This information is intended for use by health professionals

1. Name of the medicinal product

Xiapex 0.9 mg powder and solvent for solution for injection

2. Qualitative and quantitative composition

Each vial of powder contains 0.9 mg of collagenase clostridium histolyticum*.

*A formulation of two collagenase enzymes co-expressed and harvested from anaerobic fermentation of a phenotypically selected strain of Clostridium histolyticum bacterium.

Excipients with known effect

Sodium injected per joint in the treatment of Dupuytren's contracture:

Metacarpophalangeal (MP) joints: 0.9 mg.

Proximal interphalangeal (PIP) joints: 0.7 mg.

Sodium injected per plaque in the treatment of Peyronie's disease: 0.9 mg.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for solution for injection.

The powder is a white lyophilised powder.

The solvent is a clear colourless solution.

4. Clinical particulars
4.1 Therapeutic indications

Xiapex 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 (see sections 4.2 and 4.4).

4.2 Posology and method of administration

Dupuytren's contracture

Xiapex 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 Xiapex is 0.58 mg per injection into a palpable Dupuytren's cord. The volume of solvent required and the volume of reconstituted Xiapex to be administered into the Dupuytren's cord differs depending on the type of joint being treated (for the reconstitution instructions, see section 6.6, Table 13).

• 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 Xiapex is currently limited to up to 3 injections per cord and up to 8 injections in total.

Peyronie's disease

Xiapex 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 Xiapex is 0.58 mg per injection administered into a Peyronie's plaque. The volume of reconstituted Xiapex to be administered into the plaque is 0.25 ml (for reconstitution instructions, see section 6.6, Table 13). 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 Xiapex injections and one penile modelling procedure. The second Xiapex 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 Xiapex in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Xiapex 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 Xiapex in patients with Dupuytren's contracture and minimal and short-lived systemic exposure of Xiapex in patients with Peyronie's disease, no dose adjustment is necessary.

Renal impairment

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

Paediatric population

There is no relevant use of Xiapex 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 Xiapex in the paediatric population aged 0-18 years for the treatment of Peyronie's disease.

Method of administration

Intralesional use.

Xiapex must be reconstituted with the solvent provided and to the appropriate volume prior to intralesional injection (see section 6.6).

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.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Dupuytren's contracture

Injection procedure

Administration of a local anaesthetic medicinal product prior to injection of Xiapex 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 Xiapex 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 Xiapex 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. Xiapex 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 Xiapex 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 Xiapex for Peyronie's disease is not known.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

4.4 Special warnings and precautions for use

Allergic reactions

Following Xiapex 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 Xiapex for the treatment of Dupuytren's contracture, demonstrating that severe reactions including anaphylaxis can occur following Xiapex injections. Some patients with Dupuytren's contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive Xiapex injections.

In the double blind portion of the three phase 3 placebo-controlled clinical studies in Dupuytren's contracture, 17% of Xiapex-treated patients had mild reactions (i.e. pruritus) after up to 3 injections. The incidence of Xiapex-associated pruritus increased after more Xiapex 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 Xiapex-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 Xiapex injections). The incidence of Xiapex-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

Xiapex must only be injected into the Dupuytren's cord. Because Xiapex lyses collagen, care must be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Injection of Xiapex 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 Xiapex 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 Xiapex. 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 (see section 4.2) 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 Xiapex 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. Signs or symptoms that may reflect serious injury to the treated finger/hand after injection or manipulation should be promptly evaluated because surgical intervention may be required. A higher rate for skin laceration has been shown following two concurrent injections in the same hand in a controlled post-marketing trial (see also Section 4.8).

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

Injection of Xiapex 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, Xiapex 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 Xiapex injection in 5 out of 1044 patients (0.5%) in the controlled and uncontrolled clinical trials in Peyronie's disease. In other Xiapex-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

Xiapex 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 Xiapex-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 Xiapex-treated patients developed penile haematoma and 14.5% developed penile ecchymosis. The efficacy and safety of Xiapex in patients receiving anticoagulant medicinal products other than up to 150 mg acetylsalicylic acid per day prior to Xiapex administration is not known. Use of Xiapex 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 Xiapex 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 Xiapex, 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 Xiapex, 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 Xiapex >99% of Xiapex-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 Xiapex 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 Xiapex, 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 Xiapex on subsequent surgery, if needed, is not known.

Special penile conditions/diseases not studied in clinical trials

Xiapex 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 Xiapex 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'.

4.5 Interaction with other medicinal products and other forms of interaction

No formal medicinal product interaction studies with Xiapex have been performed. There is no quantifiable systemic exposure following a single injection of Xiapex in patients with Dupuytren's contracture and only minimal and short-lived systemic exposure of Xiapex in patients with Peyronie's disease.

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

Whilst there is no clinical evidence of an interaction between tetracycline and anthracycline/anthraquinolone antibiotics and anthraquinone derivatives and Xiapex, such derivatives have been shown to inhibit matrix metalloproteinase-mediated collagen degradation at pharmacologically relevant concentrations in vitro. Therefore, use of Xiapex in patients who have received tetracycline antibiotics (e.g., doxycycline) within 14 days prior to receiving an injection of Xiapex is not recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy and fertility

For Xiapex no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, or embryonal/foetal development, (see section 5.3). Parturition or postnatal development studies in animals were not conducted since human pharmacokinetic studies show that Xiapex levels are not quantifiable in the systemic circulation following injection into a Dupuytren's cord (see section 5.1). Patients develop ADAs after repeated administration, the cross-reactivity of which versus endogenous MMPs involved in pregnancy and labour cannot be excluded. The potential risk for humans on parturition and postnatal development is unknown. Therefore the use of Xiapex is not recommended in pregnancy and treatment should be postponed until after pregnancy.

Peyronie's disease occurs exclusively in adult male patients and hence there is no relevant information for use in females. Low levels of Xiapex were quantifiable in the plasma of evaluable male patients for up to 30 minutes following administration of Xiapex into the penile plaque of patients with Peyronie's disease (see section 5.2).

Breast-feeding

It is not known whether collagenase clostridium histolyticum is excreted in human milk. Caution should be exercised when Xiapex is administered to a breast-feeding woman.

4.7 Effects on ability to drive and use machines

Xiapex 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 Xiapex. 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.

4.8 Undesirable effects

Dupuytren's contracture

Summary of the safety profile

The most frequently reported adverse reactions during the Xiapex clinical studies (272 of 409 patients received up to three single injections of Xiapex 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 Xiapex (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 Xiapex in the same hand compared with subjects treated with up to three single injections in the Phase 3 placebo-controlled pivotal studies in Dupuytren's contracture.

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

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

The incidence of skin laceration (29.1%) was higher for subjects treated with two concurrent injections of Xiapex 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 Xiapex in the same hand and up to three single injections of Xiapex 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 Xiapex 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 Xiapex) 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 Xiapex 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 Xiapex in Peyronie's disease corporal rupture and other serious penile injury were reported uncommonly (see section 4.4)

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%) Xiapex-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 Xiapex 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]

4.9 Overdose

Administration of Xiapex 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

Xiapex 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 Xiapex administration is localized and does not require or result in quantifiable systemic levels of AUX-I and AUX-II, the primary pharmacodynamic activity of Xiapex 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. Xiapex 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 Xiapex 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 Xiapex 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 Xiapex 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 Xiapex 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 Xiapex 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.

Xiapex 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. Xiapex 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

Xiapex

(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 (Xiapex 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

Xiapex

Placebo

Xiapex

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 Xiapex 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

Xiapex

Placebo

Xiapex

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 Xiapex treated group had a baseline contracture of 0 degrees before treatment).

All p-values < 0.001 for all comparisons between Xiapex 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 Xiapex 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 Xiapex 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 Xiapex 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 Xiapex 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 Xiapex 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 Xiapex 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 Xiapex (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 Xiapex 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 Xiapex 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 Xiapex. These data support the long term safety profile of Xiapex 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 Xiapex 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 Xiapex are provided in Table 7.

Table 7.

Long Term Recurrence Rates for Joints Treated Successfully with XIAPEX

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 Xiapex in a previous clinical study. No new safety signals were identified among subjects who were retreated with Xiapex. Most adverse events were non-serious, mild or moderate in intensity, and related to the local administration of Xiapex 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 Xiapex.

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

The European Medicines Agency has waived the obligation to submit the results of studies with Xiapex in all subsets of the paediatric population in the treatment of Dupuytren's contracture (see section 4.2 for information on paediatric use).

Peyronie's disease

The efficacy of Xiapex 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 Xiapex 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 Xiapex 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 Xiapex 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.

Xiapex 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.

Xiapex 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

XIAPEX

N=277

Placebo

N=140

XIAPEX

N=274

Placebo

N=141

Mean age (years)

(Min-Max)

57.9

(28 - 79)

58.2

(30 - 81)

57.3

(23 - 84)

57.6

(33 - 78)

Mean duration of PD (years)

(Min-Max)

3.9

(1.0 - 35.9)

4.8

(1.0 - 50.8)

4.2

(1.1 - 30.9)

3.4

(1.1 - 17.1)

Mean Penile Curvature Deformity (degrees)

(Min-Max)

48.8

(30-90)

49.0

(30-89)

51.3

(30-90)

49.6

(30-85)

Peyronie's Disease Questionnaire (PDQ)b, – Mean Patient-Reported PD Bother Domain Score (range: 0-16) c

7.5

7.4

7.4

8.2

History of Erectile Dysfunction N (%)

128 (46.2)

75 (53.6)

134 (48.9)

76 (53.9)

a Subjects were from ITT population and received at least one dose of study drug in Study 1 or 2

b Each PDQ assessment required subjects to have had vaginal intercourse in the 3 months prior to completion

c Higher scores represent worse symptoms

Table 9. Mean percent change in penile curvature deformity from baseline to week 52 – Studies 1 and 2

Study 1

Study 2

XIAPEX

N=199

Placebo

N=104

XIAPEX

N=202

Placebo

N=107

Baseline Mean (degrees)

48.8°

49.0°

51.3°

49.6°

Mean Percent Change a

-35.0%

-17.8%

-33.2%

-21.8%

Treatment Difference

(95% CI)

-17.2% b

(-26.7%, -7.6%)

-11.4% b

(-19.5%, -3.3%)

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

b p-value < 0.01

Table 10. Mean Change in Peyronie's Disease Bother Domain Score from Baseline to Week 52 - Studies 1 and 2

Study 1

Study 2

XIAPEX

N=199

Placebo

N=104

XIAPEX

N=202

Placebo

N=107

Baseline Mean

7.5

7.4

7.4

8.2

Mean Change a

-2.8

-1.6

-2.6

-1.5

Treatment Difference

(95% CI)

-1.2 b

(-2.4, -0.03)

-1.1 b

(-2.1, -0.002)

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

b p-value < 0.05.

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

An open label phase 3 study, AUX-CC-806, evaluated the safety and efficacy of Xiapex. The study inclusion and exclusion criteria as well as the treatment schedule and the co-primary efficacy endpoints were the same as in the pivotal AUX-CC-803 and AUX-CC-804 studies. Patients were however followed up to 36 weeks. A total of 189 patients were enrolled and treated with Xiapex. All patients had participated in and completed the studies AUX-CC-803 or AUX-CC-804, in which they had received placebo.

The median age of the patients included was 60, ranging between 33 and 77 years. The median duration of disease was 4.9 years (range 2.0 to 27.9 years). Erectile dysfunction was reported in 52.9% of patients, and 27.5% reported previous trauma to penis.

Tables 11-12 provide the results of the co-primary efficacy endpoints measured in the open label phase 3 study AUX-CC-806.

Table 11. Mean Percent Change from Baseline in Curvature Deformity at Week 36 (LOCF) (mITT* Population) – study AUX-CC-806

Xiapex

N=126

Baseline value

Mean (SD)

Min, Max

46.9 (12.00)

30, 85

Week 36 value (LOCF)

Mean (SD)

Min, Max

29.9 (15.56)

0, 80

% change from baseline

Mean (SD)

Min, Max

95% CI of mean**

-36.3 (30.72)

-100, 100

-41.6, -30.9

*The mITT population was defined as all randomized subjects who had both a penile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.

**Based on the 95% CI of the mean not including zero, the percent change from baseline was considered statistically significant.

Table 12. Mean Change from Baseline in Peyronie's Disease Bother Score at Week 36 (LOCF) (mITT* Population) – study AUX-CC-806

Xiapex

N=126

Baseline value

Mean (SD)

Min, Max

6.3 (3.60)

1, 15

Week 36 value (LOCF)

Mean (SD)

Min, Max

3.9 (3.65)

0, 16

Change from baseline

Mean (SD)

Min, Max

95% CI of mean**

-2.4 (3.34)

-12, 7

-3.0, -1.8

*The mITT population was defined as all randomized subjects who had both a penile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.

**Based on the 95% CI of the mean not including zero, the mean change from baseline was considered statistically significant.

As an exploratory analysis, female sexual partners completed two questionnaires at both the screening visit and week 36: the PDQ for Female Sexual Partners (an adaptation of Peyronie's disease bother and psychological symptom domains of the PDQ for men, scoring from 0-12) and the Female Sexual Function Index (FSFI, scale from 2-36, where a higher score represents better sexual functioning). Altogether 30 female partners participated in the study. At baseline, the mean (SD) Female PDQ score was 4.7 (3.61) and 2.7 (3.06) at week 36, i.e. a change from baseline of -2.0. The mean (SD) FSFI score was 20.56 (10.08) at baseline and 26.72 (7.73) at week 36, a change from baseline of 7.54.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Xiapex in all subsets of the paediatric population in the treatment of Peyronie's disease (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

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

Following each of two intralesional administrations, separated by 24 hours, of Xiapex 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 Xiapex 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 Xiapex administered through localized injection into the Dupuytren's cord or into the Peyronie's plaque.

Biotransformation

Because Xiapex 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 Xiapex 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

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

5.3 Preclinical safety data

Repeated dose toxicity

In a single-dose phase or 61-day repeat-dose phase (3 times a week every 3 weeks for 3 cycles) study of intrapenile administration of collagenase clostridium histolyticum in dogs at exposures lower than or equal to the maximum recommended human dose on a mg/m2 basis, there was no evidence of systemic toxicity.

Reproductive toxicity

When Xiapex 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 Xiapex. Thus, the carcinogenic risk is unknown.

6. Pharmaceutical particulars
6.1 List of excipients

Powder

Sucrose

Trometamol

Hydrochloric acid 2.4% w/w (for pH adjustment)

Solvent

Calcium chloride dihydrate

Sodium chloride

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

3 years.

After reconstitution, immediate use is recommended. Reconstituted Xiapex can be kept at ambient room temperature (20°C-25°C) for up to one hour or refrigerated 2°C-8°C for up to 4 hours prior to administration. If refrigerated, the reconstituted solution must be allowed to return to ambient room temperature (20°C 25°C) for approximately 15 minutes before use.

6.4 Special precautions for storage

Store in a refrigerator (2°C 8°C).

Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Xiapex powder is supplied in a clear glass vial (3 ml, type I glass) with rubber stopper, aluminium seal and flip-off cap (polypropylene).

Solvent: 3 ml solution supplied in a clear glass vial (5 ml, type I glass) with rubber stopper, aluminium seal and flip-off cap (polypropylene).

Pack of 1 vial of powder and 1 vial of solvent

6.6 Special precautions for disposal and other handling

Instructions for use and handling

Preparation - Reconstitution procedure

The vial containing Xiapex and the vial containing the solvent for solution for injection for reconstitution must be refrigerated. Prior to use, the vial containing Xiapex 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 Xiapex 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 Xiapex 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 Xiapex. 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 Xiapex 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 Xiapex. 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 Xiapex 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.

7. Marketing authorisation holder

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

8. Marketing authorisation number(s)

EU/1/11/671/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 28 February 2011

Date of latest renewal: 18 January 2016

10. Date of revision of the text

08/12/2017

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu