described in “What You Need to Know About Коллагеназа КК 250 ЕД Treatment for Peyronie's Disease: A Patient Guide”, and give the patient a copy.

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

Purified collagenase clostridium histolyticum was not mutagenic in Salmonella typhimurium (AMES test) and was not clastogenic in both an in vivo mouse micronucleus assay and an in vitro chromosomal aberration assay in human lymphocytes.

Collagenase 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.

There are no adequate and well-controlled studies of Коллагеназа КК 250 ЕД in pregnant women. Because animal reproduction studies are not always predictive of human response, Коллагеназа КК 250 ЕД should be used during pregnancy only if clearly needed.

Based on animal data, Коллагеназа КК 250 ЕД is not predicted to increase the risk for major developmental abnormalities in humans.

Human pharmacokinetic studies showed that Коллагеназа КК 250 ЕД levels were not quantifiable in the systemic circulation following injection into a Dupuytren's cord.

Low levels of Коллагеназа КК 250 ЕД were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД, and the clinical significance of anti-product antibody formation on a developing fetus is not known.

Reproduction studies have been performed in rats with intravenous exposures up to approximately 11 times the maximum recommended human dose (MRHD) of Коллагеназа КК 250 ЕД on a mg/m² basis, and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum.

It is not known whether collagenase clostridium histolyticum is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Коллагеназа КК 250 ЕД is administered to a nursing woman.

The safety and effectiveness of Коллагеназа КК 250 ЕД in pediatric patients less than 18 years old have not been established.

Of the 249 Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД-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 Коллагеназа КК 250 ЕД were observed between these patients and younger patients.

Included as part of the PRECAUTIONS section.

In the controlled and uncontrolled portions of clinical trials in Dupuytren's contracture, flexor tendon ruptures occurred after XIAFLEX injection. 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.

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 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.

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.

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.

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.

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.

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).

See FDA-approved patient labeling (Medication Guide).

Advise patients of the following:

• Serious complications of XIAFLEX injection include tendon rupture, serious ligament damage, or skin laceration that may result in the inability to fully bend the finger and may require surgery to correct the complication.
• XIAFLEX injection is likely to result in swelling, bruising, bleeding, and/or pain of the injected site and surrounding tissue.

After the XIAFLEX injections, instruct patients:

• Not to flex or extend the fingers of the injected hand to reduce extravasation of XIAFLEX out of the cord(s).
• Not to attempt to disrupt the injected cord(s) by self-manipulation.
• To elevate the injected hand until bedtime.
• To promptly contact their physician if there is evidence of infection (e.g., fever, chills, increasing redness or edema), sensory changes in the treated finger(s), trouble bending the finger(s) after the swelling goes down (symptoms of tendon rupture), or skin laceration.
• To return to their healthcare provider's office one to three days after the injection visit for an examination of the injected hand and for possible finger extension procedure(s) to disrupt the cord.

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

• Not to perform strenuous activity with the injected hand until advised to do so.
• To wear the splint at bedtime for up to 4 months.
• To perform a series of finger flexion and extension exercises each day.

Advise patients of the following:

• Serious complications of XIAFLEX injection include corporal rupture and penile hematoma and may require surgery to correct the complication.

After the XIAFLEX injections, instruct the patient:

• That their penis may appear bruised and/or swollen
• That they may have mild-to-moderate penile pain that can be relieved by taking over-the-counter pain medications
• To promptly contact their physician if, at any time, they have severe pain or severe swelling of the penis, severe purple bruising and swelling of the penis, difficulty urinating or blood in the urine, or sudden loss of the ability to maintain an erection. These symptoms may be accompanied by a popping or cracking sound from the penis
• To return to their healthcare provider's office when directed for further injection(s) and/or penile modeling procedure(s)
• To not have sex between the first and second injections of a treatment cycle
• To wait two weeks after the second injection of a treatment cycle before resuming sexual activity, provided pain and swelling have subsided

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

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

Purified collagenase clostridium histolyticum was not mutagenic in Salmonella typhimurium (AMES test) and was not clastogenic in both an in vivo mouse micronucleus assay and an in vitro chromosomal aberration assay in human lymphocytes.

Collagenase 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.

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

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

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

Low levels of XIAFLEX were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of XIAFLEX 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 XIAFLEX, and the clinical significance of anti-product antibody formation on a developing fetus is not known.

