Xiapex

1 

ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 

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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 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 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 

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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 14). 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. 

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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. 

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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. 
 

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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). 
 
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 epinephrine 
combined 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. Caution 
should 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 swelling 
develops (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 

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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. 
 
Physicians should advise the patient to wait for at least 4 weeks after the second injection of a 
treatment cycle before resuming sexual activity taking care to ensure that any pain and swelling has 
ceased and to be cautious when resuming sexual activity. 
 
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. At five years after the initial injection of Xiapex the 
majority of subjects (>90%) were seropositive for anti-AUX-I and anti-AUX-II antibodies. In 
addition, 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 safety 
concerns related to the inhibition of endogenous MMPs have been observed, in particular no adverse 

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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. 
 
Excipients 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say 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 

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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), 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 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 Not known 
Infections and 
infestations 

  Injection site 
cellulitis 
Lymphangitis 
 

 

Blood and 
lymphatic system 
disorders 

Lymphadenopathy Lymph node 
pain 

Thrombocytopenia 
Lymphadenitis 

 

Immune system 
disorders 

  Hypersensitivity 
Anaphylactic 
reaction 

 

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System organ class Very common Common Uncommon Not known 
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 
 

 

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System organ class Very common Common Uncommon Not known 
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 
 

Digital necrosisd 
Digital fractured 

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” 
d see also section 4.4 
 
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). 
 

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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 

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System organ class Very common Common Uncommon 
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 

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System organ class Very common Common Uncommon 
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 the national reporting system 
listed in Appendix V. 
 
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 

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15 

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. 

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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. 
 

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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). 
 

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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 

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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 

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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. 
 

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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 
 
 

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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. 
 

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23 

 
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. 
 
Long-term efficacy and safety 
A phase 4, non-treatment, long-term follow-up study (AUX-CC-810) was undertaken to evaluate the 
efficacy 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 the 
5 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 no 
changes in the international index of erectile function (IIEF) scores. No new safety signals were 
identified 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 
PDQ 
bother** 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 

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24 

 Baselinea Referenceb Year 2 Year 3  Year 4 Year 5  
IIEF erectile 
function**  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, 30 
 

a Baseline was defined as the last observation prior to the first injection of Xiapex in the previous 
phase 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 previous 
phase 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 2 
subjects had penile implant during the course of the non-treatment study (AUX-CC-810), and 18 
subjects 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 1 
subject had penile implant during the course of the non-treatment study (AUX-CC-810), and 12 
subjects had prior surgical intervention for the treatment of Peyronie´s Disease. 
 
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. 
 

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25 

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. 
 

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26 

After reconstitution, immediate use is recommended. Reconstituted Xiapex can be kept at ambient 
room temperature (20ºC-25ºC) for up to one hour or refrigerated 2ºC-8˚C for up to 4 hours prior to 
administration. If refrigerated, the reconstituted solution must be allowed to return to ambient room 
temperature (20ºC-25ºC) for approximately 15 minutes before use. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2ºC-8ºC). 
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). 
Peyronie’s disease: The treatment area should be identified and marked with a surgical marker 
on the erected penis. 

 
2. 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). 

 
3. 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: 

 

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Table 14. 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.  

 
4. 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. 

 
5. 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 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

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


28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
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A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Auxilium Pharmaceuticals, LLC 
102 Witmer Road, Horsham, PA 19044. 
USA 
 
Lonza AG 
Lonzastrasse 
3930 Visp 
Switzerland 
 
Name and address of the manufacturer responsible for batch release 
 
Swedish Orphan Biovitrum AB (publ)  
SE-112 76 Stockholm  
Sweden 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures 
 
The MAH shall ensure that all physicians who are expected to prescribe/use Xiapex are appropriately 
trained in the correct administration of the medicinal product and experienced in the diagnosis and 
management of Dupuytren’s contracture and Peyronie’s disease. 

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30 

 
The MAH, in agreement with the competent authorities in the Member States, shall implement, prior 
to the launch, an educational programme for physicians aiming to ensure proper injection placement to 
minimize occurrence of injection-related adverse events and to inform on expected and potential risks 
associated with the treatment. 
 
The physician educational programme should contain the following key elements: 
 
• Injection technique and dosing interval. 
• Proper amount of volumes for both reconstitution and injection differences in the 

metocarpophalangeal (MP) and proximal interphalangeal (PIP) joints for Dupuytren’s 
contracture and for the Peyronie’s disease plaque. 

• Recognition and treatment of severe immune-mediated reaction, including anaphylaxis. 
• Information on bleeding risk in patients with coagulation disorders including those on 

concurrent anti-coagulation therapy. 
• Information on the potential risk of matrix metalloproteinases (MMP) cross reactivity including 

the development of musculoskeletal syndrome and exacerbation/initiation of autoimmune 
disorders. 

• Reminder of the need to report adverse events, including medication errors. 
• The need to inform the patient about the signs and symptoms associated with the treatment and 

when to seek attention from the health care provider. 
• The summary of product characteristics and the patient information leaflet. 

 
• Obligation to conduct post-authorisation measures 
 
Not applicable 
 

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31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

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33 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton containing 1 vial of powder and 1 vial of solvent 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xiapex 0.9 mg powder and solvent for solution for injection 
collagenase clostridium histolyticum 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each powder vial contains 0.9 mg collagenase clostridium histolyticum 
 
 
3. LIST OF EXCIPIENTS 
 
Powder: Contains sucrose, trometamol, hydrochloric acid 
Solvent: Contains calcium chloride dihydrate, sodium chloride, water for injection 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
1 vial of powder 
1 vial of solvent 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intralesional use only 
 
Reconstitute with appropriate volume before use. 
Read the package leaflet before use. 
For single use only 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE sight and REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 

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9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum AB (publ) 
SE-112 76 Stockholm 
Sweden 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/671/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 

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35 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Xiapex powder vial label 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Xiapex 0.9 mg powder for injection 
collagenase clostridium histolyticum 
Intralesional use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Solvent vial for use with Xiapex label 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Solvent for Xiapex 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
3 ml 
 
 
6. OTHER 
 
 

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B. PACKAGE LEAFLET 
 

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Package leaflet: Information for the user 
 

Xiapex 0.9 mg powder and solvent for solution for injection 
collagenase clostridium histolyticum 

 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Xiapex is and what it is used for 
2. What you need to know before you are given Xiapex 
3. How Xiapex is used 
4. Possible side effects 
5. How to store Xiapex 
6. Contents of the pack and other information 
 
 
1. What Xiapex is and what it is used for 
 
Xiapex is used for the treatment of two different conditions: Dupuytren’s contracture in adult 
patients with a palpable cord and Peyronie’s disease in adult men. 
 
Dupuytren’s contracture 
This is a disease that causes your finger(s) to bend inward. This bending is called a contracture and is 
caused by the abnormal formation of a cord containing collagen under your skin. For many people, a 
contracture causes significant difficulties with performing everyday tasks like driving, shaking hands, 
playing sports, opening jars, typing or holding objects. 
 
Peyronie’s disease 
This is a condition where adult men have a ‘plaque’ that can be felt and a curve to their penis. The 
disease can cause a change in the shape of the erect penis due to the abnormal build-up of scar tissue, 
known as a plaque, within the stretchy fibres of the penis. The plaque may interfere with the ability to 
get a straight erection because the plaque will not stretch as much as the rest of the penis. Men with 
Peyronie’s disease may have an erection that is curved or bent. 
 
The active substance in Xiapex is collagenase clostridium histolyticum, and this collagenase is 
produced using the microorganism Clostridium histolyticum. Xiapex is injected by your doctor into the 
cord in your finger/hand or plaque in your penis and works by breaking down the collagen in the cord 
or plaque. 
For Dupuytren’s disease, Xiapex breaks down the collagen forming the cord and thereby releasing the 
contracture completely or partly and enabling your finger(s) to be straighter. 
For Peyronie’s disease, Xiapex breaks down the collagen in the plaque that is causing your erect penis 
to curve, which may help the previously bent erection to become straighter and enable you to feel less 
bothered by your disease. The reduction of the curve achieved will vary between individuals. 
 
 
2. What you need to know before you are given Xiapex 
 
You must not be given Xiapex: 
• If you are allergic to collagenase clostridium histolyticum or any of the other ingredients of this 

medicine (listed in section 6). 
• For Peyronie’s disease if the treatment of your plaque involves the tube (called the urethra) that 

your urine passes through. 

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Warnings and precautions 
Talk to your doctor or pharmacist before you are given Xiapex. 
 
Allergic reactions 
Severe allergic reactions can happen in patients who receive Xiapex, because it contains proteins 
foreign to the human body. 
 
Call your doctor right away if you have any of these symptoms of an allergic reaction after an 
injection of Xiapex: 
• hives 
• swollen face 
• breathing trouble 
• chest pain 
 
The potential for a serious allergic reaction or the development of a musculoskeletal syndrome upon 
repeated use of Xiapex cannot be excluded. The symptoms of musculoskeletal syndrome could be 
joint or muscle pain, shoulder stiffness, hand swelling, fibrosis of the palms, and thickening or nodule 
forming of tendons. If you notice such symptoms you should inform your doctor. 
 
Before you are given this medicine, make sure your doctor knows: 
• if you have had an allergic reaction to a previous Xiapex injection. 
• if you have a history of problems with the normal clotting of your blood or if you are taking any 

medicines to help control the normal clotting of your blood (known as anticoagulation 
medicines). 

• if you are currently taking any anticoagulation medicines, you must not receive Xiapex within 
7 days of last dose of your anticoagulation medicine. One exception is the use of up to 150 mg 
daily dose of acetylsalicylic acid (a substance present in many medicines used to prevent blood 
clotting) which can be taken. 

 
If you are treated for Dupuytren’s contracture 
 
This medicine must only be injected into the collagen cord in your hand by your doctor. Your doctor 
will take care to avoid injecting into tendons, nerves or blood vessels. Incorrect injection into tendons, 
nerves or blood vessels may result in bleeding or damage and possible permanent injury to these 
structures. If your cord to be treated is attached to the skin, you are at higher risk of the skin splitting 
or tearing during the finger extension procedure following the injection of Xiapex. 
 
Severe injury like e.g. finger necrosis or fracture could result in loss of finger or finger parts. Before 
finger manipulation procedure will be performed tell your doctor, if you have a condition affecting 
your bones, e.g. osteopenia or osteoporosis. Contact your doctor right away if you are concerned by 
increasing pain or symptoms in the fingers after the treatment. 
 
Tell your doctor if you have previously received or are thinking about receiving Xiapex to treat a 
condition known as Peyronie's disease. This condition affects adult men, who have a ‘plaque’ that can 
be felt and a curve to their erect penis. 
 
If you are treated for Peyronie’s disease 
 
This medicine must only be injected into the plaque in your penis by your doctor. 
 
Penile fracture (corporal rupture) or other serious injury to the penis 
Receiving an injection of Xiapex may cause damage to the tubes in your penis called the corpora. 
After treatment with Xiapex, one of these tubes may break during an erection. This is called a corporal 
rupture or penile fracture. 
After treatment with Xiapex, blood vessels in your penis may also break, causing blood to collect 
under the skin (which is called a haematoma). 

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Symptoms of penile fracture (corporal rupture) or other serious injury to your penis may include: 
• a popping sound or sensation in an erect penis 
• sudden loss of the ability to maintain an erection 
• pain in your penis 
• purple bruising and swelling of your penis 
• difficulty urinating or blood in the urine 
 
Call your doctor right away if you experience any of the symptoms of penile fracture or serious 
injury to your penis listed above, as this may require surgical intervention. 
Do not have sex or have any other sexual activity for at least 4 weeks after the second injection of a 
treatment cycle with Xiapex and after any pain and swelling has ceased and be cautious when 
resuming sexual activity. 
 
Tell your doctor if you are thinking about receiving or have previously received Xiapex to treat a 
condition known as Dupuytren’s contracture. In this condition, a cord forms in the tissue in the palm 
of the hand and causes one or more fingers to bend toward the palm so that they cannot be 
straightened. 
 
Children and adolescents 
There is no relevant use of Xiapex in children and adolescents aged 0-18 years for the treatment of 
Dupuytren’s contracture or Peyronie’s disease. 
 
Other medicines and Xiapex 
Tell your doctor if you are taking, have recently taken or might take any other medicines. This 
includes medicines to help control the normal clotting of your blood (known as anticoagulation 
medicines), anthraquinone derivatives, some antibiotics (tetracyclines and 
anthracyclines/anthraquinolones) used to treat infections. There are no known interactions with 
concomitant use of medicines for erectile dysfunction and Xiapex treatment. 
 
Pregnancy and breast-feeding 
Dupuytren’s contracture 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before you are given this medicine. 
There is no experience in the use of Xiapex in pregnant women therefore the use of Xiapex is not 
recommended in pregnancy, and treatment should be postponed until after pregnancy. 
 
There is no experience in the use of Xiapex in breast-feeding women therefore the use of Xiapex is not 
recommended during breast-feeding. 
 
Peyronie's disease 
This condition does not occur in females. 
 
Driving and using machines 
If you experience dizziness, numbness or altered sensation, and headache immediately after an 
injection of Xiapex you must avoid potentially hazardous tasks such as driving or using machines until 
these effects have passed or until advised by your doctor. 
 
Swelling and pain may impair the use of the treated hand in Dupuytren’s disease. 
 
Xiapex contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-
free’. 
 
 

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3. How Xiapex is used 
 
Only doctors that have been appropriately trained in the correct use of Xiapex and are experienced in 
the management of Dupuytren’s or Peyronie’s disease are allowed to give you treatment. 
 
You will be given Xiapex as an injection directly into the area that is causing your finger/penis to bend 
(intralesional injection). Your doctor will perform all injections of Xiapex. 
 
The recommended dose of your prescribed medicine is 0.58 mg. 
 
Dupuytren’s contracture 
The total volume of the injection depends on the joint being treated. Your doctor will carefully select 
an area where the collagen cord is best accessible and will proceed with the injection into the cord. 
 
After the injection, your doctor will place a dressing on your hand. You must limit motion of the 
treated finger for a day and it is not uncommon for the finger to straighten on its own for some 
patients. Until advised by your doctor, do not flex or extend the fingers of the injected hand. Do not 
attempt to disrupt the injected cord by self manipulation at any time. Elevate the injected hand as 
much as possible until the day after the finger extension procedure. 
 
Your doctor will ask you to return approximately 24-72 hours after your injection to attempt to extend 
your finger to straighten it. Following extension of your finger, your doctor will fit you with a splint to 
wear at bedtime for up to 4 months. 
If your finger is still not able to straighten during a follow-up visit with your doctor, you may need 
additional treatments with Xiapex which may be administered approximately 4 weeks after the first 
treatment. Injections and finger extension procedures may be administered up to 3 times per cord at 
approximately 4-week intervals. Injections in up to two cords or two affected joints in the same hand 
can be administered during a treatment visit. If the disease has resulted in multiple contractures, 
additional cords may be treated at other treatment visits approximately 4 weeks apart, as determined 
by your doctor. 
 
Be sure to ask your doctor when you can resume normal activities after treatment with Xiapex. It is 
recommended to avoid strenuous activities of your finger until instructed further by your doctor. Your 
doctor may recommend you perform a series of finger flexion and extension exercises several times a 
day for several months. 
Clinical study experience with Xiapex is currently limited to up to 3 injections per cord and up to a 
total of 8 injections in the hands. 
 
Peyronie’s disease 
Your doctor will inject Xiapex into the plaque that is causing your penis to curve. 
 
• Xiapex is given as part of a treatment cycle. In each treatment cycle, you will receive one 

injection of Xiapex, followed by a second injection on a separate day (1 to 3 days later). 
• After each injection of Xiapex, your penis may be wrapped with a bandage. Your doctor will tell 

you when to remove the dressing. 
• One to three days after the second injection of Xiapex in a treatment cycle, you will need to 

return to your doctor for a manual procedure that will help stretch and help straighten your penis. 
Your doctor will tell you when to come back for this. 

• Your doctor will show you how to gently stretch and straighten your penis the right way. For 
further information see “Instructions on how to gently stretch your penis” and “Instructions 
on how to gently straighten your penis” at the end of the Patient leaflet. 

• You should only gently stretch your penis when you do not have an erection. You should 
gently stretch your penis 3 times a day for 6 weeks after each treatment cycle. 

• You should only gently straighten your penis if you have an erection that happens without 
any sexual activity (spontaneous erection). You should gently straighten your penis 1 time a 
day for 6 weeks after each treatment cycle. 

• Your doctor will tell you when you can resume sexual activity after each treatment cycle. 

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• Your doctor will also tell you when to come back if more treatment cycles are needed. 
 

Clinical study experience with Xiapex is currently limited to four treatment cycles in which a total of 8 
injections may be administered into the plaque causing the curvature. 
 
Tell your doctor right away if you have trouble stretching or straightening your penis, or if you have 
pain or other concerns. 
 
If you receive more Xiapex than you should 
As this medicine is administered to you by your doctor it is very unlikely that you will be given an 
incorrect dose. In the unlikely event that your doctor administers a higher dose than recommended, 
you may experience an increase in the severity of possible side effects listed in section 4 “Possible 
Side Effects”. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Allergic reaction 
Severe allergic reaction has been reported uncommonly (1 case). Please consult a doctor immediately 
if you experience any signs or symptoms of a serious allergic reaction, e.g., wide spread redness or 
rash, swelling, tightness in the throat or difficulty breathing. You must not be given Xiapex if you 
know that you have had a serious allergic reaction to collagenase or any of the other ingredients. 
 
Dupuytren’s contracture 
 
Most of the side effects that occurred in the clinical studies were mild or moderate in severity and 
were localised to the hand treated. 
 
The following side effects have been seen with Xiapex administered in up to two cords or joints per 
treatment visit: 
 
Very common side effects (may affect more than 1 in 10 people): 
• reactions at the injection site like bleeding, pain, swelling, tenderness and bruising 
• itching in the hand 
• feeling of pain in the hand, wrist or arm 
• swollen or enlarged glands near the elbow or under the arm 
• swelling in the hand or arm 
 
Common side effects (may affect up to 1 in 10 people): 
• reactions at the injection site like pain, warmth, swelling, presence of a blister, redness of skin 

and/or skin rash 
• skin wound at the site of injection 
• skin wound, blood blister 
• painful glands near the elbows or under the arm 
• joint swelling and pain 
• burning sensation, partial loss of sensitivity, feeling of “pins and needles” or numbness 
• dizziness, headache, nausea 
• increased perspiration 
 

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Uncommon side effects (may affect up to 1 in 100 people): 
• rupture of a tendon, ligament injury 
• low blood platelet count 
• swelling of the eyelid 
• allergic reaction 
• chronic pain 
• discomfort, injury, paralysis of the limb 
• tremor/shaking, increased sensitivity to stimuli 
• fainting 
• vomiting, diarrhoea, upper abdominal pain 
• rash, eczema 
• stiffness, creaking of the joints 
• muscle spasm, muscle weakness, musculoskeletal stiffness or discomfort 
• feeling of pain in the groin, shoulder, chest wall, or neck 
• swelling 
• fever, general pain, discomfort, tiredness, feeling hot, malaise, flu-like illness 
• cold intolerance of the treated fingers 
• reactions at the site of injection including peeling of the skin, skin discolouration, infection, 

pain, skin tightness, numbness, irritation or nodules, scab, wound 
• increased liver enzymes 
• agitation, disorientation, irritability, restlessness, difficulty sleeping 
• shortness of breath, hyperventilation 
• inflammation of the lymph nodes (lymphadenitis), inflammation of lymphatic channels 

(lymphangitis) leading to reddened skin with elevated borders, tender and warm, usually 
accompanied by a red streak, enlarged lymph nodes 

 
Frequency of side effects not known 
• fractured finger 
• loss of finger or finger parts 
 
Peyronie’s disease 
 
Penile Fracture (corporal rupture) or other serious injury to the penis 
Penile Fracture (corporal rupture) or other serious injury to the penis has uncommonly occurred. 
Call your doctor right away if you experience any of the symptoms of penile fracture or other 
serious injury to your penis which are as follows: a popping sound or sensation in an erect penis, 
sudden loss of the ability to maintain an erection, pain in your penis, purple bruising and swelling of 
your penis, difficulty urinating or blood in the urine, a collection of blood under the skin at the 
injection site. 
 
Most of the side effects that occurred in the clinical studies were mild or moderate in severity and 
most resolved within 2 weeks of the injection. 
 
The following side effects have been seen with Xiapex: 
 
Very common side effects (may affect more than 1 in 10 people): 
• bruising or swelling of the penis and pain in the penis  
• a small collection of blood under the skin at the injection site 
 
Common side effects (may affect up to 1 in 10 people): 
• reactions at the injection site such as presence of a blister, swelling, itching or a solid raised area 

under the skin 
• pain at the injection site and above the penis 
• blister or redness/discolouration of the penis 
• genital itchiness 

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• painful erection, painful sex and erectile dysfunction. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
• lymph node pain and swollen lymph nodes 
• increased white blood cells 
• fast heart rate 
• ringing in the ear 
• abdominal swelling 
• constipation 
• feeling hot 
• injection site rash 
• fever 
• weakness 
• chills 
• flu-like illness 
• drainage from a blister on the penis 
• tenderness 
• allergic reaction 
• fungal skin infection 
• infection 
• upper respiratory infection 
• skin cut 
• open wound 
• collection of blood outside of a blood vessel on scrotum 
• joint injury 
• popping sound/sensation indicating penile fracture 
• blood sugar increased 
• blood pressure increased 
• water retention 
• back pain 
• groin pain and discomfort 
• thickening near ligament at base of penis 
• tenderness in ligament at base of penis 
• headache 
• dizziness 
• unpleasant taste 
• abnormal sensation 
• burning sensation 
• increased/decreased sensitivity to stimuli to senses 
• abnormal dreams 
• depression 
• avoidance of sex 
• painful/increased urination 
• scar tissue in penis 
• penis disorder 
• worsening of Peyronie’s disease 
• sexual dysfunction 
• scrotal redness, swelling and pain 
• genital discomfort and bruising 
• pelvic pain 
• penis size reduced 
• formation of a blood clot inside the penile vein 
• cough 
• small area of inflammation 

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• night sweats 
• sore on the skin of the penis 
• skin rash producing redness 
• skin disorder/irritation 
• collection of blood outside the blood vessels 
• bruising 
• disease of the lymph vessels 
• superficial vein inflammation 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Xiapex 
 
Keep this medicine out of the sight and reach of children. 
 
Your doctor must not use this medicine after the expiry date which is stated on the carton and vial 
label after EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator at 2ºC-8ºC. Do not freeze. 
 
After reconstitution, immediate use of the medicine is recommended. Reconstituted Xiapex can be 
kept at ambient room temperature (20ºC-25ºC) for up to one hour or refrigerated at 2ºC-8˚C for up to 
4 hours prior to administration. If refrigerated, the reconstituted solution must be allowed to return to 
ambient room temperature (20ºC-25ºC) for approximately 15 minutes before use. 
 
Your doctor must not use Xiapex if the reconstituted solution is discoloured or contains particles. The 
solution must be clear, colourless with no lumps or flakes or particles. 
 
Your doctor will take care of storing, handling and disposing of Xiapex. Do not throw away any 
medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you 
no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Xiapex contains 
• The active substance is collagenase clostridium histolyticum. Each vial of Xiapex contains 

0.9 mg of collagenase clostridium histolyticum. 
• The other ingredients are sucrose, trometamol and hydrochloric acid 2.4% w/w (for pH 

adjustment). 
• The solvent contains calcium chloride dihydrate, sodium chloride and water for injections. 
 
What Xiapex looks like and contents of the pack 
Xiapex is a powder and solvent for solution for injection. The white lyophilized powder is supplied in 
a 3 ml type I clear glass vial with rubber stopper, aluminium seal and flip-off plastic cap. 
 
The solvent that is used to dissolve the powder is a clear colourless liquid. 3 ml solution is supplied in 
a 5 ml type I clear glass vial with rubber stopper, aluminium seal and flip-off plastic cap. 
 
Xiapex is supplied in a pack containing 1 vial of Xiapex powder and 1 vial of solvent. 
 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


46 

Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden 
 
Manufacturer 
Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden 
 
 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 
 

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


47 

------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Instructions for use and handling 
 
Dupuytren’s contracture 
 
1. Preparation - Reconstitution procedure 
 
The single dose vial containing Xiapex and the single dose vial containing the solvent for solution for 
injection for reconstitution must be refrigerated. 
 
1. Before use, remove the vial containing the lyophilized powder of Xiapex and the vial containing 

the diluent for reconstitution from the refrigerator and allow the two vials to stand at room 
temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial 
containing Xiapex. The cake of lyophilized powder should be intact and white in colour. 

 
2. Confirm the joint to be treated (metacarpophalangeal [MP] or proximal interphalangeal [PIP]) 

as the volume of solvent required for reconstitution is determined by the type of joint (PIP joint 
requires a smaller volume for injection). 

 
3. After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper 

and surrounding surface of the vial containing Xiapex and the vial containing the diluent for 
reconstitution with sterile alcohol (no other antiseptics should be used). 

 
4. Use only the supplied diluent for reconstitution. The diluent contains calcium which is required 

for the activity of Xiapex. 
 
5. Using a 1 ml syringe with 0.01 ml graduations with a 27-gauge 12-13 mm needle (not supplied), 

withdraw the correct volume of the diluent supplied: 
 

• 0.39 ml of solvent for cords affecting a MP joint in Dupuytren’s contracture 
• 0.31 ml of solvent for cords affecting a PIP joint in Dupuytren’s contracture 

 
6. Inject the diluent slowly into the sides of the vial containing the lyophilized powder of Xiapex. 

Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the 
lyophilized powder has gone into solution. 

 
7. The reconstituted Xiapex solution can be kept at room temperature (20º to 25ºC) for up to one 

hour or refrigerated at 2º to 8°C for up to 4 hours prior to administration. If the reconstituted 
Xiapex solution is refrigerated, allow this solution to return to room temperature for 
approximately 15 minutes before use. 

 
8. Discard the syringe and needle used for reconstitution and the diluent vial. 
 
9. When administering two injections in the same hand during a treatment visit, use a new syringe 

and separate vial of reconstituted solution (containing 0.58 mg of Xiapex) for the second 
injection. Repeat steps 1 through 8. 

 
2. Identification of treatment area 
 
1. Prior to each treatment cycle, identify the treatment area as follows:  

Confirm the joint to be treated (metacarpophalangeal [MP] or proximal interphalangeal [PIP]) 
as the volume of solvent required for reconstitution is determined by the type of joint (PIP joint 
requires a smaller volume for injection). 

 

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3. Injection procedure 
 
Administration of a local anaesthetic medicinal product prior to injection of Xiapex is not 
recommended, as it may interfere with proper placement of the injection. 
 
1. The reconstituted Xiapex solution should be clear. Inspect the solution visually for particulate 

matter and discolouration prior to administration. If the solution contains particulates, is cloudy, 
or is discoloured, do not inject the reconstituted solution.  
 

2. Reconfirm the cord to be injected. The site chosen for injection must be the area where the 
contracting cord is maximally separated from the underlying flexor tendons and where the skin 
is not intimately adhered to the cord. 

 
3. When administering two injections in the same hand during a treatment visit, begin with the 

affected finger in the most ulnar aspect of the hand and continue toward the radial aspect 
(eg, fifth finger to index finger). Within each finger, begin with the affected joint in the 
most proximal aspect of the finger and continue toward the distal aspect (eg, MP to PIP). 
For each injection, follow steps 4-10. 

 
4. Apply antiseptic at the site of the injection and allow the skin to dry. 
 
5. Using a new sterile, hubless syringe with 0.01 ml graduations and a permanently fixed, 26 or 

27 gauge, 12 or 13 mm needle (not supplied), withdraw the adequate volume of reconstituted 
solution for a 0.58 mg dose of Xiapex required for injection to deliver: 
• 0.25 ml of reconstituted Xiapex for cords affecting a MP joint or 
• 0.20 ml of reconstituted Xiapex for cords affecting a PIP joint. 

 
6. Use caution with cords as they approach the PIP flexion crease area. If injecting into a cord 

affecting the PIP joint of the fifth (little) finger, care must be taken to inject as close to the 
palmar digital crease as possible and not to insert more than 2 mm to 3 mm in depth. For PIP 
joints do not inject more than 4 mm distal to the palmar digital crease. 

