Xiapex

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.

Shelf life

3 years.

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

Contraindications

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

List of excipients

Powder

Sucrose

Trometamol

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

Solvent

Calcium chloride dihydrate

Sodium chloride

Water for injections

Undesirable effects

Dupuytren's contracture

Summary of the safety profile

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

Tabulated list of adverse reactions

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

Table 1: Tabulated list of adverse reactions.

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

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

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

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

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

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

Peyronie's disease

Summary of the safety profile

The overall safety profile was similar in the two Phase 3 double-blind placebo controlled studies (832 male patients, 551 patients received Xiapex) and in an open-label Phase 3 study (189 male patients) of patients who had previously received placebo in the controlled studies. In the two Phase 3 double-blind placebo controlled studies, most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered. The most frequently reported adverse drug reactions (>25%) during the Xiapex controlled clinical studies were penile haematoma, penile swelling and penile pain. Severe penile haematoma including severe injection site haematoma were reported with the frequency very common.

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

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.

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

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

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

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

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

Reporting of suspected adverse reactions

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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

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.

Pharmacotherapeutic group

Pharmacodynamic properties

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

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

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

Mechanism of action

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

Dupuytren's contracture

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

Peyronie's disease

The signs and symptoms of Peyronie's disease are caused by a collagen plaque. Injection of Xiapex into a Peyronie's plaque, which is comprised mostly of collagen, may result in enzymatic disruption of the plaque. Following this disruption of the plaque, penile curvature deformity and patient bother caused by Peyronie's disease are reduced.

Clinical efficacy and safety

Dupuytren's contracture

The efficacy of Xiapex 0.58 mg was evaluated in two pivotal randomized, double-blind, placebo-controlled studies, CORD I (AUX-CC-857) and CORD II (AUX-CC-859), in adult patients with Dupuytren's contracture. The double-blind study population comprised 409 patients of whom 272 received Xiapex 0.58 mg and 137 received placebo. The mean age was 63 years (range 33 to 89 years) and 80% of patients were male. At study entry, patients in the clinical studies had: (1) a finger flexion contracture with a palpable cord of at least one finger (other than the thumb) of 20° to 100° in a MP joint or 20° to 80° in PIP joint and (2) a positive “table top test” defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. The cord affecting a selected primary joint received up to 3 injections of 0.58 mg of Xiapex or placebo. A finger extension procedure was performed if needed, approximately 24 hours after injection to facilitate disruption of the cord. Each injection was separated by approximately 4 weeks.

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

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

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

Table 3.

Demographic and baseline characteristics

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

Table 4.

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

(Last injection)

Table 5.

Mean increase in range of motion from baseline

(Last injection)

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

Treatment of two concurrent injections

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

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

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

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

Long-term efficacy and safety

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

Recurrence was assessed in successfully treated joints (i.e., subjects had a reduction in contracture to 5° or less at the Day 30 evaluation after the last injection of Xiapex in a previous study) and was defined as an increase in joint contracture by at least 20° in the presence of a palpable cord, or the joint underwent medical or surgical intervention primarily to correct a new or worsening Dupuytren's contracture in that joint. Data on the long term recurrence rates following successful treatment with Xiapex are provided in Table 7.

Table 7.

Long Term Recurrence Rates for Joints Treated Successfully with XIAPEX

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

).

Peyronie's disease

The efficacy of Xiapex was evaluated in two randomized, double-blind, placebo-controlled studies, Study 1 (AUX-CC-803) and Study 2 (AUX-CC-804), in adult males with Peyronie's disease. The double-blind study population comprised 832 male patients of whom 551 patients received Xiapex and 281 received placebo. The median age was 58 years (range 23 to 84 years). At study entry, patients must have had penile curvature deformity of at least 30 degrees in the stable phase of Peyronie's disease. Patients were excluded if they had a ventral curvature deformity, an isolated hourglass deformity or a calcified plaque that could have interfered with the injection technique. At baseline, penile pain was either not present or was mild in most (98%) patients.

In these studies, patients were given up to 4 treatment cycles of Xiapex or placebo (weeks 0, 6, 12, 18), and were followed in a non-treatment follow-up period (weeks 24-52). In each treatment cycle, two injections of Xiapex 0.58 mg or two injections of placebo were administered 1 to 3 days apart. A penile modelling procedure was performed on patients at the study site 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately six-week intervals for up to three additional times, for a maximum of 8 total injection procedures and 4 total modelling procedures. In addition, patients were instructed to perform penile modelling at home for six weeks after each treatment cycle.

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

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

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

The Bother domain score is a composite of the following patient-reported items: concern about erection pain, erection appearance, and the impact of Peyronie's disease on intercourse and on frequency of intercourse.

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

Xiapex significantly reduced patient-reported bother associated with Peyronie's disease compared with placebo (Table 10). The reduction in the Bother domain score was numerically similar between patient groups stratified by degree of baseline curvature deformity (30 to 60 degrees and 61 to 90 degrees).

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

Pharmacokinetic properties

Absorption

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

Following each of two intralesional administrations, separated by 24 hours, of Xiapex 0.58 mg into the penile plaque of 19 patients with Peyronie's disease, plasma levels of AUX-I and AUX-II in patients with quantifiable levels (82% and 40% for AUX-I and AUX-II, respectively) were minimal and short-lived. The maximal individual plasma concentrations of AUX-I and AUX-II were <29 ng/mL and <71 ng/mL, respectively. All plasma levels were below the limits of quantification within 30 minutes following dosing. There was no evidence of accumulation following two sequential injections of Xiapex administered 24 hours apart. No patients had quantifiable plasma levels 15 minutes after modelling of plaque on Day 3 (i.e., 24 hours after Injection 2 on Day 2).

Distribution

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

Biotransformation

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

Elimination

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

Special population

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

Paediatric population

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

Date of revision of the text

08/12/2017

Marketing authorisation holder

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

Special precautions for storage

Store in a refrigerator (2°C 8°C).

Do not freeze.

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

Marketing authorisation number(s)

EU/1/11/671/001

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,. 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. Patients develop ADAs after repeated administration, the cross-reactivity of which versus endogenous MMPs involved in pregnancy and labour cannot be excluded. The potential risk for humans on parturition and postnatal development is unknown. Therefore the use of Xiapex is not recommended in pregnancy and treatment should be postponed until after pregnancy.

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

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.

Special warnings and precautions for use

Allergic reactions

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

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

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

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

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

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

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

Injection of Xiapex into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, Xiapex must be injected only into the Peyronie's plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis.

Corporal rupture was reported as a serious adverse reaction after Xiapex injection in 5 out of 1044 patients (0.5%) in the controlled and uncontrolled clinical trials in Peyronie's disease. In other Xiapex-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or haematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded.

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

Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to assess for corporal rupture or severe penile haematoma, which may require surgical intervention.

Use in patients with coagulation disorders

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

Immunogenicity

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

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

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

In the Peyronie's disease clinical studies, at 6 weeks after the first treatment cycle of Xiapex, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of Xiapex >99% of Xiapex-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested.

In patients treated for these two indications, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions.

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

Post-treatment surgery

The impact of treatment with Xiapex on subsequent surgery, if needed, is not known.

Special penile conditions/diseases not studied in clinical trials

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

Long-term safety of Xiapex in Peyronie's disease is not fully characterised.

Excipients

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

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.

Special precautions for disposal and other handling

Instructions for use and handling

Preparation - Reconstitution procedure

The vial containing Xiapex and the vial containing the solvent for solution for injection for reconstitution must be refrigerated. Prior to use, the vial containing Xiapex and the vial containing the solvent for solution for reconstitution must be removed from the refrigerator and allowed to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Each vial of Xiapex and sterile solvent for reconstitution should only be used for a single injection. If two cords of affected joints on the same hand are to be treated during a treatment visit, separate vials and syringes should be used for each reconstitution and injection.

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

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

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

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

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

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

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

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

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 28 February 2011

Date of latest renewal: 18 January 2016

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.