XIAPEX 0.9mg powder + solvent for injection medication leaflet

Xiapex 0.9 mg powder and solvent for solution for injection

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

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

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.

Powder and solvent for solution for injection.

The powder is a white lyophilised powder.

The solvent is a clear colourless solution.

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 curvaturedeformity of at least 30 degrees at the start of therapy (see sections 4.2 and 4.4).

Dupuytren’s contracture

Xiapex must be administered by a physician appropriately trained in the correct administration of themedicinal product and experienced in the diagnosis and management of Dupuytren’s disease.

The recommended dose of Xiapex is 0.58 mg per injection into a palpable Dupuytren’s cord. Thevolume 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 reconstitutioninstructions, see section 6.6, Table 14).

* 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 tothe injection procedure during a treatment visit. Two palpable cords affecting two joints may beinjected or one palpable cord affecting two joints in the same finger may be injected at two locationsduring a treatment visit. Each injection contains a 0.58 mg dose. If the disease has resulted in multiplecontractures, 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, asnecessary, to facilitate cord disruption. If a satisfactory response has not been achieved, the injectionand finger extension procedures may be repeated after approximately 4 weeks. Injections and fingerextension 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 8injections in total.

Peyronie’s disease

Xiapex must be administered by a physician appropriately trained in the correct administration of themedicinal product and experienced in the diagnosis and treatment of male urological diseases. Patientswith penile curvature >90° were not included in the clinical studies. Treatment in this group cantherefore not be recommended.

The recommended dose of Xiapex is 0.58 mg per injection administered into a Peyronie’s plaque. Thevolume of reconstituted Xiapex to be administered into the plaque is 0.25 ml (for reconstitutioninstructions, see section 6.6, Table 14). If more than one plaque is present, only the plaque causing thecurvature 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 administered1 to 3 days after the first injection. A penile modelling procedure is performed 1 to 3 days after thesecond injection of each treatment cycle. The interval between treatment cycles is approximately sixweeks.

Special population

Due to the lack of quantifiable systemic exposure of Xiapex in patients with Dupuytren’s contractureand minimal and short-lived systemic exposure of Xiapex in patients with Peyronie’s disease, no doseadjustment is necessary. No overall differences in safety or effectiveness were observed betweenelderly and younger patients.

Due to the lack of quantifiable systemic exposure of Xiapex in patients with Dupuytren’s contractureand minimal and short-lived systemic exposure of Xiapex in patients with Peyronie’s disease, no doseadjustment is necessary.

Due to the lack of quantifiable systemic exposure of Xiapex in patients with Dupuytren’s contractureand minimal and short-lived systemic exposure of Xiapex in patients with Peyronie’s disease, no doseadjustment is necessary.

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.

Intralesional use.

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

A single-use syringe containing 0.01-ml graduations with a permanently fixed 27-gauge 12 or 13 mmneedle (not supplied) should be used to withdraw the volume of reconstituted solution. There will be asmall 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’scord 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 beconfirmed and the volume of solvent required for reconstitution is determined by the type of joint (PIPjoint requires a smaller volume for injection). The injection procedure is detailed in the package leafletand 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 ofthe 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 ofthe 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 extensionprocedure.

Finger extension procedure

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

While the patient’s wrist is in the flexed position, a moderate stretching pressure should be applied tothe 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 flexedposition. If the first finger extension procedure does not result in disruption of the cord, a second andthird attempt can be performed at 5- to 10-minute intervals. No more than 3 attempts per affected jointare recommended to disrupt a cord.

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

Following the finger extension procedure(s) and fitting patient with a splint (with treated joint inmaximum 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 severalmonths.

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 penileblock before injection.

The location of the target treatment area in the Peyronie’s plaque is identified at the point of maximumconcavity (or focal point) in the erect penis state and marked with a surgical marker. Xiapex should beinjected into the target plaque when the penis is in a flaccid state. The injection procedure is detailedin 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-upvisit 1 to 3 days after the second injection of each treatment cycle, the trained physician shouldperform a penile modelling procedure on the flaccid penis to stretch and elongate the treated plaquethat Xiapex has disrupted. Local anaesthesia may be applied before the modelling if desired. Wearinggloves the physician should grasp the plaque or indurated portion of the flaccid penis about 1 cmproximal and distal to the injection site. Direct pressure on the injection site should be avoided. Thetarget plaque is used as a fulcrum point with both hands, to firmly apply a steady pressure to elongateand stretch the plaque. The goal is to gradually create bending opposite to the patient’s penilecurvature, with stretching to the point of moderate resistance.

The penile pressure should be hold for 30 seconds, thereafter released with a resting period for30 seconds before repeating the penile modelling technique for a total of 3 modelling attempts at30 seconds for each attempt.

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

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

The safety of more than one treatment course of Xiapex for Peyronie’s disease is not known.

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.

