Collagenase Clostridium Histolyticum
Chemical Name: Collagenase (Clostridium histolyticum gene colG isoenzyme AUX-I
Molecular Formula: C5632H8679N1481O1785S17C5220H7993N1353O1617S25
CAS Number: 955089-04-0
FDA approved a REMS for collagenase clostridium histolyticum to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of collagenase clostridium histolyticum and consists of the following: communication plan, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().
Uses for Collagenase Clostridium Histolyticum
Dupuytren’s disease is a progressive fibroproliferative condition of the palmar fascia in the hand.2 7 Abnormal collagen deposition results in nodule and cord formation; may eventually limit hand movement by causing the affected fingers to chronically bend toward the palm with loss of ability to straighten these fingers resulting in contracture.2 7
Collagenase Clostridium Histolyticum Dosage and Administration
Restricted Distribution Program
Available only under restricted (managed) distribution program.7
Drug must be ordered from authorized distribution partner; clinicians must verify enrollment in the Xiaflex Xperience program before drug can be obtained.7 9 14 Only clinicians registered with the program are able to prescribe the drug.14
Administer by intralesional injection.1
Confirm collagen cord to be injected.1 7 Select injection site where cord is maximally separated from underlying flexor tendons and where skin is not closely adhered to cord.1 7 11 Apply antiseptic at injection site; allow skin to dry.1 7 11
Place needle into collagen cord with caution.1 7 11 To minimize potential for injection into other tissues, avoid passing needle tip completely through the cord.1 7 11 (See Tendon Rupture, Ligament Damage, or Other Serious Injury under Cautions.) If needle insertion into a tendon is suspected or paresthesia is reported, withdraw and reposition needle into the cord.1 7
After confirming proper needle position, inject approximately one-third of total dose into the collagen cord.1 7 11 Withdraw needle from cord and reposition in a slightly more distal location to initial injection site; inject another one-third of total dose within the cord.1 7 11 Repeat procedure a third time and reposition needle proximally to initial injection site; inject final portion of dose into the cord.1 7 11
For injection of a collagen cord affecting a proximal interphalangeal (PIP) joint of the fifth finger, do not insert the needle >2–3 mm in depth; inject drug as close to the palmar digital crease as possible (not >4 mm distal to crease).1 7 11
Following injection, advise patient to limit motion of treated finger, and to keep injected hand elevated until bedtime; also provide follow-up instructions for cord disruption.1 7 (See Advice to Patients.) If a joint contracture persists following initial injection, a finger extension procedure is recommended approximately 24 hours after administration to facilitate cord disruption.1 7 11 Local anesthesia may be used to control pain during finger extension procedure.1 7 10
If cord disruption has not occurred after the first finger extension procedure, a second and third attempt may be performed at 5- to 10- minute intervals.1 However, >3 attempts per visit are not recommended.1 If cord disruption has not occurred after 3 attempts, a follow-up visit may be scheduled in approximately 4 weeks.1 If contracted cord persists after 4 weeks, an additional injection may be administered and finger extension procedure performed.1
Before use, store vials of lyophilized powder and sterile diluent at 2–8°C.1 7 Prior to reconstitution, remove vials containing lyophilized powder and diluent from the refrigerator; allow to stand at room temperature at least 15 minutes but not >60 minutes.1 7 Only use diluent supplied by the manufacturer.1
Using a 1 mL syringe with 0.01 mL graduations and a 27-gauge 0.5-inch needle, withdraw 0.39 or 0.31 mL of diluent for injection into collagen cords affecting a metacarpophalangeal (MP) or a PIP joint, respectively.1 7
Inject diluent slowly toward sides of vial labeled as containing 0.9 mg of lyophilized powder.1 7 Swirl contents of vial slowly to ensure that powder is in solution; avoid shaking or inverting the vial.1 7 Discard syringe and needle used for reconstitution and diluent vial.1 7
Prior to administration, reconstituted solution may be stored at room temperature for up to 1 hour or at 2–8°C for up to 4 hours.1 7 If reconstituted solution is stored at 2–8°C, allow solution to return to room temperature for approximately 15 minutes before use.1 7
Initially, 0.58 mg.1 7 Using a 1 mL syringe, withdraw 0.25 or 0.2 mL of reconstituted solution from the single-dose vial for a cord associated with an MP or PIP joint contracture, respectively.1 7 Administer total dose of 0.58 mg in approximately 3 equally divided injections into different sites along the cord.1 (See Administration under Dosage and Administration.)
If an MP or PIP joint contracture persists 4 weeks following initial treatment and finger extension procedure, a single 0.58-mg dose injected into the cord and finger extension (approximately 24 hours following injection) may be repeated.1 7
No special population dosage recommendations at this time.1
Cautions for Collagenase Clostridium Histolyticum
Manufacturer states none known.1
Tendon Rupture, Ligament Damage, or Other Serious Injury
Injection into collagen structures of the hand may result in damage and possibly permanent injury (e.g., tendon rupture, ligament damage).1 4 5 8 Flexor tendon rupture, pulley rupture, ligament injury, complex regional pain syndrome (CRPS), tendinitis, and sensory abnormality of the hand also reported.1 7 8
Use special care when treating the PIP joint of the fifth finger, since tendon ruptures reported near the digital PIP joint crease.1 7 11 For cord injection affecting the PIP joint, do not insert the needle >2–3 mm in depth; inject drug as close to the palmar digital crease as possible (not >4 mm distal to crease).1 7 11 (See Administration under Dosage and Administration.)
Risk of severe hypersensitivity reactions (including anaphylaxis) following injection.1 4 5 Be prepared to manage severe allergic reactions.1 4 5 7 Severe allergic reactions not observed in clinical studies but patients developed increasing IgE-anti-drug antibody titers with successive injections; mild allergic reactions (e.g., pruritus) reported after up to 3 injections.1 4 5 7 10 11
Use caution in patients with coagulation disorders including those receiving anticoagulants (except low-dose aspirin).1 4 7 Safety and efficacy in patients receiving anticoagulants (other than low-dose aspirin up to 150 mg daily) within 7 days prior to injection not known.1 7 (See Interactions.)
Category B.1 (See Users Guide)
Safety and efficacy not established in children <18 years of age.1
No overall differences in safety and efficacy relative to younger adults.1
Common Adverse Effects
Interactions for Collagenase Clostridium Histolyticum
Anticoagulants (e.g., aspirin, clopidogrel, prasugrel, warfarin)
Collagenase Clostridium Histolyticum Pharmacokinetics
May remain confined to tissues near injection site, but tissue distribution not evaluated to date.2
Metabolism may occur at injection site from local synthesis and release of α-2-macroglobulin (α2M) by fibroblasts and tissue macrophages followed by endocytosis and lysosomal proteolysis, but elimination not evaluated to date.2
Studies not performed to date to evaluate effects in patients with impaired hepatic or renal function.2
Powder for Injection
In vitro data suggest that collagenases AUX-I and AUX-II work synergistically to hydrolyze collagen.1
No clinical data available regarding relative contribution of collagenase AUX-I or AUX-II to overall efficacy of the drug for Dupuytren’s contracture.1
Advice to Patients
Importance of understanding that treatment can only be prescribed by clinicians registered with the Xiaflex Xperience program.14 (See Restricted Distribution Program under Dosage and Administration.)
Importance of providing a copy of patient information (medication guide) and instructing patients to carefully read this information before initiation of therapy and prior to each injection; distribution of medication guide required.4 5 6 7
Risk of swelling, bruising, bleeding, and/or pain at injection site and in surrounding tissue.1
Importance of informing patients to contact their clinician if signs of infection (e.g., fever, chills, increasing redness or edema), sensory changes (e.g., numbness, tingling, increased pain) in the treated finger, or difficulty bending the treated finger toward the wrist (after initial swelling subsides) develop following injection.1 6
Importance of patients informing clinicians if they are or plan to become pregnant or plan to breast-feed.6
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., anticoagulants) and OTC (e.g., aspirin) drugs, vitamins, and herbal supplements, as well as any concomitant illnesses (e.g., bleeding disorders).6
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
For injection, for intralesional use
AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 30, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. Auxilium Pharmaceuticals. Xiaflex™ (collagenase clostridium histolyticum) for injection, for intralesional use prescribing information. Malvern, PA; 2010 Feb.
2. Auxilium Pharmaceuticals. Briefing document for collagenase clostridium histolyticum (AA4500) in the treatment of advanced Dupuytren’s disease. Arthritis Advisory Committee Meeting; 2009 Sep 16. Available from FDA web site. Accessed 2010 Apr 19.
3. Food and Drug Administration. Search orphan drug designations and approvals. From FDA web site. Accessed 2010 Apr 19.
4. Auxilium Pharmaceuticals. Risk evaluation and mitigation strategy (REMS): Xiaflex™ (collagenase clostridium histolyticum). Available from website. Accessed 2010 Apr 19.
5. Auxilium Pharmaceuticals. Dear healthcare provider letter regarding Xiaflex™ (collagenase clostridium histolyticum). Available from website. Accessed 2010 Apr 19.
6. Auxilium Pharmaceuticals. Medication guide Xiaflex™ (collagenase clostridium histolyticum). Malvern, PA; 2010 Feb.
7. Auxilium Pharmaceuticals. Training guide for the administration of Xiaflex™ (collagenase clostridium histolyticum). Available from website. Accessed 2010 Apr 20. (
8. Hurst LC, Badalamente MA, Hentz VR et al. Injectable collagenase clostridium histolyticum for Dupuytren’s contracture. N Engl J Med. 2009; 361:968-79. [PubMed 19726771]
9. Auxilium Pharmaceuticals. Authorized Xiaflex™ (collagenase clostridium histolyticum) distribution partners. Available from website. Accessed 2010 May 28. (
10. Badalamente MA, Hurst LC, Hentz VR. Collagen as a clinical target: nonoperative treatment of Dupuytren’s disease. J Hand Surg Am. 2002; 27:788-98. [PubMed 12239666]
11. Hurst LC, Badalamente MA, Hentz VR et al. Injectable collagenase clostridium histolyticum for Dupuytren’s contracture. N Engl J Med. 2009; 361:1-5. Supplementary appendix. Available from website. [PubMed 19528190]
12. Badalamente MA, Hurst LC. Efficacy and safety of injectable mixed collagenase subtypes in the treatment of Dupuytren’s contracture. J Hand Surg Am. 2007 Jul-Aug; 32:767-74.
13. Watt AJ, Curtin CM, Hentz VR. Collagenase injection as nonsurgical treatment of dupuytren’s disease: 8-year follow-up. J Hand Surg Am. 2010; 35:534-9, 539.e1. [PubMed 20353858]
14. Auxilium Pharmaceuticals. Obtaining Xiaflex™ (collagenase clostridium histolyticum). Available from website. Accessed 2010 Jul 29.
15. Auxilium Pharmaceuticals: Personal communication.
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