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

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

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

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 XIAFLEX were observed between these patients and younger patients.

Effects on ability to drive and use machines

Коллагеназа КК 250 ЕД may have a major influence on the ability to drive and use machines due to the swelling and pain which may impair the use of the treated hand in Dupuytren's disease. Other minor influences on the ability to drive and use machines include dizziness, paresthesia, hypoesthesia, and headache that have also been reported following injection of Коллагеназа КК 250 ЕД. Patients must be instructed to avoid potentially hazardous tasks such as driving or using machines until it is safe to do so or as advised by the physician.

Dosage (Posology) and method of administration

Dupuytren's contracture

Коллагеназа КК 250 ЕД must be administered by a physician appropriately trained in the correct administration of the medicinal product and experienced in the diagnosis and management of Dupuytren's disease.

Posology

The recommended dose of Коллагеназа КК 250 ЕД is 0.58 mg per injection into a palpable Dupuytren's cord. The volume of solvent required and the volume of reconstituted Коллагеназа КК 250 ЕД to be administered into the Dupuytren's cord differs depending on the type of joint being treated.

- For cords affecting MP joints each dose is administered in an injection volume of 0.25 ml.

- For cords affecting PIP joints, each dose is administered in an injection volume of 0.20 ml.

Injections in up to two cords or two affected joints in the same hand can be administered 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. Each injection contains a 0.58 mg dose. If the disease has resulted in multiple contractures, additional cords may be treated at other treatment visits approximately 4 weeks apart.

Approximately 24-72 hours after injection, a finger extension procedure may be performed, as necessary, to facilitate cord disruption. If a satisfactory response has not been achieved, the injection and finger extension procedures may be repeated after approximately 4 weeks. Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.

Clinical study experience with Коллагеназа КК 250 ЕД is currently limited to up to 3 injections per cord and up to 8 injections in total.

Peyronie's disease

Коллагеназа КК 250 ЕД must be administered by a physician appropriately trained in the correct administration of the medicinal product and experienced in the diagnosis and treatment of male urological diseases. Patients with penile curvature >90° were not included in the clinical studies. Treatment in this group can therefore not be recommended.

Posology

The recommended dose of Коллагеназа КК 250 ЕД is 0.58 mg per injection administered into a Peyronie's plaque. The volume of reconstituted Коллагеназа КК 250 ЕД to be administered into the plaque is 0.25 ml. If more than one plaque is present, only the plaque causing the curvature deformity should be injected.

A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two Коллагеназа КК 250 ЕД injections and one penile modelling procedure. The second Коллагеназа КК 250 ЕД injection is administered 1 to 3 days after the first injection. A penile modelling procedure is performed 1 to 3 days after the second injection of each treatment cycle. The interval between treatment cycles is approximately six weeks.

Special population

Elderly

Due to the lack of quantifiable systemic exposure of Коллагеназа КК 250 ЕД in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Коллагеназа КК 250 ЕД in patients with Peyronie's disease, no dose adjustment is necessary. No overall differences in safety or effectiveness were observed between elderly and younger patients.

Hepatic impairment

Due to the lack of quantifiable systemic exposure of Коллагеназа КК 250 ЕД in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Коллагеназа КК 250 ЕД in patients with Peyronie's disease, no dose adjustment is necessary.

Renal impairment

Due to the lack of quantifiable systemic exposure of Коллагеназа КК 250 ЕД in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Коллагеназа КК 250 ЕД in patients with Peyronie's disease, no dose adjustment is necessary.

Paediatric population

There is no relevant use of Коллагеназа КК 250 ЕД in the paediatric population aged 0-18 years for the treatment of Dupuytren's contracture.

Peyronie's disease occurs exclusively in adult male patients and hence there is no relevant use of Коллагеназа КК 250 ЕД in the paediatric population aged 0-18 years for the treatment of Peyronie's disease.

Method of administration

Intralesional use.

Коллагеназа КК 250 ЕД must be reconstituted with the solvent provided and to the appropriate volume prior to intralesional injection.

A single-use syringe containing 0.01-ml graduations with a permanently fixed 27-gauge 12 or 13 mm needle (not supplied) should be used to withdraw the volume of reconstituted solution. There will be a small amount of reconstituted solution left in the vial.

Dupuytren's contracture

Injection procedure

Administration of a local anaesthetic medicinal product prior to injection of Коллагеназа КК 250 ЕД into a Dupuytren's cord is not recommended, as it may interfere with proper placement of the injection.

The joint to be treated (metacarpophalangeal [MP] or proximal interphalangeal [PIP]) should be confirmed and the volume of solvent required for reconstitution is determined by the type of joint (PIP joint requires a smaller volume for injection). The injection procedure is detailed in the package leaflet and the physician training material and must be followed.

Patients should be instructed:

- To return to see their physician approximately 24-72 hours after injection for an examination of the injected hand and a finger extension procedure to disrupt the cord.

- Not to flex or extend the fingers of the injected hand to reduce extravasation of Коллагеназа КК 250 ЕД out of the cord until the finger extension procedure is completed.

- Not to attempt to disrupt the injected cord by self-manipulation at any time.

- To elevate the injected hand as much as possible until the day after the finger extension procedure.

Finger extension procedure

At the follow-up visit approximately 24-72 hours after injection, it should be determined if the contracture has resolved. If a cord contracture remains, a passive finger extension procedure will be performed in an attempt to disrupt the cord. Local anaesthesia may be used, if needed, during the finger extension procedure.

While the patient's wrist is in the flexed position, a moderate stretching pressure should be applied to the injected cord by extending the finger for approximately 10 to 20 seconds. For cords affecting the PIP joint, the finger extension procedure should be performed when the MP joint is in the flexed position. If the first finger extension procedure does not result in disruption of the cord, a second and third attempt can be performed at 5- to 10-minute intervals. No more than 3 attempts per affected joint are recommended to disrupt a cord.

If the cord has not disrupted after 3 attempts of extension, a follow-up visit may be scheduled approximately 4 weeks after the injection. If, at that subsequent visit the contracted cord persists, an additional injection and finger extension procedure may be performed.

Following the finger extension procedure(s) and fitting patient with a splint (with treated joint in maximum extension), the patients should be instructed to:

- Not perform strenuous activity with the injected hand until advised to do so.

- Wear the splint at bedtime for up to 4 months.

- Perform a series of finger flexion and extension exercises several times a day for several months.

Peyronie's disease

Injection procedure

Administration of regional anaesthesia (penile block) or topical anaesthesia could be applied prior to Коллагеназа КК 250 ЕД injection when desired. In the pivotal clinical studies about 30% of the patients received penile block before injection.

The location of the target treatment area in the Peyronie's plaque is identified at the point of maximum concavity (or focal point) in the erect penis state and marked with a surgical marker. Коллагеназа КК 250 ЕД should be injected into the target plaque when the penis is in a flaccid state. The injection procedure is detailed in the package leaflet and the physician training material and must be followed.

Penile modelling procedure

Penile modelling helps relieve curvature deformity and straighten the penile shaft. At the follow-up visit 1 to 3 days after the second injection of each treatment cycle, the trained physician should perform a penile modelling procedure on the flaccid penis to stretch and elongate the treated plaque that Коллагеназа КК 250 ЕД has disrupted. Local anaesthesia may be applied before the modelling if desired. Wearing gloves the physician should grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Direct pressure on the injection site should be avoided. The target plaque is used as a fulcrum point with both hands, to firmly apply a steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient's penile curvature, with stretching to the point of moderate resistance.

The penile pressure should be hold for 30 seconds, thereafter released with a resting period for 30 seconds before repeating the penile modelling technique for a total of 3 modelling attempts at 30 seconds for each attempt.

In addition to the in-office penile modelling procedure, patients should be provided instructions on the appropriate technique to self-perform penile modelling activities at home each day for the 6-week period following the physician penile plaque modelling visit of each treatment cycle, according to the detailed instructions provided in the package leaflet.

If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the physician 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 Коллагеназа КК 250 ЕД for Peyronie's disease is not known.

Коллагеназа КК 250 ЕД should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren's contracture.

Коллагеназа КК 250 ЕД, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use. The dose of Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 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.

Table 1: Volumes Needed for Reconstitution and Administration for Dupuytren’s Contracture

Four weeks after the Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД at other treatment visits approximately 4 weeks apart.

1. Before use, remove the vial(s) containing the lyophilized powder of Коллагеназа КК 250 ЕД and the vial(s) containing the diluent for reconstitution from the refrigerator and allow the vials to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial(s) containing Коллагеназа КК 250 ЕД. The cake of lyophilized powder should be intact and white in color.
2. After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper and surrounding surface of the vial(s) containing Коллагеназа КК 250 ЕД and the vial(s) containing the diluent for econstitution with sterile alcohol (no other antiseptics should be used).
3. Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of Коллагеназа КК 250 ЕД.
4. Using a 1 mL syringe that contains 0.01 mL graduations with a 27-gauge ½-inch needle (not supplied), withdraw a volume of the diluent s upplied, as follows:
   • 0.39 mL for cords affecting a MP joint or
   • 0.31 mL for cords affecting a PIP joint.
5. Inject the diluent slowly into the sides of the vial containing the lyophilized powder of Коллагеназа КК 250 ЕД. Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. If administering two injections in the same hand during a treatment visit, use a new syringe to reconstitute a second vial of Коллагеназа КК 250 ЕД with a second vial of diluent.
6. The reconstituted Коллагеназа КК 250 ЕД 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. If the reconstituted Коллагеназа КК 250 ЕД solution is refrigerated, allow this solution to return to room temperature for approximately 15 minutes before use.
7. Discard the syringe(s) and needle(s) used for reconstitution and the diluent vial(s).

1. The reconstituted Коллагеназа КК 250 ЕД solution should be clear. Inspect the solution visually for particulate matter and discoloration prior to administration. If the solution contains particulates, is cloudy, or is discolored, do not inject the reconstituted solution.
2. Administration of a local anesthetic agent prior to injection is not recommended, as it may interfere with proper placement of the Коллагеназа КК 250 ЕД injection.
3. If injecting into a cord affecting the PIP joint of the fifth finger, care should be taken to inject as close to the palmar digital crease as possible (as far proximal to the digital PIP joint crease), and the needle insertion should not be more than 2 to 3 mm in depth. Tendon ruptures occurred after Коллагеназа КК 250 ЕД injections near the digital PIP joint crease.
4. Reconfirm the cord(s) to be injected. The site chosen for each injection should be the area where the contracting cord is maximally separated from the underlying flexor tendons and where the skin is not intimately adhered to the cord.
5. Apply an antiseptic at the site(s) of the injection(s) and allow the skin to dry.

1. Using a new 1 mL hubless syringe that contains 0.01 mL graduations with a permanently fixed, 27- gauge ½-inch needle (not supplied), withdraw a volume of reconstituted solution (containing 0.58 mg of Коллагеназа КК 250 ЕД) as follows:
   • 0.25 mL for cords affecting a MP joint or
   • 0.20 mL for cords affecting a PIP joint.
2. With your non-dominant hand, secure the patient's hand to be treated while simultaneously applying tension to the cord. With your dominant hand, place the needle into the cord, using caution to keep the needle within the cord. Avoid having the needle tip pass completely through the cord to help minimize the potential for injection of Коллагеназа КК 250 ЕД into tissues other than the cord. After needle placement, if there is any concern that the needle is in the flexor tendon, apply a small amount of passive motion at the distal interphalangeal (DIP) joint. If insertion of the needle into a tendon is suspected or paresthesia is noted by the patient, withdraw the needle and reposition it into the cord.
3. If the needle is in the proper location, there will be some resistance noted during the injection procedure. After confirming that the needle is correctly placed in the cord, inject approximately one-third of the dose.
4. Next, withdraw the needle tip from the cord and reposition it in a slightly more distal location (approximately 2 to 3 mm) to the initial injection in the cord and inject another one-third of the dose.
5. Again withdraw the needle tip from the cord and reposition it a third time proximal to the initial injection (approximately 2 to 3 mm) and inject the final portion of the dose into the cord.
6. When administering two injections in the same hand during a treatment visit, use a new syringe and separate vial of reconstituted solution for each injection. Repeat steps a through f.
7. When administering two injections in the same hand during a treatment visit, begin with the affected finger in the most medial aspect of the hand and continue toward the lateral aspect (eg, fifth finger to index finger). When administering two injections in a cord affecting two joints in the same finger, begin with the affected joint in the most proximal aspect of the finger and continue toward the distal aspect (eg, MP to PIP).
8. Wrap the patient's treated hand with a soft, bulky, gauze dressing.
9. Instruct the patient to limit motion of the treated finger(s) and to keep the injected hand elevated until bedtime.
10. Instruct the patient not to attempt to disrupt the injected cord(s) by self-manipulation and to return to the healthcare provider's office the next day for follow-up and a finger extension procedure(s), if needed.
11. Discard the unused portion of the reconstituted solution and diluent after injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.

1. At the follow-up visit approximately 24 to 72 hours after the injection(s ), if a contracture remains, perform a passive finger extension procedure on each treated joint (as described below) to facilitate cord disruption. If two joints in one finger were treated, perform the finger extension procedure on the affected MP joint before performing the finger extension procedure on the affected PIP joint.
2. Local anesthesia may be used. Avoid direct pressure on the injection site as it will likely be tender. Care should be taken during release of contracture, as some patients may experience skin splitting. If this occurs, cover the area with gauze and apply gentle pressure until bleeding stops. Standard wound care with regular dressings should be applied.
3. While the patient's wrist is in the flexed position, apply moderate stretching pressure to the injected cord by extending the finger for approximately 10 to 20 seconds. For cords affecting the PIP joint, perform the finger extension procedure when the MP joint is in the flexed position.
4. If the first finger extension procedure does not result in disruption of the cord, a second and third attempt can be performed at 5- to 10-minute intervals. However, no more than 3 attempts per joint are recommended to disrupt a cord.
5. If the cord has not been disrupted after 3 attempts, a follow-up visit may be scheduled in approximately 4 weeks. If, at that subsequent visit, the contracted cord persists, an additional Коллагеназа КК 250 ЕД injection with finger extension procedures may be performed.
6. Following the finger extension procedure(s), fit patient with a splint and provide instructions for use at bedtime for up to 4 months to maintain finger extension. Also, instruct the patient to perform finger extension and flexion exercises several times a day for several months.

Коллагеназа КК 250 ЕД should be administered by a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of Коллагеназа КК 250 ЕД in the treatment of Peyronie's disease.

Коллагеназа КК 250 ЕД, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use. The dose of Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД injection procedures and one penile modeling procedure. The second Коллагеназа КК 250 ЕД 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 Коллагеназа КК 250 ЕД is not known.

Table 2 displays an overview of the volume of sterile diluent for reconstitution and the reconstituted Коллагеназа КК 250 ЕД solution to be used in the intralesional injection.

Table 2: Volumes Needed for Reconstitution and Administration

Reconstituted Коллагеназа КК 250 ЕД solution remaining in the vial after the injection should be discarded.

1. Before use, remove the vial containing the lyophilized powder of Коллагеназа КК 250 ЕД and the vial containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial containing Коллагеназа КК 250 ЕД. The cake of lyophilized powder should be intact and white in color.
2. After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper and surrounding surface of the vial containing Коллагеназа КК 250 ЕД and the vial containing the diluent for reconstitution with sterile alcohol (no other antiseptics should be used).
3. Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of Коллагеназа КК 250 ЕД.
4. Using a 1 mL syringe with 0.01 mL graduations with a 27-gauge ½-inch needle (not supplied), withdraw a volume of 0.39 mL of the diluent supplied.
5. Inject the diluent slowly into the sides of the vial containing the lyophilized powder of Коллагеназа КК 250 ЕД. Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution.
6. The reconstituted Коллагеназа КК 250 ЕД 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. If the reconstituted Коллагеназа КК 250 ЕД solution is refrigerated, allow this solution to return to room temperature for approximately 15 minutes before use.
7. Discard the syringe and needle used for reconstitution and the diluent vial.

1. Prior to each treatment cycle, identify the treatment area as follows:
   • Induce a penile erection. A single intracavernosal injection of 10 or 20 micrograms of alprostadil may be used for this purpose. Apply antiseptic at the site of injection and allow the skin to dry prior to the intracavernosal injection.
   • Locate the plaque at the point of maximum concavity (or focal point) in the bend of the penis.
   • Mark the point with a surgical marker. This indicates the target area in the plaque for Коллагеназа КК 250 ЕД deposition.

1. The reconstituted Коллагеназа КК 250 ЕД solution should be clear. Inspect the solution visually for particulate matter and discoloration prior to administration. If the solution contains particulates, is cloudy, or is discolored, do not inject the reconstituted solution.
2. Apply antiseptic at the site of the injection and allow the skin to dry.
3. Administer suitable local anesthetic, if desired.
4. Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge ½- inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing 0.58 mg of Коллагеназа КК 250 ЕД).
5. The penis should be in a flaccid state before Коллагеназа КК 250 ЕД is injected. Place the needle tip on the side of the target plaque in alignment with the point of maximal concavity. Orient the needle so that it enters the edge of the plaque and advance the needle into the plaque itself from the side. Do not advance the needle beneath the plaque nor perpendicularly towards the corpora cavernosum.
6. Insert and advance the needle transversely through the width of the plaque, towards the opposite side of the plaque without passing completely through it. Proper needle position is tested and confirmed by carefully noting resistance to minimal depression of the syringe plunger.
7. With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly inject Коллагеназа КК 250 ЕД into the plaque. Withdraw the needle slowly so as to deposit the full dose along the needle track within the plaque. For plaques that are only a few millimeters in width, the distance of withdrawal of the syringe may be very minimal. The goal is always to deposit the full dose entirely within the plaque.
8. Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a dressing as necessary.
9. Discard the unused portion of the reconstituted solution and diluent after each injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.
10. The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from the first injection.

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:

• Administer suitable local anesthetic, if desired.
• Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Avoid direct pressure on the injection site.
• Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient's penile curvature, with stretching to the point of moderate resistance. Hold pressure for 30 seconds then release.
• After a 30 second rest period, repeat the penile modeling technique for a total of 3 modeling attempts at 30 seconds for each attempt.

In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle as follows:

• During spontaneous erections, gently attempt to straighten the penis without producing pain and hold the penis in a straightened position for 30 seconds.
• The flaccid penis should be gently stretched three times daily. Slow, gentle force should be used without producing pain.

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

XIAFLEX, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use. The dose of XIAFLEX 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 XIAFLEX 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 XIAFLEX 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.

Table 1: Volumes Needed for Reconstitution and Administration for Dupuytren’s Contracture

Four weeks after the XIAFLEX 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 XIAFLEX 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 XIAFLEX at other treatment visits approximately 4 weeks apart.

1. Before use, remove the vial(s) containing the lyophilized powder of XIAFLEX and the vial(s) containing the diluent for reconstitution from the refrigerator and allow the vials to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial(s) containing XIAFLEX. The cake of lyophilized powder should be intact and white in color.
2. After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper and surrounding surface of the vial(s) containing XIAFLEX and the vial(s) containing the diluent for econstitution with sterile alcohol (no other antiseptics should be used).
3. Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of XIAFLEX.
4. Using a 1 mL syringe that contains 0.01 mL graduations with a 27-gauge ½-inch needle (not supplied), withdraw a volume of the diluent s upplied, as follows:
   • 0.39 mL for cords affecting a MP joint or
   • 0.31 mL for cords affecting a PIP joint.
5. Inject the diluent slowly into the sides of the vial containing the lyophilized powder of XIAFLEX. Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. If administering two injections in the same hand during a treatment visit, use a new syringe to reconstitute a second vial of XIAFLEX with a second vial of diluent.
6. 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. If the reconstituted XIAFLEX solution is refrigerated, allow this solution to return to room temperature for approximately 15 minutes before use.
7. Discard the syringe(s) and needle(s) used for reconstitution and the diluent vial(s).

1. The reconstituted XIAFLEX solution should be clear. Inspect the solution visually for particulate matter and discoloration prior to administration. If the solution contains particulates, is cloudy, or is discolored, do not inject the reconstituted solution.
2. Administration of a local anesthetic agent prior to injection is not recommended, as it may interfere with proper placement of the XIAFLEX injection.
3. If injecting into a cord affecting the PIP joint of the fifth finger, care should be taken to inject as close to the palmar digital crease as possible (as far proximal to the digital PIP joint crease), and the needle insertion should not be more than 2 to 3 mm in depth. Tendon ruptures occurred after XIAFLEX injections near the digital PIP joint crease.
4. Reconfirm the cord(s) to be injected. The site chosen for each injection should be the area where the contracting cord is maximally separated from the underlying flexor tendons and where the skin is not intimately adhered to the cord.
5. Apply an antiseptic at the site(s) of the injection(s) and allow the skin to dry.

1. Using a new 1 mL hubless syringe that contains 0.01 mL graduations with a permanently fixed, 27- gauge ½-inch needle (not supplied), withdraw a volume of reconstituted solution (containing 0.58 mg of XIAFLEX) as follows:
   • 0.25 mL for cords affecting a MP joint or
   • 0.20 mL for cords affecting a PIP joint.
2. With your non-dominant hand, secure the patient's hand to be treated while simultaneously applying tension to the cord. With your dominant hand, place the needle into the cord, using caution to keep the needle within the cord. Avoid having the needle tip pass completely through the cord to help minimize the potential for injection of XIAFLEX into tissues other than the cord. After needle placement, if there is any concern that the needle is in the flexor tendon, apply a small amount of passive motion at the distal interphalangeal (DIP) joint. If insertion of the needle into a tendon is suspected or paresthesia is noted by the patient, withdraw the needle and reposition it into the cord.
3. If the needle is in the proper location, there will be some resistance noted during the injection procedure. After confirming that the needle is correctly placed in the cord, inject approximately one-third of the dose.
4. Next, withdraw the needle tip from the cord and reposition it in a slightly more distal location (approximately 2 to 3 mm) to the initial injection in the cord and inject another one-third of the dose.
5. Again withdraw the needle tip from the cord and reposition it a third time proximal to the initial injection (approximately 2 to 3 mm) and inject the final portion of the dose into the cord.
6. When administering two injections in the same hand during a treatment visit, use a new syringe and separate vial of reconstituted solution for each injection. Repeat steps a through f.
7. When administering two injections in the same hand during a treatment visit, begin with the affected finger in the most medial aspect of the hand and continue toward the lateral aspect (eg, fifth finger to index finger). When administering two injections in a cord affecting two joints in the same finger, begin with the affected joint in the most proximal aspect of the finger and continue toward the distal aspect (eg, MP to PIP).
8. Wrap the patient's treated hand with a soft, bulky, gauze dressing.
9. Instruct the patient to limit motion of the treated finger(s) and to keep the injected hand elevated until bedtime.
10. Instruct the patient not to attempt to disrupt the injected cord(s) by self-manipulation and to return to the healthcare provider's office the next day for follow-up and a finger extension procedure(s), if needed.
11. Discard the unused portion of the reconstituted solution and diluent after injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.

1. At the follow-up visit approximately 24 to 72 hours after the injection(s ), if a contracture remains, perform a passive finger extension procedure on each treated joint (as described below) to facilitate cord disruption. If two joints in one finger were treated, perform the finger extension procedure on the affected MP joint before performing the finger extension procedure on the affected PIP joint.
2. Local anesthesia may be used. Avoid direct pressure on the injection site as it will likely be tender. Care should be taken during release of contracture, as some patients may experience skin splitting. If this occurs, cover the area with gauze and apply gentle pressure until bleeding stops. Standard wound care with regular dressings should be applied.
3. While the patient's wrist is in the flexed position, apply moderate stretching pressure to the injected cord by extending the finger for approximately 10 to 20 seconds. For cords affecting the PIP joint, perform the finger extension procedure when the MP joint is in the flexed position.
4. If the first finger extension procedure does not result in disruption of the cord, a second and third attempt can be performed at 5- to 10-minute intervals. However, no more than 3 attempts per joint are recommended to disrupt a cord.
5. If the cord has not been disrupted after 3 attempts, a follow-up visit may be scheduled in approximately 4 weeks. If, at that subsequent visit, the contracted cord persists, an additional XIAFLEX injection with finger extension procedures may be performed.
6. Following the finger extension procedure(s), fit patient with a splint and provide instructions for use at bedtime for up to 4 months to maintain finger extension. Also, instruct the patient to perform finger extension and flexion exercises several times a day for several months.

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

XIAFLEX, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use. The dose of XIAFLEX 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 XIAFLEX injection procedures and one penile modeling procedure. The second XIAFLEX 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 XIAFLEX is not known.

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

Table 2: Volumes Needed for Reconstitution and Administration

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

1. Before use, remove the vial containing the lyophilized powder of XIAFLEX and the vial containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial containing XIAFLEX. The cake of lyophilized powder should be intact and white in color.
2. After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper and surrounding surface of the vial containing XIAFLEX and the vial containing the diluent for reconstitution with sterile alcohol (no other antiseptics should be used).
3. Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of XIAFLEX.
4. Using a 1 mL syringe with 0.01 mL graduations with a 27-gauge ½-inch needle (not supplied), withdraw a volume of 0.39 mL of the diluent supplied.
5. Inject the diluent slowly into the sides of the vial containing the lyophilized powder of XIAFLEX. Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution.
6. 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. If the reconstituted XIAFLEX solution is refrigerated, allow this solution to return to room temperature for approximately 15 minutes before use.
7. Discard the syringe and needle used for reconstitution and the diluent vial.

1. Prior to each treatment cycle, identify the treatment area as follows:
   • Induce a penile erection. A single intracavernosal injection of 10 or 20 micrograms of alprostadil may be used for this purpose. Apply antiseptic at the site of injection and allow the skin to dry prior to the intracavernosal injection.
   • Locate the plaque at the point of maximum concavity (or focal point) in the bend of the penis.
   • Mark the point with a surgical marker. This indicates the target area in the plaque for XIAFLEX deposition.

1. The reconstituted XIAFLEX solution should be clear. Inspect the solution visually for particulate matter and discoloration prior to administration. If the solution contains particulates, is cloudy, or is discolored, do not inject the reconstituted solution.
2. Apply antiseptic at the site of the injection and allow the skin to dry.
3. Administer suitable local anesthetic, if desired.
4. Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge ½- inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing 0.58 mg of XIAFLEX).
5. The penis should be in a flaccid state before XIAFLEX is injected. Place the needle tip on the side of the target plaque in alignment with the point of maximal concavity. Orient the needle so that it enters the edge of the plaque and advance the needle into the plaque itself from the side. Do not advance the needle beneath the plaque nor perpendicularly towards the corpora cavernosum.
6. Insert and advance the needle transversely through the width of the plaque, towards the opposite side of the plaque without passing completely through it. Proper needle position is tested and confirmed by carefully noting resistance to minimal depression of the syringe plunger.
7. With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly inject XIAFLEX into the plaque. Withdraw the needle slowly so as to deposit the full dose along the needle track within the plaque. For plaques that are only a few millimeters in width, the distance of withdrawal of the syringe may be very minimal. The goal is always to deposit the full dose entirely within the plaque.
8. Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a dressing as necessary.
9. Discard the unused portion of the reconstituted solution and diluent after each injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.
10. The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from the first injection.

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:

• Administer suitable local anesthetic, if desired.
• Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Avoid direct pressure on the injection site.
• Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient's penile curvature, with stretching to the point of moderate resistance. Hold pressure for 30 seconds then release.
• After a 30 second rest period, repeat the penile modeling technique for a total of 3 modeling attempts at 30 seconds for each attempt.

In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle as follows:

• During spontaneous erections, gently attempt to straighten the penis without producing pain and hold the penis in a straightened position for 30 seconds.
• The flaccid penis should be gently stretched three times daily. Slow, gentle force should be used without producing pain.

Special precautions for disposal and other handling

Instructions for use and handling

Preparation - Reconstitution procedure

The vial containing Коллагеназа КК 250 ЕД and the vial containing the solvent for solution for injection for reconstitution must be refrigerated. Prior to use, the vial containing Коллагеназа КК 250 ЕД and the vial containing the solvent for solution for reconstitution must be removed from the refrigerator and allowed to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Each vial of Коллагеназа КК 250 ЕД and sterile solvent for reconstitution should only be used for a single injection. If two cords of affected 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.

Using an aseptic technique, the following procedure for reconstitution must be followed:

1. Dupuytren's contracture: The joint to be treated (MP or PIP) should be confirmed as the volume of solvent required for reconstitution is determined by the type of joint (PIP joint requires a smaller volume for injection).

2. Peyronie's disease: The treatment area should be identified and marked with a surgical marker on the erected penis.

3. The flip-off plastic caps should be removed from both vials. The rubber stopper and surrounding surface of the vial containing Коллагеназа КК 250 ЕД and the vial containing the solvent for reconstitution should be swabbed with sterile alcohol (no other antiseptics must be used).

4. Only the supplied solvent must be used for reconstitution; it contains calcium which is required for the activity of Коллагеназа КК 250 ЕД. Using a sterile syringe calibrated with 0.01 ml graduations, the appropriate amount of solvent supplied should be withdrawn in order to deliver as follows:

5. The solvent should slowly be injected into the sides of the vial containing the lyophilised powder of Коллагеназа КК 250 ЕД. The vial containing the solution should not be inverted or shaken. The solution should slowly be swirled to ensure that all of the lyophilised powder has gone into solution. The syringe and needle used for reconstitution are thereafter removed and discarded.

6. The solution should visually be inspected for particulate matter and discoloration prior to administration. The reconstituted solution of Коллагеназа КК 250 ЕД must be clear. If the solution contains particles, is cloudy or discoloured, it should not be injected.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.