Following Xiapex injection, severe allergic reaction could occur, and patients should be observed for30 minutes before leaving the clinic in order to monitor for any signs or symptoms of a serious allergicreaction, 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 orsymptoms. 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 previousexposure to Xiapex for the treatment of Dupuytren’s contracture, demonstrating that severe reactionsincluding anaphylaxis can occur following Xiapex injections. Some patients with Dupuytren’scontracture 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’scontracture, 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, agreater proportion of Xiapex-treated patients (4%) compared to placebo-treated patients (1%) hadlocalized 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 injectionsadministered.

Tendon rupture or other serious injury to the injected finger/hand in the treatment of Dupuytren’scontracture

Xiapex must only be injected into the Dupuytren’s cord. Because Xiapex lyses collagen, care must betaken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures ofthe hand. Injection of Xiapex into collagen containing structures may result in damage to thosestructures, and possible permanent injury such as tendon rupture or ligament damage. Care should betaken when injecting Xiapex into cords contracting the PIP joints as clinical studies indicate anincreased 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. Wheninjecting a cord affecting a PIP joint of the fifth finger, the needle insertion must not be more than 2 to3 mm in depth and not more than 4 mm distal to the palmar digital crease. Patients should beinstructed to comply with the treatment instructions (see section 4.2) and to promptly contact thephysician if there is trouble bending the finger after the swelling goes down (symptoms of tendonrupture).

Most patients experiencing tendon/ligament rupture or injury have gone on to have successful surgicalrepair. Early diagnosis and prompt evaluation and treatment are important because tendonrupture/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 aresult of the pharmacological effect of Xiapex and the finger extension procedure on the skinoverlying 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 injectionor manipulation should be promptly evaluated because surgical intervention may be required. A higherrate for skin laceration has been shown following two concurrent injections in the same hand in acontrolled post-marketing trial (see also Section 4.8).

Cases of finger necrosis have been reported, which in some cases led to amputation of finger parts.

Pre-existing reduced peripheral circulation, e.g. Raynaud syndrome, and the use of epinephrinecombined with local anaesthetics in these patients may contribute to this (see also section 4.8).

Cases of digital phalangeal fractures have been reported after finger manipulation procedure. Cautionshould be exercised when performing finger extension procedures in patients with bone fragility,which may predispose to digital phalangeal fracture (e.g. in patients with osteopenia/osteoporosis).

Diagnostic imaging is recommended after manipulation if finger deformity, pain or increased swellingdevelops (see also section 4.8).

Corporal rupture (fracture of penis) or other serious injury to the penis in the treatment of Peyronie’sdisease

Injection of Xiapex into collagen-containing structures such as the corpora cavernosa of the penis mayresult 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 avoidinjecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containingstructures of the penis.

Corporal rupture was reported as a serious adverse reaction after Xiapex injection in 5 out of1044 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, suddenpenile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, adiagnosis of corporal rupture cannot be excluded.

Severe penile haematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in thecontrolled and uncontrolled clinical studies in Peyronie’s disease.

Physicians should advise the patient to wait for at least 4 weeks after the second injection of atreatment cycle before resuming sexual activity taking care to ensure that any pain and swelling hasceased and to be cautious when resuming sexual activity.

Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in orderto 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 takinganticoagulants. In the three double-blind, placebo-controlled phase 3 studies in Dupuytren’scontracture, 73% of Xiapex-treated patients reported an ecchymosis or a contusion and 38% reported ahaemorrhage 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 anticoagulantmedicinal products other than up to 150 mg acetylsalicylic acid per day prior to Xiapex administrationis not known. Use of Xiapex in patients who have received anticoagulants (with the exception of up to150 mg acetylsalicylic acid daily) within 7 days prior to receiving an injection of Xiapex is notrecommended.

As with any non-human protein medicinal product, patients may develop antibodies to the therapeuticprotein. 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 themedicinal product (AUX-I and AUX-II).

In the Dupuytren’s contracture clinical trials at 30 days post the first injection, 92% of patients hadcirculating antibodies detected against AUX-I and 86% of patients against AUX-II. At five years afterthe initial injection of Xiapex, 92.8% and 93.4% of subjects were seropositive for anti-AUX-I andanti-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 hadantibodies 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 highand 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 theywere also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in60% and 51.8%, respectively, of patients tested. At five years after the initial injection of Xiapex themajority of subjects (>90%) were seropositive for anti-AUX-I and anti-AUX-II antibodies. Inaddition, seropositivity for neutralizing anti-AUX-I and anti-AUX-II antibodies was maintained.

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 safetyconcerns related to the inhibition of endogenous MMPs have been observed, in particular no adverseevents indicating the development or exacerbation of autoimmune diseases or the development of amusculoskeletal syndrome (MSS). Whilst there is no clinical evidence from the current safety data of amusculoskeletal syndrome developing following the administration of Xiapex, the potential for it tooccur cannot be excluded. If this syndrome were to develop, it would occur progressively and ischaracterized 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 thetendons.

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 injectiontechnique, chordee in the presence or absence of hypospadias, thrombosis of the dorsal penile arteryand/or vein, infiltration by a benign or malignant mass resulting in penile curvature, infiltration by aninfectious agent, such as in lymphogranuloma venereum, ventral curvature from any cause andisolated hourglass deformity of the penis has not been studied and treatment in these patients should beavoided.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium- free’.