 
7. With your non-dominant hand, secure the patient’s hand to be treated while simultaneously 

applying tension to the cord. With your dominant hand, place the needle into the cord, using 
caution to keep the needle within the cord. Avoid having the needle tip pass completely through 
the cord to help minimise the potential for injection of Xiapex into tissues other than the cord. 
After needle placement, if there is any concern that the needle is in the flexor tendon, apply a 
small amount of passive motion at the distal interphalangeal (DIP) joint. If insertion of the 
needle into a tendon is suspected or paresthesia is noted by the patient, withdraw the needle and 
reposition it into the cord. If the needle is in the proper location, there will be some resistance 
noted during the injection procedure. See Figure 1 below for an illustration of the injection 
technique. 

 
8. After confirming that the needle is correctly placed in the cord, inject approximately one-third 

of the dose. 
 
9. Next, keeping the needle under the skin at all times, withdraw the needle tip from the cord and 

reposition it in a slightly more distal location (approximately 2-3 mm) to the initial injection in 
the cord and inject another one-third of the dose. 

 
10. Again keeping the needle under the skin at all times, withdraw the needle tip from the cord and 

reposition it a third time proximal to the initial injection (approximately 2-3 mm) and inject the 
final portion of the dose into the cord (see Figure 2). 

 

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The figures 1 and 2 below are for illustrative purposes only and may not be representative of the 
precise location of anatomical structures in an individual patient. 
 
Figure 1: Illustration of the injection technique. 
 

 
 
 
Figure 2: Three step injection of Xiapex into the cord. 
 

 
 
11. Wrap the patient’s treated hand with a soft, bulky, gauze dressing. 
 
12. Discard the unused portion of the reconstituted solution and solvent after injection. Do not store, 

pool, or use any vials containing unused reconstituted solution or solvent. 
 
13. Patients should be instructed: 

• 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 attempt to disrupt the injected cord by self manipulation at any time. 

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

• To promptly contact their doctor if there is evidence of infection (e.g., fever, chills, 
increasing redness or oedema) or trouble bending the finger after the swelling goes down 
(symptoms of tendon rupture). 

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

 
4. Finger extension procedure 
 
1. At the follow-up visit approximately 24-72 hours after injection, determine 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. 
 

2. If cords of two affected joints in one finger were treated, perform the finger extension 
procedure on the cord affecting the MP joint before performing the procedure on the cord 
affecting the PIP joint. 

 
3.  Local anaesthesia may be used, if needed, during the finger extension procedure. 
 
4. While the patient’s wrist is in the flexed position, apply moderate stretching pressure to the 

injected cord by extending the finger for approximately 10 to 20 seconds. For cords affecting 
the PIP joint, perform the finger extension procedure when the MP joint is in the flexed 
position. 

 
5. 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. 

 
6. If the cord has not disrupted after 3 attempts of extension per cord, 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. 

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

maximum extension), 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. 
 

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The following information is intended for Peyronie’s disease patients only: 

Instructions on how to gently stretch your penis 

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

• With one hand, hold the tip of your penis with your fingers. With the other hand, hold the base 
of your penis with the fingers (see Figure 3). 

• Gently pull your penis away from your body to its full length and hold the stretch for 
30 seconds. 

• Let go of the tip of your penis and let your penis return to its normal length. 
 
Figure 3: Illustration how to stretch your penis 

 
 
 
Instructions on how to gently straighten your penis 

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

• With one hand hold your penis. With your other hand, gently bend your penis in the opposite 
direction of the curve (see Figure 4). Hold the penis in this more straightened position for 
30 seconds, then let go. 

Figure 4: Illustration how to straighten your penis 

 

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52 

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The following information is intended for healthcare professionals only: 
 
Instructions for use and handling 
 
Peyronie’s disease 
 
1. Preparation - Reconstitution procedure 
 
The single dose vial containing Xiapex and the single dose vial containing the solvent for solution for 
injection for reconstitution must be refrigerated. 
 
a) Before use, remove the vial containing the lyophilized powder of Xiapex and the vial containing 

the diluent for reconstitution from the refrigerator and allow the two vials to stand at room 
temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial 
containing Xiapex. The cake of lyophilized powder should be intact and white in colour. 
 

b) After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper 
and surrounding surface of the vial containing Xiapex and the vial containing the diluent for 
reconstitution with sterile alcohol (no other antiseptics should be used).  
 

c) Use only the supplied diluent for reconstitution. The diluent contains calcium which is required 
for the activity of Xiapex.  
 

d) Using a 1 ml syringe with 0.01 ml graduations with a 27-gauge 12-13 mm needle (not supplied), 
withdraw the correct volume of the diluent supplied: 

 
• 0.39 ml of solvent for the penile plaque in Peyronie’s disease 
 

e) Inject the diluent slowly into the sides of the vial containing the lyophilized powder of Xiapex. 
Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the 
lyophilized powder has gone into solution. 

 
f) The reconstituted Xiapex solution can be kept at room temperature (20º to 25ºC) for up to one 

hour or refrigerated at 2º to 8°C for up to 4 hours prior to administration. If the reconstituted 
Xiapex solution is refrigerated, allow this solution to return to room temperature for 
approximately 15 minutes before use. 

 
g) Discard the syringe and needle used for reconstitution and the diluent vial. 
 
2. Identification of treatment area 
 
a) Prior to each treatment cycle, identify the treatment area as follows: 

• Induce a penile erection  
• Locate the plaque at the point of maximum concavity (or focal point) in the bend of the 

penis 
• Mark the point with a surgical marker. This indicates the target area in the plaque for 

Xiapex deposition 
 
3. Injection procedure 
 
a) The reconstituted Xiapex solution should be clear. Inspect the solution visually for particulate 

matter and discolouration prior to administration. If the solution contains particulates, is cloudy, 
or is discoloured, do not inject the reconstituted solution. 
 

b) Apply antiseptic at the site of the injection and allow the skin to dry. 
 

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53 

c) Administer suitable local anaesthetic, if desired. 
 

d) Using a new hubless syringe containing 0.01 ml graduations with a permanently fixed 27-gauge 
12 or 13 mm needle (not supplied), withdraw a volume of 0.25 ml of reconstituted solution 
(containing 0.58 mg of Xiapex). 

 
e) The penis should be in a flaccid state before Xiapex is injected. Place the needle tip on the side 

of the target plaque in alignment with the point of maximal concavity. Orient the needle so that 
it enters the plaque from the side, NOT downwards or perpendicularly towards the corpora 
cavernosum. 

 
f) Insert and advance the needle transversely through the width of the plaque, towards the opposite 

side of the plaque without passing completely through it. Proper needle position is tested and 
confirmed by carefully noting resistance to minimal depression of the syringe plunger. 

 
g) With the tip of the needle placed within the plaque, initiate injection, maintaining steady 

pressure to slowly inject the drug into the plaque. Withdraw the needle slowly so as to deposit 
the full dose along the needle track within the plaque. For plaques that are only a few 
millimetres in width, the distance of withdrawal of the syringe may be very minimal. The goal 
is always to deposit the full dose entirely within the plaque. 

 
h) Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a 

dressing as necessary. 
 
i) Discard the unused portion of the reconstituted solution and diluent after each injection. Do not 

store, pool, or use any vials containing unused reconstituted solution or diluent. 
 
j) The second injection of each treatment cycle should be made approximately 2 to 3 mm apart 

from the first injection. 
 
4. Penile modelling procedure 
 
Penile modelling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 
1 to 3 days after the second injection of each treatment cycle, perform a penile modelling procedure 
(as described below) on the flaccid penis to stretch and elongate the plaque that Xiapex has disrupted: 

• Administer suitable local anaesthetic, if desired. 
• Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm 

proximal and distal to the injection site. Avoid direct pressure on the injection site. 
• Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure 

to elongate and stretch the plaque. The goal is to gradually create bending opposite to the 
patient’s penile curvature, with stretching to the point of moderate resistance. Hold 
pressure for 30 seconds then release. 

• After a 30 second rest period, repeat the penile modelling technique for a total of 3 
modelling attempts at 30 seconds for each attempt. 

 
The patient should then be instructed 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. 

 

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54 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 

 
 

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Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for collagenase clostridium 
histolyticum, the scientific conclusions of the CHMP are as follows: 
 
The review of data presented in the PSUR for Xiapex, covering the period from 28 February 2018 to 
27 February 2019, identified post-marketing and literature case reports of finger necrosis and/or 
amputation and of finger fractures in patients with Dupuytren’s contracture treated with collagenase 
clostridium histolyticum. Taking into account the plausibility of the mechanism of collagenase 
clostridium histolyticum and the subsequent manipulation procedure in patients with Dupuytren’s 
contracture, the PRAC considers that the product information for Xiapex should be updated to 
include a warning with regards to finger necrosis resulting in some cases in finger amputation and a 
warning with regards to finger fracture should be included in section 4.4 of the SmPC. Reduced 
peripheral circulation may be one contributing factor for finger necrosis. For patients with an 
increased risk of fracture, e.g. patients with osteopenia/osteoporosis, special caution is needed during 
the manipulation procedure. The section 4.8 of the SmPC is updated to include the adverse reactions 
“digital necrosis” and “digital fracture” with a frequency “not known”. The package leaflet is 
updated accordingly. 

In addition, based on the review of post marketing case reports of penile fracture in patients with 
Peyronie’s disease, the PRAC considers that the product information for Xiapex should be updated to 
include a new wording for section 4.4 of the SmPC and section 2 of the PIL to increase the minimum 
time span between injection and resumption of sexual activity to at least 4 weeks and to be cautious 
when resuming sexual activity. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

Grounds for the variation to the terms of the Marketing Authorisation  
 
On the basis of the scientific conclusions for collagenase clostridium histolyticum the CHMP is of the 
opinion that the benefit-risk balance of the medicinal product(s) containing collagenase clostridium 
histolyticum is unchanged subject to the proposed changes to the product information. 
 
The CHMP recommends that the terms of the Marketing Authorisation should be varied. 
 
 

 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS