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Xiapex 0.9 mg powder and solvent for solution for injection

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:

Sodium injected per joint:

Metacarpophalangeal (MP) joints: 0.9 mg.

Proximal interphalangeal (PIP) joints: 0.7 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

(Powder 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.

4.2 Posology And Method Of Administration

Xiapex must be administered by a physician appropriately trained in the correct administration of the 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 reconstituted Xiapex to be administered into the Dupuytren's cord differs depending on the type of joint being treated (see Table 1).

Approximately 24 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. Only one cord must be treated at a time. If the disease has resulted in multiple contractures, treatment of each cord must be undertaken in a sequential order, as determined by the physician. Clinical study experience with Xiapex is currently limited to up to 3 injections per cord and up to 8 injections in total.

Patients should be instructed to return to see their physician the next day for an examination of the injected hand and a finger extension procedure to disrupt the cord.

Special population

Elderly

Due to the lack of quantifiable systemic exposure of Xiapex 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, no dose adjustment is necessary.

Renal Impairment

Due to the lack of quantifiable systemic exposure, 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.

Method of administration

Intralesional use.

For single use only

Volume for reconstitution

Xiapex must only be reconstituted with the solvent provided and to the appropriate volume prior to use:

- For metacarpophalangeal (MP) joints use 0.39 ml of solvent.

- For proximal interphalangeal (PIP) joints use 0.31 ml of solvent (see Table 1).

Volume for injection

- 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.

Table 1. Volumes needed for reconstitution and administration

   

Joint to be treated

Solvent required for reconstitution

Injection volume to deliver Xiapex 0.58 mg dose†

MP joints

0.39 ml

0.25 ml

PIP joints

0.31 ml

0.20 ml

†Note that injection volume for delivery of a 0.58 mg dose is less than the total volume of solvent used for reconstitution.

   

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 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.

Detailed instructions for the physician in the preparation of the medicinal product for injection (reconstitution procedure) are provided in section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Allergic reactions

In the double blind portion of the three phase 3 placebo-controlled clinical studies, 17% of Xiapex-treated patients had mild allergic reactions (i.e. pruritus). Although there were no severe allergic reactions observed in the Xiapex studies (e.g., those associated with respiratory impairment, hypotension, or end-organ dysfunction) physicians must be prepared to address any severe local or systemic allergic reactions including the potential for anaphylaxis that may occur following injection. Whilst there is no evidence from the clinical data of an increased risk of serious allergic reactions upon repeated injections, the potential for such reactions following repeated use cannot be excluded.

Tendon rupture or other serious injury to the injected extremity

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. 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 promptly contact the physician if there is trouble bending the finger after the swelling goes down (symptoms of tendon rupture).

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.

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, 73% of Xiapex-treated patients reported an ecchymosis or a contusion and 38% reported a haemorrhage at the injection site. 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 were tested at multiple time points for antibodies to the protein components of the medicinal product (AUX-I and AUX-II). At 30 days post the first injection, 92% of patients had circulating antibodies detected against AUX-I and 86% of patients against AUX-II. After a third or fourth injection, all subjects developed positive antibodies to both AUX-I and AUX-II. No apparent correlation of antibody development to clinical response or adverse reactions was observed. 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.

Long-term safety

Long-term safety of Xiapex is not fully characterised. The impact of treatment with Xiapex on subsequent surgery, if needed, is not known.

Excipients

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the lack of quantifiable systemic exposure, no formal medicinal product interaction studies with Xiapex have been performed.

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 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.

Breast-feeding

No effect on the breastfed newborn/infant is anticipated since the systemic exposure of the breast-feeding woman to Xiapex is negligible. Xiapex can be used during breast-feeding.

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. 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

Xiapex 0.58 mg was studied in patients with Dupuytren's contracture in three randomised, double-blind, placebo-controlled studies. 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.

The most frequently reported adverse reactions during the Xiapex clinical studies 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 (3 cases), tendonitis (1 case), other ligament injury (1 case) and complex regional pain syndrome (1 case) related to the medicinal product were reported.

Table 2 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (

Table 2: Tabulated list of adverse reactions.

System organ class

Very common

Common

Uncommon

Infections and infestations

   

injection site cellulitis

Blood and lymphatic system disorders

lymphadenopathy

lymph node pain

thrombocytopenia

Immune system disorders

   

hypersensitivity

Psychiatric disorders

   

disorientation

agitation

insomnia

irritability

restlessness

Nervous system disorders

 

paresthesia

hypoesthesia

burning sensation

dizziness

headache

complex regional pain syndrome

monoplegia

syncope vasovagal

tremor

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 blister

blister

rash

erythema

hyperhidrosis

rash erythematous

rash macular

eczema

swelling face

pain of skin

skin exfoliation

skin lesion

skin disorder

scab

skin discoloration

skin tightness

Musculoskeletal and connective tissue disorders

pain in extremity

arthralgia

joint swelling

myalgia

axillary mass

chest wall pain

groin pain

joint crepitation

joint stiffness

limb discomfort

muscle spasms

muscular weakness

musculoskeletal discomfort

musculoskeletal stiffness

neck pain

shoulder pain

Reproductive system and breast disorders

   

breast tenderness

hypertrophy breast

General disorders and administration site conditions

oedema peripheral*

injection site haemorrhage

injection site pain

injection site swelling

tenderness

axillary pain

inflammation

injection site inflammation

swelling

injection site erythema

injection site pruritus

injection site warmth

injection site vesicles

local swelling

pyrexia

pain

discomfort

fatigue

feeling hot

influenza like illness

injection site anaesthesia

injection site desquamation

injection site discoloration

injection site irritation

injection site nodule

injection site reaction

malaise

Investigations

   

lymph node palpable

alanine aminotransferase increased

aspartate aminotransferase increased

body temperature increased

Injury, poisoning and procedural complications

contusion

skin laceration

tendon rupture

ligament injury

limb injury

open wound

wound dehiscence

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

4.9 Overdose

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

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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

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

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

Mechanism of action

Collagenases are proteinases that hydrolyze collagen under physiological conditions. 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. 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 (?, ?, ?, and ?) 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 (?, ?, and ?,) 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.

Clinical results

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. 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

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)

22 (8.8)

19 (15.2)

Gender, n (%)

   

Male

210 (84.3)

91 (72.8)

Female

39 (15.7)

34 (27.2)

Family history of Dupuytren's disease, n (%)

   

Yes

107 (43.0)

62 (49.6)

No

142 (57.0)

63 (50.4)

Physician Rating of Severity at Baseline

 

 

Mild

38 (15.4 %)

21 (16.8 %)

Moderate

148 (59.9 %)

71 (56.8 %)

Severe

61 (24.7 %)

33 (26.4 %)

Missing1

2 (0.8 %)

-

Note: Includes all patients who received at least 1 injection of double-blind study medicinal product (Xiapex 0.58 mg or placebo).

1 Not used to calculate physician rating of severity at baseline percentage – actual denominator of N=247 used.

   

Table 4.

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

(Last injection)

TREATED PRIMARY JOINTS

CORD I

CORD II

   

Xiapex

Placebo

Xiapex

Placebo

 

All Joints

p-value

N=203c

N=103c

N=45

N=21

64.0 %

<0.001

6.8 %

-

44.4 %

<0.001

4.8 %

-

 

MP Jointsa

p-value

N=133

N=69

N=20

N=11

76.7 %

<0.001

7.2 %

-

65.0 %

0.003

9.1 %

-

 

PIP Jointsb

p-value

N=70

N=34

N=25

N=10

40.0 %

<0.001

5.9 %

-

28.0 %

0.069

0.0 %

-

 

a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Xiapex treated group had a baseline contracture of 0 degrees before treatment).

       

Table 5.

Mean increase in range of motion from baseline

(Last injection)

TREATED PRIMARY JOINTS

CORD I

CORD II

   

Xiapex

Placebo

Xiapex

Placebo

 

All Joints

N=203 c

N=103 c

N=45

N=21

Mean Baseline (SD)

Mean Final (SD)

Mean increase (SD)

43.9 (20.1)

80.7 (19.0)

36.7 (21.0)

45.3 (18.7)

49.5 (22.1)

4.0 (14.8)

40.3 (15.2)

75.8 (17.7)

35.4 (17.8)

44.0 (16.5)

51.7 (19.6)

7.6 (14.9)

MP Jointsa

N=133

N=69

N=20

N=11

Mean Baseline (SD)

Mean Final (SD)

Mean increase (SD)

42.6 (20.0)

83.7 (15.7)

40.6 (20.0)

45.7 (19.2)

49.7 (21.1)

3.7 (12.6)

39.5 (11.8)

79.5 (11.1)

40.0 (13.5)

41.4 (20.8)

50.0 (21.5)

8.6 (14.7)

PIP Jointsb

N=70

N=34

N=25

N=10

Mean Baseline (SD)

Mean Final (SD)

Mean increase (SD)

46.4 (20.4)

74.9 (23.1)

29.0 (20.9)

44.4 (17.9)

49.1 (24.4)

4.7 (18.5)

41.0 (17.7)

72.8 (21.3)

31.8 (20.1)

47.0 (10.3)

53.5 (18.3)

6.5 (15.8)

a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Xiapex treated group had a baseline contracture of 0 degrees before treatment).

All p-values < 0.001 for all comparisons between Xiapex and placebo, except for PIP joints in Study CORD II which was not eligible for statistical testing due to a hierarchical testing procedure.

       

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





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