No formal medicinal product interaction studies with Xiapex have been performed. There is noquantifiable systemic exposure following a single injection of Xiapex in patients with Dupuytren’scontracture and only minimal and short-lived systemic exposure of Xiapex in patients with Peyronie’sdisease.

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

Whilst there is no clinical evidence of an interaction between tetracycline andanthracycline/anthraquinolone antibiotics and anthraquinone derivatives and Xiapex, suchderivatives have been shown to inhibit matrix metalloproteinase-mediated collagen degradation atpharmacologically relevant concentrations in vitro. Therefore, use of Xiapex in patients who havereceived tetracycline antibiotics (e.g., doxycycline) within 14 days prior to receiving an injection of

Xiapex is not recommended.

For Xiapex no clinical data on exposed pregnancies are available. Animal studies do not indicatedirect 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 sincehuman pharmacokinetic studies show that Xiapex levels are not quantifiable in the systemiccirculation following injection into a Dupuytren’s cord (see section 5.1). Patients develop ADAs afterrepeated administration, the cross-reactivity of which versus endogenous MMPs involved inpregnancy and labour cannot be excluded. The potential risk for humans on parturition and postnataldevelopment is unknown. Therefore, the use of Xiapex is not recommended in pregnancy andtreatment should be postponed until after pregnancy.

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

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

Xiapex may have a major influence on the ability to drive and use machines due to the swelling andpain which may impair the use of the treated hand in Dupuytren’s disease. Other minor influences onthe ability to drive and use machines include dizziness, paresthesia, hypoesthesia, and headache thathave also been reported following injection of Xiapex. Patients must be instructed to avoid potentiallyhazardous tasks such as driving or using machines until it is safe to do so or as advised by thephysician.

Dupuytren’s contracture

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

Table 1 presents adverse reactions listed by system organ class and frequency categories, using thefollowing convention: very common (≥1/10), common (≥1/100 to <1/10), and 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 theclinical programme are those that occurred in the Phase 3 double blind placebo-controlled studies forthe 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 twoconcurrent injections in the same hand.

Table 1: Tabulated list of adverse reactions.

System organ class Very common Common Uncommon Not known

Infections and Injection siteinfestations cellulitis

Lymphangitis

Blood and Lymphadenopathy Lymph node Thrombocytopenialymphatic system pain Lymphadenitisdisorders

Immune system Hypersensitivitydisorders Anaphylacticreaction

System organ class Very common Common Uncommon Not known

Psychiatric Disorientationdisorders Agitation

Insomnia

Irritability

Restlessness

Nervous system Paresthesia Complex regionaldisorders Hypoesthesia pain syndrome

Burning Monoplegiasensation Syncope

Dizziness vasovagal

Headache Tremor

Hyperaesthesia

Eye disorders Eyelid oedema

Vascular disorders Haematoma

Respiratory, Dyspnoeathoracic and Hyperventilationmediastinaldisorders

Gastrointestinal Nausea Diarrhoeadisorders Vomiting

Abdominal painupper

Skin and Pruritus Blood blistera Erythematous orsubcutaneous tissue Ecchymosis Blister macular rashdisorders Rash Eczema

Erythema Swelling face

Hyperhidrosis Skin disorders,like exfoliation,lesions, pain,tightness,discoloration orscab

Musculoskeletal and Pain in extremity Arthralgia Pain in chest wall,connective tissue Axillary mass groin, neck ordisorders Joint swelling shoulder

Myalgia Musculoskeletaldiscomfort orstiffness, jointstiffness orcrepitation

Limb discomfort

Tendonitis

Muscle spasms orweakness

Reproductive Breast tendernesssystem and breast Hypertrophydisorders breast

System organ class Very common Common Uncommon Not known

General disorders Oedema Axillary pain Local swellingand administration peripheralc Inflammation Pyrexiasite conditions Injection site Injection site Painhaemorrhage, warmth, Discomfortpain or swelling erythema, Fatigue

Tenderness inflammation, Feeling hotvesicles or Influenza likepruritus illness

Swelling Injection sitereaction, malaise,irritation,anaesthesia,desquamation,nodule ordiscoloration

Cold intoleranceof the treatedfingers

Investigations Lymph nodepalpable

Alanineaminotransferaseincreased

Aspartateaminotransferaseincreased

Body temperatureincreased

Injury, poisoning Contusion Skin Tendon rupture Digital necrosisdand procedural lacerationa,b Ligament injury Digital fracturedcomplications Limb injury

Open wound

Wound dehiscencea reported with a higher incidence (very common) in patients who received two concurrentinjections of Xiapex in the same hand compared with subjects treated with up to three singleinjections 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”d see also section 4.4

The incidence of skin laceration (29.1%) was higher for subjects treated with two concurrentinjections of Xiapex in historically-controlled clinical study AUX-CC-867 compared with subjectstreated 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 occurredon the manipulation day. A higher incidence of skin laceration may be attributable to more vigorousfinger 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 thesame 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 extensionprocedure (i.e., 24 hours, 48 hours, and ≥72 hours after injection) among patients who received twoconcurrent injections of Xiapex in Study AUX-CC-867.

