Administration of Iruxol mono 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 Iruxol mono are unknown. It is possible that multiple simultaneous or excessive doses of Iruxol mono 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.
Treatment of Peyronie's plaques that involve the penile urethra due to potential risk to this structure.
Iruxol mono is contraindicated in:
XIAFLEX is contraindicated in:
Dupuytren's contracture
Summary of the safety profile
The most frequently reported adverse reactions during the Iruxol mono clinical studies (272 of 409 patients received up to three single injections of Iruxol mono 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 Iruxol mono (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.
| System organ class | Very common | Common | Uncommon |
| Infections and infestations | Injection site cellulitis Lymphangitis | ||
| Blood and lymphatic system disorders | Lymphadenopathy | Lymph node pain | Thrombocytopenia Lymphadenitis |
| Immune system disorders | Hypersensitivity Anaphylactic reaction | ||
| Psychiatric disorders | Disorientation Agitation Insomnia Irritability Restlessness | ||
| Nervous system disorders | Paresthesia Hypoesthesia Burning sensation Dizziness Headache | Complex regional pain syndrome Monoplegia Syncope vasovagal Tremor Hyperaesthesia | |
| Eye disorders | Eyelid oedema | ||
| Vascular disorders | Haematoma Hypotension | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea Hyperventilation | ||
| Gastrointestinal disorders | Nausea | Diarrhoea Vomiting Abdominal pain upper | |
| Skin and subcutaneous tissue disorders | Pruritus Ecchymosis | Blood blistera Blister Rash Erythema Hyperhidrosis | Erythematous or macular rash Eczema Swelling face Skin disorders, like exfoliation, lesions, pain, tightness, discoloration or scab |
| Musculoskeletal and connective tissue disorders | Pain in extremity | Arthralgia Axillary mass Joint swelling Myalgia | Pain in chest wall, groin, neck or shoulder Musculoskeletal discomfort or stiffness, joint stiffness or crepitation Limb discomfort Tendonitis Muscle spasms or weakness |
| Reproductive system and breast disorders | Breast tenderness Hypertrophy breast | ||
| General disorders and administration site conditions | Oedema peripheralc Injection site haemorrhage, pain or swelling Tenderness | Axillary pain Inflammation Injection site warmth, erythema, inflammation, vesicles or pruritus Swelling | Local swelling Pyrexia Pain Discomfort Fatigue Feeling hot Influenza like illness Injection site reaction, malaise, irritation, anaesthesia, desquamation, nodule or discoloration Cold intolerance of the treated fingers |
| Investigations | Lymph node palpable Alanine aminotransferase increased Aspartate aminotransferase increased Body temperature increased | ||
| Injury, poisoning and procedural complications | Contusion | Skin lacerationa,b | Tendon rupture Ligament injury Limb injury Open wound Wound dehiscence |
a reported with a higher incidence (very common) in patients who received two concurrent injections of Iruxol mono 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 “lacerationâ€
c “oedema peripheral†includes “injection site oedema†and “oedemaâ€
The incidence of skin laceration (29.1%) was higher for subjects treated with two concurrent injections of Iruxol mono 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 Iruxol mono in the same hand and up to three single injections of Iruxol mono 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 Iruxol mono 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 Iruxol mono) 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 Iruxol mono 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 Iruxol mono 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%) Iruxol mono-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.
| System organ class | Very common | Common | Uncommon |
| Infections and infestations | Fungal skin infection Infection Upper respiratory infection | ||
| Blood and lymphatic system disorders | Lymph node pain Eosinophilia Lymphadenopathy | ||
| Immune system disorders | Drug hypersensitivity Anaphylactic reaction* | ||
| Metabolism and nutrition disorders | Fluid retention | ||
| Psychiatric disorders | Abnormal dreams Depression Sexual inhibition | ||
| Nervous system disorders | Headache Dizziness Dysgeusia Paraesthesia Burning sensation Hyperaesthesia Hypoaesthesia | ||
| Ear and labyrinth disorders | Tinnitus | ||
| Cardiac disorders | Tachycardia | ||
| Vascular disorders | Haematoma Hypertension Haemorrhage Lymphangiopathy Thrombophlebitis superficial | ||
| Respiratory, thoracic and mediastinal disorders | Cough | ||
| Gastrointestinal disorders | Abdominal distension Constipation | ||
| Skin and subcutaneous tissue disorders | Blood blister Skin discolouration | Erythema Penile ulceration Rash erythematous Night sweats Skin disorder, nodule, granuloma, blister, irritation or oedema Pigmentation disorder Skin hyperpigmentation | |
| Musculoskeletal and connective tissue disorders | Back, pubic or groin pain Ligament disorder Ligament pain Musculoskeletal discomfort | ||
| Renal and urinary disorders | Dysuria Micturition urgency | ||
| Reproductive system and breast disorders | Penile haematomaa, swellingb, painc or ecchymosisd | Penile blister Pruritus genital Painful erection Erectile dysfunction Dyspareunia Penile erythema | Penile adhesion Penis disorder Progression of Peyronie's disease Sexual dysfunction Scrotal erythema Genital discomfort Genital haemorrhage Pelvic pain Penile size reduced Penile vein thrombosis Scrotal oedema Scrotal pain |
| General disorders and administration site conditions | Injection site vesicles or pruritus Localised oedema Nodule Suprapubic pain | Feeling hot Injection site reaction or discolouration Pyrexia Swelling Asthenia Chills Cyst Induration Influenza like illness Oedema Secretion discharge Tenderness | |
| Investigations | Blood glucose increased Blood pressure systolic increased Body temperature increased | ||
| Injury, poisoning and procedural complications | Procedural pain | Fracture of penis Skin laceration Open wound Scrotal haematoma Joint injury Penis injury |
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 Iruxol mono 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:
The following serious adverse reactions in patients with Peyronie's disease are discussed in greater detail elsewhere in the labeling:
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Out of 1082 patients who received 0.58 mg of Iruxol mono in the controlled and uncontrolled portions of the Iruxol mono studies (2630 Iruxol mono injections), 3 (0.3%) patients had a flexor tendon rupture of the treated finger within 7 days of the injection.
