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Drug Details

Xiapex 0.9 mg powder and solvent for solution for injection

• Presentation
  Powder and solvent for solution for injection. (Powder for injection). The powder is a white lyophilised powder. The solvent is a clear colourless solution.
• Description
  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
• Indications
  Xiapex is indicated for the treatment of Dupuytren's contracture in adult patients with a palpable cord
• Adult Dosage
  

  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

• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients

   

• Special Precautions
  

  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'

• Interactions
  

  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.

• Adverse Drug Reactions
  

  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 (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.

   

  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”