Peyronie’s disease

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 malepatients) of patients who had previously received placebo in the controlled studies. In the two Phase 3double-blind placebo-controlled studies, most adverse reactions were local events of the penis andgroin and the majority of these events were of mild or moderate severity, and most (79%) resolvedwithin 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 drugreactions (≥25%) during the Xiapex controlled clinical studies were penile haematoma, penile swellingand penile pain. Severe penile haematoma including severe injection site haematoma were reportedwith the frequency very common.

In the controlled and uncontrolled clinical studies of Xiapex in Peyronie’s disease corporal rupture andother 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 2combined.

Table 2 presents adverse reactions listed by system organ class and frequency categories, using thefollowing 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 theclinical 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 Fungal skin infectioninfestations Infection

Upper respiratory infection

Blood and lymphatic Lymph node painsystem disorders Eosinophilia

Lymphadenopathy

Immune system disorders Drug hypersensitivity

Anaphylactic reaction*

Metabolism and nutrition Fluid retentiondisorders

Psychiatric disorders Abnormal dreams

Depression

Sexual inhibition

Nervous system disorders Headache

Dizziness

Dysgeusia

Paraesthesia

Burning sensation

Hyperaesthesia

Hypoaesthesia

System organ class Very common Common Uncommon

Ear and labyrinth Tinnitusdisorders

Cardiac disorders Tachycardia

Vascular disorders Haematoma

Lymphangiopathy

Thrombophlebitis superficial

Respiratory, thoracic and Coughmediastinal disorders

Gastrointestinal disorders Abdominal distension

Skin and subcutaneous Blood blister Erythematissue disorders Skin Penile ulcerationdiscolouration Rash erythematous

Night sweats

Skin disorder, nodule,granuloma, blister, irritationoroedema

Pigmentation disorder

Skin hyperpigmentation

Musculoskeletal and Back, pubic or groin painconnective tissue Ligament disorderdisorders Ligament pain

Musculoskeletal discomfort

Renal and urinary Dysuriadisorders Micturition urgency

Reproductive system and Penile haematomaa, Penile blister Penile adhesionbreast disorders swellingb, painc Pruritus genital Penis disorderor ecchymosisd Painful erection Progression of Peyronie’s

Erectile diseasedysfunction Sexual dysfunction

Dyspareunia Scrotal erythema

Penile erythema Genital discomfort

Genital haemorrhage

Pelvic pain

Penile size reduced

Penile vein thrombosis

Scrotal oedema

Scrotal pain

System organ class Very common Common Uncommon

General disorders and Injection site Feeling hotadministration site vesicles or pruritus Injection site reaction orconditions Localised oedema discolouration

Nodule Pyrexia

Suprapubic pain Swelling

Asthenia

Chills

Cyst

Induration

Influenza like illness

Oedema

Secretion discharge

Tenderness

Investigations Blood glucose increased

Blood pressure systolicincreased

Body temperature increased

Injury, poisoning and Procedural pain Fracture of penisprocedural complications Skin laceration

Open wound

Scrotal haematoma

Joint injury

Penis injurya Includes: injection site haematoma and penile haematoma were reported with the verbatim term ofpenile 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 forthe treatment of Dupuytren’s contracture.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Administration of Xiapex at greater than recommended doses is expected to be associated withincreased local reactions at the site of injection. Routine supportive care and symptomatic treatmentmust be provided in the case of overdose.

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 clostridiumhistolyticum 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 chainsconsisting of approximately 1000 amino acids of known sequence with a molecular weight of 114 kDaand 113 kDa respectively as determined by mass spectrometry. The two polypeptides are purified bychromatographic steps customary for the separation and isolation of biotherapeutic proteins to yield aconsistent, well characterized and controlled mixture of two collagenase enzymes.

Because the collagen lysis process following Xiapex administration is localized and does not requireor result in quantifiable systemic levels of AUX-I and AUX-II, the primary pharmacodynamic activityof Xiapex cannot be evaluated in subjects and therefore, such studies have not been undertaken.

Collagenases are proteinases that hydrolyze collagen under physiological conditions. Xiapex iscomprised of a mixture of Class I (AUX-I) and Class II (AUX-II) clostridial collagenases in a definedmass ratio. The two classes of collagenases have similar but complementary substrate specificity. Bothcollagenases effectively cleave interstitial collagen but at different sites on the molecule; additionally,they prefer different conformations (triple helical versus denatured or cleaved). These differencesaccount 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 hydrolysisnear 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 sitesare located within the interior of the collagen molecule and generate smaller collagen fragments. Bothclasses 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 triplehelical collagen with higher affinity than Class II collagenase. Together, these collagenases work toprovide broad hydrolytic activity towards collagen.

Dupuytren’s contracture

Injection of Xiapex into a Dupuytren’s cord, which is comprised mostly of interstitial collagen types Iand 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 Xiapexinto a Peyronie’s plaque, which is comprised mostly of collagen, may result in enzymatic disruption ofthe plaque. Following this disruption of the plaque, penile curvature deformity and patient bothercaused by Peyronie’s disease are reduced.

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 patientswith Dupuytren’s contracture. The double-blind study population comprised 409 patients of whom272 received Xiapex 0.58 mg and 137 received placebo. The mean age was 63 years (range 33 to89 years) and 80% of patients were male. At study entry, patients in the clinical studies had: (1) afinger flexion contracture with a palpable cord of at least one finger (other than the thumb) of 20° to100° in a MP joint or 20° to 80° in PIP joint and (2) a positive “table top test” defined as the inability tosimultaneously place the affected finger(s) and palm flat against a table top. The cord affecting aselected primary joint received up to 3 injections of 0.58 mg of Xiapex or placebo. A finger extensionprocedure was performed if needed, approximately 24 hours after injection to facilitate disruption ofthe cord. Each injection was separated by approximately 4 weeks.

The primary endpoint of each study was to evaluate the proportion of patients who achieved areduction 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% reductionfrom baseline in degree of contracture, percent change from baseline in degree of contracture, changefrom baseline in range of motion, subject global assessment of treatment satisfaction and physicianglobal assessment of severity.

Xiapex demonstrated a clinically significant benefit compared to placebo in the proportion of patientsachieving 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 whoachieved a contracture of the selected joint to 5° or less, the mean number of injections required toachieve this was 1.5 in the 2 studies. Xiapex also demonstrated a clinically significant benefitcompared to placebo in decreasing the degree of contracture and increasing both the range of motionfrom baseline for all joints treated (MP plus PIP, MP only, PIP only) and the subject global assessmentof treatment satisfaction.

Table 3 provides demographic and baseline characteristics for the study population and Tables 4-5provide the results of the major efficacy endpoints measured in the 2 double-blind placebo-controlledstudies 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)

Xiapex Placebo

VARIABLE (N=249) (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 studymedicinal product (Xiapex 0.58 mg or placebo).1 Not used to calculate physician rating of severity at baseline percentage-actualdenominator of N=247 used.

Table 4.

Percentage of patients who achieved reduction in contracture to 5° or less(Last injection)

TREATED CORD I CORD II

PRIMARY JOINTS Xiapex Placebo Xiapex Placebo

N=203c N=103c N=45 N=21

All Joints 64.0 % 6.8 % 44.4 % 4.8 %p-value <0.001 - <0.001 -

N=133 N=69 N=20 N=11

MP Jointsa 76.7 % 7.2 % 65.0 % 9.1 %p-value <0.001 - 0.003 -

N=70 N=34 N=25 N=10

PIP Jointsb 40.0 % 5.9 % 28.0 % 0.0 %p-value <0.001 - 0.069 -a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primaryjoints were excluded from the efficacy analysis (1 joint from the placebogroup was not evaluated and 1 joint from the Xiapex treated group hada baseline contracture of 0 degrees before treatment).

Table 5.

Mean increase in range of motion from baseline(Last injection)

TREATED CORD I CORD II

PRIMARY JOINTS Xiapex Placebo Xiapex Placebo

All Joints N=203 c N=103 c N=45 N=21

Mean Baseline (SD) 43.9 (20.1) 45.3 (18.7) 40.3 (15.2) 44.0 (16.5)

Mean Final (SD) 80.7 (19.0) 49.5 (22.1) 75.8 (17.7) 51.7 (19.6)

Mean increase (SD) 36.7 (21.0) 4.0 (14.8) 35.4 (17.8) 7.6 (14.9)

MP Jointsa N=133 N=69 N=20 N=11

Mean Baseline (SD) 42.6 (20.0) 45.7 (19.2) 39.5 (11.8) 41.4 (20.8)

Mean Final (SD) 83.7 (15.7) 49.7 (21.1) 79.5 (11.1) 50.0 (21.5)

Mean increase (SD) 40.6 (20.0) 3.7 (12.6) 40.0 (13.5) 8.6 (14.7)

PIP Jointsb N=70 N=34 N=25 N=10

Mean Baseline (SD) 46.4 (20.4) 44.4 (17.9) 41.0 (17.7) 47.0 (10.3)

Mean Final (SD) 74.9 (23.1) 49.1 (24.4) 72.8 (21.3) 53.5 (18.3)

Mean increase (SD) 29.0 (20.9) 4.7 (18.5) 31.8 (20.1) 6.5 (15.8)a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary jointswere excluded from the efficacy analysis (1 joint from the placebo group wasnot evaluated and 1 joint from the Xiapex treated group had a baselinecontracture 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 ahierarchical testing procedure.

Physician-rated change in contracture severity was reported as very much improved or much improvedin 86% and 80% of the subjects in the Xiapex group compared to 3% and 5% of subjects in theplacebo 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 IIstudies reported either being quite satisfied or very satisfied with their treatment with Xiapex versusapproximately 30% treated with placebo (p<0.001). Greater patient satisfaction was correlated withimproved 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 wasevaluated in clinical study AUX-CC-867, a historically-controlled, open-label multi-centre trial in 715adult subjects (1450 Xiapex injections) with Dupuytren’s contracture. The finger extension procedureswere performed approximately 24 to 72 hours after injection.