The data described below are based on two pooled randomized, double-blind, placebo-controlled trials through Day 90 in patients with Dupuytren's contracture (Studies 1 and 2). In these trials, patients were treated with up to 3 injections of 0.58 mg of Iruxol mono or placebo with approximately 4-week intervals between injections and the patients had finger extension procedures the day after injection, if needed, to facilitate disruption of the cord. These trials were comprised of 374 patients of whom 249 and 125 received 0.58 mg of Iruxol mono 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 Iruxol monotreated and placebo-treated patients had an adverse reaction after up to 3 injections, respectively. Over 95% of Iruxol mono-treated patients had an adverse reaction of the injected extremity after up to 3 injections. Approximately 81% of these local reactions resolved without intervention within 4 weeks of Iruxol mono injections. The adverse reaction profile was similar for each injection, regardless of the number of injections administered. However, the incidence of pruritus increased with more injections.
The most frequently reported adverse drug reactions (≥ 25%) in the Iruxol mono 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 Iruxol mono-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 Iruxol mono-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
| Adverse Reaction | Iruxol mono N=249 | Placebo N=125 |
| All Adverse Reactions | 98% | 51% |
| Edema Peripherala | 73% | 5% |
| Contusionb | 70% | 3% |
| Injection Site Hemorrhage | 38% | 3% |
| Injection Site Reactionc | 35% | 6% |
| Pain in Extremity | 35% | 4% |
| Tenderness | 24% | 0% |
| Injection Site Swellingd | 24% | 6% |
| Prurituse | 15% | 1% |
| Lymphade no pathyf | 13% | 0% |
| Skin Laceration | 9% | 0% |
| Lymph Node Pain | 8% | 0% |
| Erythema | 6% | 0% |
| Axillary Pain | 6% | 0% |
| aMost of these events were swelling of the injected hand. bIncludes the terms: contusion (any body system) and ecchymosis cIncludes the terms: injection site reaction, injection site erythema, injection site inflammation, injection site irritation, injection site pain, and injection site warmth dIncludes the terms: injection site swelling and injection site edema eIncludes the terms: pruritus and injection site pruritus fIncludes the terms: lymphadenopathy and axillary mass |
Some patients developed vasovagal syncope after finger extension procedures.
The safety of two concurrent injections of Iruxol mono 0.58 mg into Dupuytren's cords in the same hand was evaluated in a historically-controlled, open-label multi-center trial in 715 adult subjects with Dupuytren's contracture (Study 3). In Study 3, finger extension procedures were performed approximately 24 to 72 hours after injection. The patient demographics were similar to Studies 1 and 2.
Out of 715 patients who received two concurrent injections of Iruxol mono 0.58 mg in the same hand (1450 Iruxol mono 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 Iruxol mono-treated patients after two concurrent injections of Iruxol mono 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 Iruxol mono in Study 3
| Adverse Reaction | Iruxol mono N=715 |
| Subjects with ≥ 1 adverse reaction | 95% |
| Edema peripheral | 77% |
| Contusion | 59% |
| Pain in extremity | 51% |
| Laceration | 22% |
| Pruritus | 15% |
| Injection site pain | 14% |
| Lymphadenopathy | 13% |
| Blood blister | 12% |
| Injection site hematoma | 8% |
| Axillary pain | 7% |
| Injection site hemorrhage | 6% |
| Injection site swelling | 5% |
| Ecchymosis | 5% |
An observational, open label study was conducted in subjects who had participated in Iruxol mono clinical trials for Dupuytren's contracture (Study 4). A subset of patients who had recurrence of contracture in a joint that was previously successfully treated with Iruxol mono in Study 4 were retreated (Study 5). No new safety signals were identified among subjects who were retreated with Iruxol mono.
Clinical Studies Experience In Patients With Peyronie’s DiseaseBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In the controlled and uncontrolled clinical studies of Iruxol mono in Peyronie's disease, 1044 patients received a total of 7466 Iruxol mono injections.
Corporal Rupture And Other Serious Penile InjuryThe 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 Iruxol mono and placebo, respectively. In these trials, patients were given up to 4 treatment cycles of Iruxol mono or placebo. In each cycle, two injections of Iruxol mono 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% Iruxol mono-treated patients, 61% placebo-treated). Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered.
The most frequently reported adverse drug reactions (≥ 25%) in the Iruxol mono 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 Iruxol mono-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 Iruxol mono-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
| Adverse Reaction | Iruxol mono N=551 | Placebo N=281 |
| All Adverse Reactions | 84.2% | 36.3% |
| Penile hematomaa | 65.5% | 19.2% |
| Penile swellingb | 55.0% | 3.2% |
| Penile painc | 45.4% | 9.3% |
| Penile ecchymosesd | 14.5% | 6.8% |
| Blood blister | 4.5% | 0 |
| Penile blister | 3.3% | 0 |
| Pruritus genital | 3.1% | 0 |
| Painful erection | 2.9% | 0 |
| Erectile dysfunction | 1.8% | 0.4% |
| Skin discoloration | 1.8% | 0 |
| Procedural pain | 1.6% | 0.7% |
| Injection site vesicles | 1.3% | 0 |
| Localized edema | 1.3% | 0 |
| Dyspareunia | 1.1% | 0 |
| Injection site pruritus | 1.1% | 0 |
| Nodule | 1.1% | 0 |
| Suprapubic pain | 1.1% | 0 |
| aIncludes: injection site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of subjects. bIncludes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection site edema. cIncludes: injection site pain, penile pain, and injection site discomfort. dIncludes: contusion, ecchymoses, penile hemorrhage, and injection site hemorrhage. |
Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of Iruxol mono-treated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined.
Reports Of Penile “Popping” Sounds Or SensationsA 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%) Iruxol mono-treated patients and 1/281 (0.3%) placebo-treated patients.
There were no clinically meaningful differences in the incidence of adverse events following treatment with Iruxol mono based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use.
Iruxol mono was not associated with shortening of penile length in clinical trials in the treatment of Peyronie's disease.
ImmunogenicityDuring clinical studies in Dupuytren's contracture and Peyronie's disease, patients were tested at multiple time points for antibodies to the protein components of Iruxol mono (AUX-I and AUX-II).
In the Dupuytren's contracture clinical studies (Studies 1 and 2), at 30 days post the first injection of Iruxol mono 0.58 mg, 92% of patients had antibodies against AUX-I detected and 86% of patients had antibodies against AUX-II detected. After the fourth injection of Iruxol mono, every Iruxol mono-treated patient developed high titers of antibodies to both AUX-I and AUX-II. After five years more than 90 percent of patients remained seropositive for anti-AUX-I and anti-AUX-II antibody (Study 4). Neutralizing antibodies were assayed for all patients (204) in Study 1. Neutralizing antibodies to AUX-I or AUX-II, were detected in 10% and 21%, respectively, of patients treated with Iruxol mono. Among patients in Study 3 who reported no prior exposure to Iruxol mono, 97% of patients had antibodies against AUX-I and AUX-II after two concurrent doses of Iruxol mono 0.58 mg (total dose of 1.16 mg) in the same hand. In Study 5, treatment of recurrent contractures with Iruxol mono resulted in similar immunogenicity results as seen in Studies 1 and 2.
In the Peyronie's disease clinical studies, at 6 weeks after the first treatment cycle of Iruxol mono 0.58 mg, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of Iruxol mono, >99% of Iruxol mono-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested.
In patients treated for these two indications, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions.
Since the protein components in Iruxol mono (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:
The following serious adverse reactions in patients with Peyronie's disease are discussed in greater detail elsewhere in the labeling:
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
| Adverse Reaction | XIAFLEX N=249 | Placebo N=125 |
| All Adverse Reactions | 98% | 51% |
| Edema Peripherala | 73% | 5% |
| Contusionb | 70% | 3% |
| Injection Site Hemorrhage | 38% | 3% |
| Injection Site Reactionc | 35% | 6% |
| Pain in Extremity | 35% | 4% |
| Tenderness | 24% | 0% |
| Injection Site Swellingd | 24% | 6% |
| Prurituse | 15% | 1% |
| Lymphade no pathyf | 13% | 0% |
| Skin Laceration | 9% | 0% |
| Lymph Node Pain | 8% | 0% |
| Erythema | 6% | 0% |
| Axillary Pain | 6% | 0% |
| aMost of these events were swelling of the injected hand. bIncludes the terms: contusion (any body system) and ecchymosis cIncludes the terms: injection site reaction, injection site erythema, injection site inflammation, injection site irritation, injection site pain, and injection site warmth dIncludes the terms: injection site swelling and injection site edema eIncludes the terms: pruritus and injection site pruritus fIncludes the terms: lymphadenopathy and axillary mass |
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
| Adverse Reaction | XIAFLEX N=715 |
| Subjects with ≥ 1 adverse reaction | 95% |
| Edema peripheral | 77% |
| Contusion | 59% |
| Pain in extremity | 51% |
| Laceration | 22% |
| Pruritus | 15% |
| Injection site pain | 14% |
| Lymphadenopathy | 13% |
| Blood blister | 12% |
| Injection site hematoma | 8% |
| Axillary pain | 7% |
| Injection site hemorrhage | 6% |
| Injection site swelling | 5% |
| Ecchymosis | 5% |
An observational, open label study was conducted in subjects who had participated in XIAFLEX clinical trials for Dupuytren's contracture (Study 4). A subset of patients who had recurrence of contracture in a joint that was previously successfully treated with XIAFLEX in Study 4 were retreated (Study 5). No new safety signals were identified among subjects who were retreated with XIAFLEX.
Clinical Studies Experience In Patients With Peyronie’s DiseaseBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In the controlled and uncontrolled clinical studies of XIAFLEX in Peyronie's disease, 1044 patients received a total of 7466 XIAFLEX injections.
Corporal Rupture And Other Serious Penile InjuryThe 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
| Adverse Reaction | XIAFLEX N=551 | Placebo N=281 |
| All Adverse Reactions | 84.2% | 36.3% |
| Penile hematomaa | 65.5% | 19.2% |
| Penile swellingb | 55.0% | 3.2% |
| Penile painc | 45.4% | 9.3% |
| Penile ecchymosesd | 14.5% | 6.8% |
| Blood blister | 4.5% | 0 |
| Penile blister | 3.3% | 0 |
| Pruritus genital | 3.1% | 0 |
| Painful erection | 2.9% | 0 |
| Erectile dysfunction | 1.8% | 0.4% |
| Skin discoloration | 1.8% | 0 |
| Procedural pain | 1.6% | 0.7% |
| Injection site vesicles | 1.3% | 0 |
| Localized edema | 1.3% | 0 |
| Dyspareunia | 1.1% | 0 |
| Injection site pruritus | 1.1% | 0 |
| Nodule | 1.1% | 0 |
| Suprapubic pain | 1.1% | 0 |
| aIncludes: injection site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of subjects. bIncludes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection site edema. cIncludes: injection site pain, penile pain, and injection site discomfort. dIncludes: contusion, ecchymoses, penile hemorrhage, and injection site hemorrhage. |
Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of XIAFLEX-treated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined.
Reports Of Penile “Popping” Sounds Or SensationsA 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.
ImmunogenicityDuring 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.
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 Iruxol mono 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 Iruxol mono. Thus, the carcinogenic risk is unknown.
Iruxol mono 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.
Iruxol mono is indicated for the treatment of adult patients with Dupuytren's contracture with a palpable cord.
Iruxol mono 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: Other Drugs For Disorders of the Musculo-Skeletal System - Enzymes, ATC code: M09AB02
Iruxol mono 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 Iruxol mono administration is localized and does not require or result in quantifiable systemic levels of AUX-I and AUX-II, the primary pharmacodynamic activity of Iruxol mono 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. Iruxol mono 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 Iruxol mono 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 Iruxol mono 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 Iruxol mono 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 Iruxol mono 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 Iruxol mono 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.
Iruxol mono 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. Iruxol mono 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)
| VARIABLE | Iruxol mono (N=249) | Placebo (N=125) |
| Age (years) | ||
| Mean | 62.7 | 64.2 |
| Age category (years), n (%) |
|
|
| < 45 | 9 (3.6) | 5 (4.0) |
| 45 - 54 | 33 (13.2) | 17 (13.6) |
| 55 - 64 | 103 (41.4) | 44 (35.2) |
| 65 - 74 | 82 (33.0) | 40 (32.0) |
| > 75 | 22 (8.8) | 19 (15.2) |
| Gender, n (%) | ||
| Male | 210 (84.3) | 91 (72.8) |
| Female | 39 (15.7) | 34 (27.2) |
| Family history of Dupuytren's disease, n (%) |
|
|
| Yes | 107 (43.0) | 62 (49.6) |
| No | 142 (57.0) | 63 (50.4) |
| Physician Rating of Severity at Baseline |
|
|
| Mild | 38 (15.4 %) | 21 (16.8 %) |
| Moderate | 148 (59.9 %) | 71 (56.8 %) |
| Severe | 61 (24.7 %) | 33 (26.4 %) |
| Missing1 | 2 (0.8 %) | - |
| Note: Includes all patients who received at least 1 injection of double-blind study medicinal product (Iruxol mono 0.58 mg or placebo). 1 Not used to calculate physician rating of severity at baseline percentage - actual denominator of N=247 used. | ||
Table 4.
Percentage of patients who achieved reduction in contracture to 5° or less
(Last injection)
| TREATED PRIMARY JOINTS | CORD I | CORD II | ||
| Iruxol mono | Placebo | Iruxol mono | Placebo | |
| All Joints p-value | N=203c | N=103c | N=45 | N=21 |
| 64.0 % <0.001 | 6.8 % - | 44.4 % <0.001 | 4.8 % - | |
| MP Jointsa p-value | N=133 | N=69 | N=20 | N=11 |
| 76.7 % <0.001 | 7.2 % - | 65.0 % 0.003 | 9.1 % - | |
| PIP Jointsb p-value | N=70 | N=34 | N=25 | N=10 |
| 40.0 % <0.001 | 5.9 % - | 28.0 % 0.069 | 0.0 % - | |
| a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Iruxol mono treated group had a baseline contracture of 0 degrees before treatment). | ||||
Table 5.
Mean increase in range of motion from baseline
(Last injection)
| TREATED PRIMARY JOINTS | CORD I | CORD II | ||
| Iruxol mono | Placebo | Iruxol mono | Placebo | |
| All Joints | N=203 c | N=103 c | N=45 | N=21 |
| Mean Baseline (SD) Mean Final (SD) Mean increase (SD) | 43.9 (20.1) 80.7 (19.0) 36.7 (21.0) | 45.3 (18.7) 49.5 (22.1) 4.0 (14.8) | 40.3 (15.2) 75.8 (17.7) 35.4 (17.8) | 44.0 (16.5) 51.7 (19.6) 7.6 (14.9) |
| MP Jointsa | N=133 | N=69 | N=20 | N=11 |
| Mean Baseline (SD) Mean Final (SD) Mean increase (SD) | 42.6 (20.0) 83.7 (15.7) 40.6 (20.0) | 45.7 (19.2) 49.7 (21.1) 3.7 (12.6) | 39.5 (11.8) 79.5 (11.1) 40.0 (13.5) | 41.4 (20.8) 50.0 (21.5) 8.6 (14.7) |
| PIP Jointsb | N=70 | N=34 | N=25 | N=10 |
| Mean Baseline (SD) Mean Final (SD) Mean increase (SD) | 46.4 (20.4) 74.9 (23.1) 29.0 (20.9) | 44.4 (17.9) 49.1 (24.4) 4.7 (18.5) | 41.0 (17.7) 72.8 (21.3) 31.8 (20.1) | 47.0 (10.3) 53.5 (18.3) 6.5 (15.8) |
| a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Iruxol mono treated group had a baseline contracture of 0 degrees before treatment). All p-values < 0.001 for all comparisons between Iruxol mono and placebo, except for PIP joints in Study CORD II which was not eligible for statistical testing due to a hierarchical testing procedure. | ||||
Physician-rated change in contracture severity was reported as very much improved or much improved in 86% and 80% of the subjects in the Iruxol mono 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 Iruxol mono 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 Iruxol mono 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 Iruxol mono 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 Iruxol mono 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.
| Table 6. Total fixed flexion contracture and range of motion following administration of two concurrent injections of Iruxol mono 0.58 mg in the same hand, mITT population, study AUX-CC-867 (first treatment cycle) | |||||
| Same Finger, 1 MP, 1 PIP (n=350) | Different Fingers, Both MPs (n=244) | Different Fingers, Both PIPs (n=72) | Different Fingers, 1 MP, 1 PIP (n=58) | Total (n=724) | |
| Total FFC (°) |
|
|
|
|
|
| Baseline, mean (SD) | 102 (31) | 89 (31) | 109 (37) | 96 (28) | 98 (32) |
| Day 31, mean (SD) | 30 (27) | 17 (28) | 47 (39) | 31 (29) | 27 (30) |
| Change, mean (SD) | 72 (29) | 72 (29) | 62 (32) | 65 (34) | 70 (30) |
| % Change, mean (SD) | 72 (22) | 84 (23) | 60 (29) | 68 (27) | 74 (25) |
| Total ROM (°) |
|
|
|
|
|
| Baseline, mean (SD) | 87 (31) | 92 (34) | 93 (36) | 92 (29) | 90 (33) |
| Day 31, mean (SD) | 154 (29) | 163 (30) | 148 (42) | 155 (31) | 156 (31) |
| Change, mean (SD) | 67 (30) | 71 (34) | 55 (28) | 63 (37) | 67 (32) |
| FFC = Fixed flexion contracture ROM = Range of motion | |||||
Clinical success (a reduction of contracture to ≤5° within 30 days) after two concurrent injections of Iruxol mono (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 Iruxol mono 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 Iruxol mono 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 Iruxol mono. These data support the long term safety profile of Iruxol mono 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 Iruxol mono 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 Iruxol mono are provided in Table 7.
Table 7.
Long Term Recurrence Rates for Joints Treated Successfully with Iruxol mono
| Follow-up Interval (days) | N (%) of Joints in Each Intervala | N (%) of Recurrent Joints in Each Intervalb | Cumulative Nominal Recurrence by Joint Type (%) | Cumulative Nominal Recurrence Rate (%)c | Nominal Change in Recurrence Rate vs Previous Year (%) | |
| MP | PIP | |||||
| 0-365 | 20 (3.2) | 19 (6.3) | 1.8 | 6.4 | 3.0 | - |
| 366-730 | 114 (18.3) | 103 (33.9) | 14.2 | 33.7 | 19.6 | 16.6 |
| 731-1095 | 125 (20.1) | 97 (31.9) | 27.1 | 56.4 | 35.2 | 15.6 |
| 1096-1460 | 85 (13.6) | 45 (14.8) | 34.8 | 62.2 | 42.4 | 7.2 |
| 1461-1825 | 169 (27.1) | 27 (8.9) | 39.5 | 65.7 | 46.7 | 4.3 |
| > 1825 | 110 (17.7) | 13 (4.3) | 41.9 | 66.9 | 48.8 | 2.1 |
| a A joint was considered in an interval if the duration of assessment falls in the interval. The duration of assessment started at the day of success (visit after the last injection where the 0° to 5° measurement was first recorded). The duration of assessment ended at the last available measurement or at the day of medical intervention for joints that did not recur and the recurrence day for recurrent joints. b A recurrent joint was a joint evaluated by the investigator as having a worsening Dupuytren's contracture due to a palpable cord. The recurrence day was the visit where the recurrence was reported or the day of intervention if a joint was treated for a worsening Dupuytren's contracture. For joints reported as recurring in a previous study, the day of recurrence was the first visit with a fixed flexion contracture measurement of 20° or greater following the report of recurrence. c The nominal rate of recurrence was the total number of recurrences occurring prior to the last day of the interval divided by the total number of joints (×100). | ||||||
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 Iruxol mono in a previous clinical study. No new safety signals were identified among subjects who were retreated with Iruxol mono. Most adverse events were non-serious, mild or moderate in intensity, and related to the local administration of Iruxol mono 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 Iruxol mono.
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 Iruxol mono 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 Iruxol mono 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 Iruxol mono or placebo (weeks 0, 6, 12, 18), and were followed in a non-treatment follow-up period (weeks 24-52). In each treatment cycle, two injections of Iruxol mono 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.
Iruxol mono 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.
Iruxol mono 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.
| Table 8. Baseline disease characteristics of patientsa with Peyronie's Disease (PD) | ||||
| Study 1 | Study 2 | |||
Absorption
Following administration of either a single dose of 0.58 mg of Iruxol mono to 16 patients with Dupuytren's contracture, or two concurrent injections of 0.58 mg of Iruxol mono in the same hand in 12 patients with Dupuytren's contracture, no quantifiable levels of Iruxol mono were detected in plasma from 5 minutes to 30 days post injection.
Following each of two intralesional administrations, separated by 24 hours, of Iruxol mono 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 Iruxol mono 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 Iruxol mono administered through localized injection into the Dupuytren's cord or into the Peyronie's plaque.
Biotransformation
Because Iruxol mono 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 Iruxol mono 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
Iruxol mono 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 Iruxol mono 0.58 mg into a Dupuytren's cord in 20 patients or two concurrent injections of Iruxol mono 0.58 mg into Dupuytren's cords of 12 patients, no quantifiable levels of Iruxol mono (AUX-I or AUX-II) were detected in plasma up to 30 days post injection.
Following each of two intralesional administrations, separated by 24 hours, of Iruxol mono 0.58 mg into the penile plaque of 19 subjects with Peyronie's disease, plasma levels of AUX-I and AUX-II in subjects with quantifiable levels (79% and 40% for AUX-I and AUX-II, respectively) were minimal and short-lived. The maximal plasma concentrations of AUX-I and AUX-II were <29 ng/mL and <71 ng/mL, respectively, and were observed approximately within 10 minutes after injection. All plasma levels were below the limits of quantification within 30 minutes following dosing. There was no evidence of accumulation following two sequential injections of Iruxol mono 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).
Allergic reactions
Following Iruxol mono 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 Iruxol mono for the treatment of Dupuytren's contracture, demonstrating that severe reactions including anaphylaxis can occur following Iruxol mono injections. Some patients with Dupuytren's contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive Iruxol mono injections.
In the double blind portion of the three phase 3 placebo-controlled clinical studies in Dupuytren's contracture, 17% of Iruxol mono-treated patients had mild reactions (i.e. pruritus) after up to 3 injections. The incidence of Iruxol mono-associated pruritus increased after more Iruxol mono 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 Iruxol mono-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 Iruxol mono injections). The incidence of Iruxol mono-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
Iruxol mono must only be injected into the Dupuytren's cord. Because Iruxol mono lyses collagen, care must be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Injection of Iruxol mono 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 Iruxol mono 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 Iruxol mono. 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 Iruxol mono 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 Iruxol mono into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, Iruxol mono 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 Iruxol mono injection in 5 out of 1044 patients (0.5%) in the controlled and uncontrolled clinical trials in Peyronie's disease. In other Iruxol mono-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
Iruxol mono 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 Iruxol mono-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 Iruxol mono-treated patients developed penile haematoma and 14.5% developed penile ecchymosis. The efficacy and safety of Iruxol mono in patients receiving anticoagulant medicinal products other than up to 150 mg acetylsalicylic acid per day prior to Iruxol mono administration is not known. Use of Iruxol mono 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 Iruxol mono 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 Iruxol mono, 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 Iruxol mono, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of Iruxol mono >99% of Iruxol mono-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 Iruxol mono 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 Iruxol mono, 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 Iruxol mono on subsequent surgery, if needed, is not known.
Special penile conditions/diseases not studied in clinical trials
Iruxol mono 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 Iruxol mono 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'.
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Tendon Rupture Or Other Serious Injury To The Injected Finger/Hand In The Treatment Of Dupuytren’s ContractureIn the controlled and uncontrolled portions of clinical trials in Dupuytren's contracture, flexor tendon ruptures occurred after Iruxol mono injection. Injection of Iruxol mono into collagen-containing structures such as tendons or ligaments of the hand may result in damage to those structures and possible permanent injury such as tendon rupture or ligament damage. Therefore, Iruxol mono 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 Iruxol mono-associated serious local adverse reactions included pulley rupture, ligament injury, complex regional pain syndrome (CRPS), sensory abnormality of the hand, and skin laceration (tear). In a historically controlled post-marketing trial, the incidence of skin laceration (22%) was higher for subjects treated with two concurrent injections of Iruxol mono compared with subjects treated with up to three single injections in the placebo-controlled premarketing trials (9%). Cases of skin laceration requiring skin graft after finger extension procedures have been reported post-marketing. Signs or symptoms that may reflect serious injury to the injected finger/hand should be promptly evaluated because surgical intervention may be required.
Corporal Rupture (Penile Fracture) Or Other Serious Injury To The Penis In The Treatment Of Peyronie’s DiseaseCorporal rupture was reported as an adverse reaction after Iruxol mono injections in 5 of 1044 (0.5%) Iruxol mono treated patients in the controlled and uncontrolled clinical trials in Peyronie's disease.
In other Iruxol mono-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 Iruxol mono into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, Iruxol mono 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.
Iruxol mono REMS ProgramBecause of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie's disease, Iruxol mono is available only through the Iruxol mono REMS Program.
Required components of the Iruxol mono REMS Program include the following:
Further information is available at www.Iruxol monoREMS.com or 1-877-313-1235.
Hypersensitivity Reactions, Including AnaphylaxisIn the controlled portions of the clinical trials in Dupuytren's contracture (Studies 1 and 2), a greater proportion of Iruxol mono-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of Iruxol mono-associated pruritus increased after more Iruxol mono 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 Iruxol mono-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 Iruxol mono injection procedures). The incidence of Iruxol mono-associated pruritus was similar after each injection regardless of the number of injections administered.
Because Iruxol mono contains foreign proteins, severe allergic reactions to Iruxol mono can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to Iruxol mono for the treatment of Dupuytren's contracture. Some patients with Dupuytren's contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive Iruxol mono injections. Healthcare providers should be prepared to address severe allergic reactions following Iruxol mono injections.
Risk Of bleeding In Patients With Abnormal CoagulationIn the Iruxol mono trials in Dupuytren's contracture (Studies 1 and 2), 70% and 38% of Iruxol mono-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively (see Table 3). In the Iruxol mono controlled trials in Peyronie's disease (Studies 1 and 2), 65.5% of Iruxol mono-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 Iruxol mono in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to Iruxol mono administration is not known. In addition, it is recommended to avoid use of Iruxol mono in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin).
Patient Counseling InformationSee FDA-approved patient labeling (Medication Guide).
Patient Counseling For Dupuytren’s ContractureAdvise patients of the following:
After the Iruxol mono injections, instruct patients:
Following the finger extension procedure(s) and fitting patient with a splint, instruct patients:
Advise patients of the following:
After the Iruxol mono injections, instruct the patient:
Provide the patient instructions on the appropriate technique to perform penile modeling activities at home, as described in “What You Need to Know About Iruxol mono Treatment for Peyronie's Disease: A Patient Guide”, and give the patient a copy.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisLong-term animal studies to evaluate the carcinogenic potential of collagenase clostridium histolyticum have not been conducted.
MutagenesisPurified 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.
Impairment Of FertilityCollagenase 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.
Use In Specific Populations Pregnancy Pregnancy Category BThere are no adequate and well-controlled studies of Iruxol mono in pregnant women. Because animal reproduction studies are not always predictive of human response, Iruxol mono should be used during pregnancy only if clearly needed.
Risk SummaryBased on animal data, Iruxol mono is not predicted to increase the risk for major developmental abnormalities in humans.
Human DataHuman pharmacokinetic studies showed that Iruxol mono levels were not quantifiable in the systemic circulation following injection into a Dupuytren's cord.
Low levels of Iruxol mono were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of Iruxol mono into the penile plaque of subjects with Peyronie's disease.
Almost all patients develop anti-product antibodies (anti-AUX-I and anti-AUX-II) after treatment with Iruxol mono, and the clinical significance of anti-product antibody formation on a developing fetus is not known.
Animal DataReproduction studies have been performed in rats with intravenous exposures up to approximately 11 times the maximum recommended human dose (MRHD) of Iruxol mono on a mg/m² basis, and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum.
Nursing MothersIt 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 Iruxol mono is administered to a nursing woman.
Pediatric UseThe safety and effectiveness of Iruxol mono in pediatric patients less than 18 years old have not been established.
Geriatric UseOf the 249 Iruxol mono-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 Iruxol mono-treated patients in the double-blind, placebo-controlled, clinical trials in Peyronie's disease (Studies 1 and 2), 100 (18%) were 65 years of age or older and 5 (0.9 %) were 75 years of age or older. No overall differences in safety or effectiveness of Iruxol mono were observed between these patients and younger patients.
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Tendon Rupture Or Other Serious Injury To The Injected Finger/Hand In The Treatment Of Dupuytren’s ContractureIn 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 (Penile Fracture) Or Other Serious Injury To The Penis In The Treatment Of Peyronie’s DiseaseCorporal 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.
XIAFLEX REMS ProgramBecause 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:
Further information is available at www.XIAFLEXREMS.com or 1-877-313-1235.
Hypersensitivity Reactions, Including AnaphylaxisIn the controlled portions of the clinical trials in Dupuytren's contracture (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of XIAFLEX-associated pruritus increased after more XIAFLEX injections in patients with Dupuytren's contracture.
In the double-blind, placebo-controlled portions of the clinical trials in Peyronie's disease (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered.
Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to XIAFLEX for the treatment of Dupuytren's contracture. Some patients with Dupuytren's contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive XIAFLEX injections. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections.
Risk Of bleeding In Patients With Abnormal CoagulationIn 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).
Patient Counseling InformationSee FDA-approved patient labeling (Medication Guide).
Patient Counseling For Dupuytren’s ContractureAdvise patients of the following:
After the XIAFLEX injections, instruct patients:
Following the finger extension procedure(s) and fitting patient with a splint, instruct patients:
Advise patients of the following:
After the XIAFLEX injections, instruct the patient:
Provide the patient instructions on the appropriate technique to perform penile modeling activities at home, as described in “What You Need to Know About XIAFLEX Treatment for Peyronie's Disease: A Patient Guide”, and give the patient a copy.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisLong-term animal studies to evaluate the carcinogenic potential of collagenase clostridium histolyticum have not been conducted.
MutagenesisPurified 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.
Impairment Of FertilityCollagenase 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.
Use In Specific Populations Pregnancy Pregnancy Category BThere 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.
Risk SummaryBased on animal data, XIAFLEX is not predicted to increase the risk for major developmental abnormalities in humans.
Human DataHuman 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.
Animal DataReproduction 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.
Nursing MothersIt 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.
Pediatric UseThe safety and effectiveness of XIAFLEX in pediatric patients less than 18 years old have not been established.
Geriatric UseOf 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.
Iruxol mono 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 Iruxol mono. 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.
Dupuytren's contracture
Iruxol mono 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 Iruxol mono is 0.58 mg per injection into a palpable Dupuytren's cord. The volume of solvent required and the volume of reconstituted Iruxol mono 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 Iruxol mono is currently limited to up to 3 injections per cord and up to 8 injections in total.
Peyronie's disease
Iruxol mono 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 Iruxol mono is 0.58 mg per injection administered into a Peyronie's plaque. The volume of reconstituted Iruxol mono 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 Iruxol mono injections and one penile modelling procedure. The second Iruxol mono 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 Iruxol mono in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Iruxol mono 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 Iruxol mono in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Iruxol mono in patients with Peyronie's disease, no dose adjustment is necessary.
Renal impairment
Due to the lack of quantifiable systemic exposure of Iruxol mono in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Iruxol mono in patients with Peyronie's disease, no dose adjustment is necessary.
Paediatric population
There is no relevant use of Iruxol mono 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 Iruxol mono in the paediatric population aged 0-18 years for the treatment of Peyronie's disease.
Method of administration
Intralesional use.
Iruxol mono 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 Iruxol mono 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 Iruxol mono 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 Iruxol mono 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. Iruxol mono 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 Iruxol mono 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 Iruxol mono for Peyronie's disease is not known.
Dosage And Administration For Dupuytren’s Contracture Dosing Overview For Dupuytren’s ContractureIruxol mono should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren's contracture.
Iruxol mono, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use. The dose of Iruxol mono is 0.58 mg per injection into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint.. Each vial of Iruxol mono and sterile diluent should only be used for a single injection. If two joints on the same hand are to be treated during a treatment visit, separate vials and syringes should be used for each reconstitution and injection. Table 1 displays an overview of the volumes of sterile diluent for reconstitution and the reconstituted Iruxol mono 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
| For cords affecting MP joints | For cords affecting PIP joints | |
| Sterile Diluent for Reconstitution | ||
| Volume | 0.39 mL | 0.31 mL |
| Reconstituted Iruxol mono Solution to be Injected1 | ||
| Volume | 0.25 mL | 0.20 mL |
| 1The reconstituted Iruxol mono solution to be used in the intralesional injection contains 0.58 mg of Iruxol mono. Note: The entire reconstituted Iruxol mono solution contains 0.9 mg of Iruxol mono. Reconstituted Iruxol mono solution remaining in the vial after the injection should be discarded. | ||
Four weeks after the Iruxol mono injection and finger extension procedure, if a MP or PIP contracture remains, the cord may be re-injected with a single dose of 0.58 mg of Iruxol mono and the finger extension procedure may be repeated (approximately 24 to 72 hours after injection). Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.
Perform up to two injections in the same hand according to the injection procedure during a treatment visit. Two palpable cords affecting two joints may be injected or one palpable cord affecting two joints in the same finger may be injected at two locations during a treatment visit. If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with Iruxol mono at other treatment visits approximately 4 weeks apart.
Reconstitution Of The Lyophilized Powder For Dupuytren’s ContractureIruxol mono should be administered by a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of Iruxol mono in the treatment of Peyronie's disease.
Iruxol mono, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use. The dose of Iruxol mono is 0.58 mg per injection administered into a Peyronie's plaque. If more than one plaque is present, inject into the plaque causing the curvature deformity.
A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two Iruxol mono injection procedures and one penile modeling procedure. The second Iruxol mono injection procedure is performed 1 to 3 days after the first. The penile modeling procedure is performed 1 to 3 days after the second injection of the treatment cycle. The interval between treatment cycles is approximately six weeks. The treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures.
If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered.
The safety of more than one treatment course of Iruxol mono is not known.
Table 2 displays an overview of the volume of sterile diluent for reconstitution and the reconstituted Iruxol mono solution to be used in the intralesional injection.
Table 2: Volumes Needed for Reconstitution and Administration
| Sterile Diluent for Reconstitution | |
| Volume | 0.39 mL |
| Reconstituted Iruxol mono Solution to be Injected1 | |
| Volume | 0.25 mL |
| 1The reconstituted Iruxol mono solution to be used in the intralesional injection contains 0.58 mg of Iruxol mono. Note: The entire reconstituted Iruxol mono solution contains 0.9 mg of Iruxol mono. | |
Reconstituted Iruxol mono solution remaining in the vial after the injection should be discarded.
Reconstitution Of The Lyophilized Powder For Peyronie’s DiseasePenile modeling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 1 to 3 days after the second injection of each treatment cycle, perform a penile modeling procedure (as described below) on the flaccid penis to stretch and elongate the treated plaque:
In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle as follows:
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
| For cords affecting MP joints | For cords affecting PIP joints | |
| Sterile Diluent for Reconstitution | ||
| Volume | 0.39 mL | 0.31 mL |
| Reconstituted XIAFLEX Solution to be Injected1 | ||
| Volume | 0.25 mL | 0.20 mL |
| 1The reconstituted XIAFLEX solution to be used in the intralesional injection contains 0.58 mg of XIAFLEX. Note: The entire reconstituted XIAFLEX solution contains 0.9 mg of XIAFLEX. Reconstituted XIAFLEX solution remaining in the vial after the injection should be discarded. | ||
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.
Reconstitution Of The Lyophilized Powder For Dupuytren’s ContractureXIAFLEX 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
| Sterile Diluent for Reconstitution | |
| Volume | 0.39 mL |
| Reconstituted XIAFLEX Solution to be Injected1 | |
| Volume | 0.25 mL |
| 1The reconstituted XIAFLEX solution to be used in the intralesional injection contains 0.58 mg of XIAFLEX. Note: The entire reconstituted XIAFLEX solution contains 0.9 mg of XIAFLEX. | |
Reconstituted XIAFLEX solution remaining in the vial after the injection should be discarded.
Reconstitution Of The Lyophilized Powder For Peyronie’s DiseasePenile modeling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 1 to 3 days after the second injection of each treatment cycle, perform a penile modeling procedure (as described below) on the flaccid penis to stretch and elongate the treated plaque:
In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle as follows:
Instructions for use and handling
Preparation - Reconstitution procedure
The vial containing Iruxol mono and the vial containing the solvent for solution for injection for reconstitution must be refrigerated. Prior to use, the vial containing Iruxol mono 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 Iruxol mono 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 Iruxol mono 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 Iruxol mono. 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:
| Table 13. Volumes needed for administration | ||
| Treatment area | Solvent required for reconstitution | Injection volume to deliver Iruxol mono 0.58 mg dose†|
| Dupuytren's MP joints | 0.39 ml | 0.25 ml |
| Dupuytren's PIP joints | 0.31 ml | 0.20 ml |
| Peyronie's plaque | 0.39 ml | 0.25 ml |
| †Note that injection volume for delivery of a 0.58 mg dose is less than the total volume of solvent used for reconstitution. | ||
5. The solvent should slowly be injected into the sides of the vial containing the lyophilised powder of Iruxol mono. 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 Iruxol mono 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.