Primary efficacy endpoint was fixed flexion contracture in the treated joint pair subgroup. Asignificant mean improvement (74.4%) from baseline to Day 31 was observed overall in fixed flexioncontracture following administration of two concurrent injections of Xiapex 0.58 mg (one injection perjoint) 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 offinger 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 twoconcurrent injections of Xiapex 0.58 mg in the same hand, mITT population, study AUX-

CC-867 (first treatment cycle)

Different Different Different

Same Finger, Fingers, Fingers, Fingers,1 MP, 1 PIP Both MPs Both 1 MP, 1 PIP Total(n=350) (n=244) PIPs (n=58) (n=724)(n=72)

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%) comparedwith 28.6% of PIP joints following a single injection per affected joint. Time of finger extension afterinjection had no impact on the rate of clinical success for either MP or PIP joints. Clinicallymeaningful 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 toevaluate recurrence of contracture and long-term safety in subjects who received up to 8 singleinjections of Xiapex 0.58 mg in a previous Phase 3 open-label or double-blind with open-labelextension study. No new safety signals were identified among subjects who were followed for 5 yearsafter their initial injection of Xiapex in a previous clinical study. The majority of adverse eventsreported during the long-term follow-up period were non-serious, mild or moderate in intensity, andwere not related to the local administration of Xiapex. These data support the long-term safety profileof 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 to5° or less at the Day 30 evaluation after the last injection of Xiapex in a previous study) and wasdefined as an increase in joint contracture by at least 20° in the presence of a palpable cord, or the jointunderwent medical or surgical intervention primarily to correct a new or worsening Dupuytren’scontracture 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

Cumulative Nominal Nominal

Follow-up N (%) of N (%) of

Recurrent Recurrence by Joint Cumulative Change in

Interval Joints in Joints in Type (%) Nominal Recurrence(days) Each Recurrence Rate vs

Intervala Each c

Intervalb MP PIP Rate (%) Previous

Year (%)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 16.6731-1095 125 (20.1) 97 (31.9) 27.1 56.4 35.2 15.61096-1460 85 (13.6) 45 (14.8) 34.8 62.2 42.4 7.21461-1825 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 2.1a A joint was considered in an interval if the duration of assessment falls in the interval. Theduration 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 availablemeasurement or at the day of medical intervention for joints that did not recur and therecurrence day for recurrent joints.

b A recurrent joint was a joint evaluated by the investigator as having a worsening Dupuytren'scontracture due to a palpable cord. The recurrence day was the visit where the recurrencewas reported or the day of intervention if a joint was treated for a worsening Dupuytren'scontracture. For joints reported as recurring in a previous study, the day of recurrence wasthe first visit with a fixed flexion contracture measurement of 20° or greater following thereport of recurrence.

c The nominal rate of recurrence was the total number of recurrences occurring prior to the lastday 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 ofcontracture in a joint that was effectively treated with Xiapex in a previous clinical study. No newsafety signals were identified among subjects who were retreated with Xiapex. Most adverse eventswere non-serious, mild or moderate in intensity, and related to the local administration of Xiapex or tothe 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 afterretreatment with up to three injections of Xiapex.

In the retreatment study AUX-CC-862, 150 anti-AUX-I antibody positive samples and 149anti-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.

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 (seesection 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. Thedouble-blind study population comprised 832 male patients of whom 551 patients received Xiapexand 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 isolatedhourglass deformity or a calcified plaque that could have interfered with the injection technique. Atbaseline, 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. Apenile modelling procedure was performed on patients at the study site 1 to 3 days after the secondinjection of the cycle. The treatment cycle was repeated at approximately six-week intervals for up tothree additional times, for a maximum of 8 total injection procedures and 4 total modellingprocedures. In addition, patients were instructed to perform penile modelling at home for six weeksafter 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 abouterection pain, erection appearance, and the impact of Peyronie’s disease on intercourse and onfrequency of intercourse.

Xiapex treatment significantly improved penile curvature deformity in patients with Peyronie’sdisease compared with placebo (Table 9). The improvement in curvature deformity was numericallysimilar among patients with baseline deformity from 30 to 60 degrees and those with curvaturedeformity from 61 to 90 degrees.

Xiapex significantly reduced patient-reported bother associated with Peyronie’s disease comparedwith placebo (Table 10). The reduction in the Bother domain score was numerically similar betweenpatient groups stratified by degree of baseline curvature deformity (30 to 60 degrees and 61 to90 degrees).

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

Table 8. Baseline disease characteristics of patientsawith Peyronie’s Disease (PD)

Study 1 Study 2

XIAPEX Placebo XIAPEX Placebo

N=277 N=140 N=274 N=141

Mean age (years) 57.9 58.2 57.3 57.6(Min-Max) (28 - 79) (30 - 81) (23 - 84) (33 - 78)

Mean duration of PD (years) 3.9 4.8 4.2 3.4(Min-Max) (1.0 - 35.9) (1.0 - 50.8) (1.1 - 30.9) (1.1 - 17.1)

Mean Penile Curvature

Deformity (degrees) 48.8 49.0 51.3 49.6(Min-Max) (30-90) (30-89) (30-90) (30-85)

Peyronie’s Disease

Questionnaire (PDQ)b, -

Mean Patient-Reported PD 7.5 7.4 7.4 8.2

Bother Domain Score (range:0-16) c

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 2b Each PDQ assessment required subjects to have had vaginal intercourse in the3 months prior to completionc Higher scores represent worse symptoms

Table 9. Mean percent change in penile curvature deformityfrom baseline to week 52 - Studies 1 and 2

Study 1 Study 2

XIAPEX Placebo XIAPEX Placebo

N=199 N=104 N=202 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 -17.2% b -11.4% b(95% CI) (-26.7%, -7.6%) (-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, andtheir interaction and using last observation carried forward (LOCF) in the modifiedintent-to-treat (mITT) population. The mITT population was defined as all randomizedsubjects who had both a penile curvature deformity measurement and a PDQ assessmentat baseline and at one or more subsequent time points.

b p-value < 0.01

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

Study 1 Study 2

XIAPEX Placebo XIAPEX Placebo

N=199 N=104 N=202 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 -1.2 b -1.1 b(95% CI) (-2.4, -0.03) (-2.1, -0.002)a Mean change, treatment difference, 95% CI, and p-value all based on an ANOVAmodel with factors for treatment, stratum of baseline penile curvature, and theirinteraction and using last observation carried forward (LOCF) in the modifiedintent-to-treat (mITT) population. The mITT population was defined as allrandomized 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 studyinclusion and exclusion criteria as well as the treatment schedule and the co-primary efficacyendpoints were the same as in the pivotal AUX-CC-803 and AUX-CC-804 studies. Patients werehowever followed up to 36 weeks. A total of 189 patients were enrolled and treated with Xiapex. Allpatients had participated in and completed the studies AUX-CC-803 or AUX-CC-804, in which theyhad received placebo.

The median age of the patients included was 60, ranging between 33 and 77 years. The medianduration 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 labelphase 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) 46.9 (12.00)

Min, Max 30, 85

Week 36 value (LOCF)

Mean (SD) 29.9 (15.56)

Min, Max 0, 80% change from baseline

Mean (SD) -36.3 (30.72)

Min, Max -100, 10095% CI of mean** -41.6, -30.9

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

**Based on the 95% CI of the mean not including zero, the percent change from baseline wasconsidered 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) 6.3 (3.60)

Min, Max 1, 15

Week 36 value (LOCF)

Mean (SD) 3.9 (3.65)

Min, Max 0, 16

Change from baseline

Mean (SD) -2.4 (3.34)

Min, Max -12, 795% CI of mean** -3.0, -1.8

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

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

As an exploratory analysis, female sexual partners completed two questionnaires at both the screeningvisit and week 36: the PDQ for Female Sexual Partners (an adaptation of Peyronie’s disease botherand 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 scorewas 4.7 (3.61) and 2.7 (3.06) at week 36, i.e. a change from baseline of -2.0. The mean (SD) FSFIscore was 20.56 (10.08) at baseline and 26.72 (7.73) at week 36, a change from baseline of 7.54.

Long-term efficacy and safety

A phase 4, non-treatment, long-term follow-up study (AUX-CC-810) was undertaken to evaluate theefficacy and safety up to 5 years after the first injection of Xiapex in the pivotal 12-month double-blind placebo-controlled phase 3 studies or in the 9-month open-label phase 3 studies. Through the5 year follow up period (Table 13), subjects demonstrated an improvement in penile curvature and in

PDQ bother compared with the last observed value from the previous phase 3 studies. There were nochanges in the international index of erectile function (IIEF) scores. No new safety signals wereidentified during the 5 year follow-up period.

Table 13: Long Term Efficacy variables - study AUX-CC-810

Baselinea Referenceb Year 2 Year 3 Year 4 Year 5

Curvature*(degrees) N=247 N=247 N=51 N=43 N=225 N=180

Mean±SD 51.8±15.04 31.0±16.10 25.8±12.99 25.2±13.31 29.1±17.21 27.0±16.13

Median 50.0 30.0 26.0 27.0 30.0 29.5

Min, Max 30, 90 0, 81 0, 55 0, 60 0, 85 0, 70

PDQbother** N=183 N=183 N=34 N=29 N=154 N=123

Mean±SD 6.5±3.47 3.4±3.30 3.2±3.30 2.7±2.84 2.5±3.01 2.4±2.89

Median 6.0 2.0 2.5 1.0 1.0 1.0

Min, Max 0, 15 0, 14 0, 14 0, 9 0, 12 0, 13

Baselinea Referenceb Year 2 Year 3 Year 4 Year 5

IIEF erectilefunction** N=181 N=183 N=37 N=31 N=167 N=134

Mean±SD 23.2±6.47 24.9±6.12 22.9±7.70 22.9±8.13 23.3±7.54 23.6±7.48

Median 26.0 27.0 26.0 26.0 27.0 27.0

Min, Max 2, 30 3, 30 3, 30 1, 30 3, 30 1, 30a Baseline was defined as the last observation prior to the first injection of Xiapex in the previousphase 3 study (i.e AUX-CC-802, AUX-CC-803, AUX-CC-804 or AUX-CC-806)b Reference was defined as the last post-baseline non-missing observed value from the previousphase 3 study (i.e AUX-CC-802, AUX-CC-803, AUX-CC-804 or AUX-CC-806)

* Note: 29 subjects were excluded from this analysis. 9 subjects received commercial Xiapex and 2subjects had penile implant during the course of the non-treatment study (AUX-CC-810), and 18subjects had prior surgical intervention for the treatment of Peyronie´s Disease.

**Note: 22 subjects were excluded from this analysis. 9 subjects received commercial Xiapex and 1subject had penile implant during the course of the non-treatment study (AUX-CC-810), and 12subjects had prior surgical intervention for the treatment of Peyronie´s Disease.

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 (seesection 4.2 for information on paediatric use).

Following administration of either a single dose of 0.58 mg of Xiapex to 16 patients with Dupuytren’scontracture, or two concurrent injections of 0.58 mg of Xiapex in the same hand in 12 patientswith Dupuytren's contracture, no quantifiable levels of Xiapex were detected in plasma from5 minutes to 30 days post injection.

Following each of two intralesional administrations, separated by 24 hours, of Xiapex 0.58 mg into thepenile plaque of 19 patients with Peyronie’s disease, plasma levels of AUX-I and AUX-II in patientswith 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 minutesfollowing 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 aftermodelling of plaque on Day 3 (i.e., 24 hours after Injection 2 on Day 2).

There has been no evidence of systemic toxicity to date in the clinical studies conducted with Xiapexadministered through localized injection into the Dupuytren’s cord or into the Peyronie’s plaque.

Because Xiapex is not a substrate for cytochrome P450 or other medicinal product metabolizingenzyme pathways, and because no active metabolites are expected, no metabolism studies have beenperformed.

No formal studies on elimination have been performed. There is no quantifiable systemic exposurefollowing a single injection of Xiapex in patients with Dupuytren’s contracture and only minimal andshort-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.

Xiapex has not been studied in children and adolescents aged 0-18 years and hence nopharmacokinetic data are available.

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

When Xiapex was given intravenously every other day to male and female rats before cohabitationand through mating and implantation, no effects on the oestrus cycle, tubal transport, implantation andpre-implantation development and/or on libido or epididymal sperm maturation were noted withintravenous 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 ofteratogenicity) in rats. No systemic toxicity was observed in this study at any dose level.

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

Standard two-year rodent bioassays have not been performed with Xiapex. Thus, the carcinogenic riskis unknown.

Sucrose

Trometamol

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

Calcium chloride dihydrate

Sodium chloride

Water for injections

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

3 years.

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

Store in a refrigerator (2ºC-8ºC).

Do not freeze.

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

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

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

Pack of 1 vial of powder and 1 vial of solvent

Instructions for use and handling

Preparation - Reconstitution procedure

The vial containing Xiapex and the vial containing the solvent for solution for injection forreconstitution must be refrigerated. Prior to use, the vial containing Xiapex and the vial containing thesolvent for solution for reconstitution must be removed from the refrigerator and allowed to stand atroom temperature for at least 15 minutes and no longer than 60 minutes. Each vial of Xiapex andsterile solvent for reconstitution should only be used for a single injection. If two cords of affectedjoints on the same hand are to be treated during a treatment visit, separate vials and syringesshould 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 volumeof solvent required for reconstitution is determined by the type of joint (PIP joint requires asmaller volume for injection).

Peyronie’s disease: The treatment area should be identified and marked with a surgical markeron the erected penis.

2. The flip-off plastic caps should be removed from both vials. The rubber stopper andsurrounding surface of the vial containing Xiapex and the vial containing the solvent forreconstitution should be swabbed with sterile alcohol (no other antiseptics must be used).

3. Only the supplied solvent must be used for reconstitution; it contains calcium which is requiredfor the activity of Xiapex. Using a sterile syringe calibrated with 0.01 ml graduations, theappropriate amount of solvent supplied should be withdrawn in order to deliver as follows:

Table 14. Volumes needed for administration

Treatment area Solvent Injection volumerequired for to deliverreconstitution 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 totalvolume of solvent used for reconstitution.

4. The solvent should slowly be injected into the sides of the vial containing the lyophilisedpowder of Xiapex. The vial containing the solution should not be inverted or shaken. Thesolution should slowly be swirled to ensure that all of the lyophilised powder has gone intosolution. The syringe and needle used for reconstitution are thereafter removed and discarded.

5. The solution should visually be inspected for particulate matter and discoloration prior toadministration. The reconstituted solution of Xiapex must be clear. If the solution containsparticles, is cloudy or discoloured, it should not be injected.

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

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

EU/1/11/671/001

Date of first authorisation: 28 February 2011

Date of latest renewal: 18 January 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu