Collagenase Clostridium Histolyticum

Class: Enzymes
Chemical Name: Collagenase (Clostridium histolyticum gene colG isoenzyme AUX-I
Molecular Formula: C5632H8679N1481O1785S17C5220H7993N1353O1617S25
CAS Number: 955089-04-0

Warning(s)

REMS:

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. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Enzymatic agent containing a mixture of 2 proteinases derived from Clostridium histolyticum that hydrolyze collagen, resulting in lysis of collagen deposits.1 2 7

Uses for Collagenase Clostridium Histolyticum

Dupuytren’s Contracture

Treatment of Dupuytren’s contracture in adults having a palpable collagen cord.1 2 7 8 10 12 13 Designated an orphan drug by FDA for the treatment of advanced Dupuytren’s disease.3

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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

May be a useful alternative to surgery, particularly in patients reluctant to have surgical intervention or who desire minimal recovery time.8 10 12 13

Collagenase Clostridium Histolyticum Dosage and Administration

General

  • Recommended for administration only by qualified clinicians experienced in injection procedures of the hand and in treatment of patients with Dupuytren’s contracture.1 5 6 7

  • Use of local anesthetic prior to administration not recommended by manufacturer; may interfere with proper placement of injection.1 7

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

  • Additional information on authorized distribution partners and enrollment in the Xiaflex Xperience program is available at 877-942-3539 or .7 9

Administration

Intralesional Administration

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

For full instructions on intralesional administration of collagenase clostridium histolyticum and on the finger extension procedure following injection, refer to prescribing information at .1 4 5 7

Reconstitution

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

Swab rubber stopper and surrounding surface of vials containing lyophilized powder and diluent aseptically with sterile alcohol; other antiseptic agents should notbe used.1 7

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

Discard any unused portion of reconstituted solution after injection.1 7 Avoid use of reconstituted solution if it contains particulates, is cloudy, or discolored.1 7

Dosage

Adults

Dupuytren’s Contracture
Intralesional Injection

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

Intralesional injections of drug may be administered up to 3 times per cord at approximately 4-week intervals.1 7

Inject one cord at a time.1 7 If a patient has multiple palpable cords with MP or PIP joint contractures, these cords may be injected one at a time in sequential order.1 7

Special Populations

No special population dosage recommendations at this time.1

Cautions for Collagenase Clostridium Histolyticum

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

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

Inject only into a collagen cord associated with an MP or PIP joint contracture.1 5 7 Avoid injection into tendons, nerves, blood vessels, or other collagen-containing structures of the hand.1 5 7

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.)

Sensitivity Reactions

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

General Precautions

Coagulation Disorders

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.)

Specific Populations

Pregnancy

Category B.1 (See Users Guide)

Lactation

Not known whether drug is distributed into milk.1 Use caution.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.1

Common Adverse Effects

Peripheral edema (e.g., swelling of injected hand), contusion, injection site reaction, injection site hemorrhage, pain in injected extremity.1 6 7 8 10

Interactions for Collagenase Clostridium Histolyticum

Not a substrate for CYP isoenzymes or other drug metabolizing enzyme pathways.2 Pharmacokinetic drug interactions not evaluated.2

Specific Drugs

Drug

Interaction

Comments

Anticoagulants (e.g., aspirin, clopidogrel, prasugrel, warfarin)

Potential risk of abnormal coagulation1 7 8

Safety and efficacy in patients receiving anticoagulants (other than low-dose aspirin up to 150 mg daily) within 7 days prior to injection not known1 7

Use with caution 1 6 7

Collagenase Clostridium Histolyticum Pharmacokinetics

Absorption

Bioavailability

Following single-dose intralesional injection, no detectable plasma concentrations for up to 30 days.1 2

Distribution

Extent

May remain confined to tissues near injection site, but tissue distribution not evaluated to date.2

Elimination

Metabolism

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

Special Populations

Studies not performed to date to evaluate effects in patients with impaired hepatic or renal function.2

Stability

Storage

Parenteral

Powder for Injection

2–8°C; do not freeze.1 Reconstituted solutions are stable at room temperature ≤1 hour or at 2–8°C ≤4 hours.1 7

Actions

  • Enzymatic agent isolated and purified from fermentation of Clostridium histolyticum.1 2 7

  • Mixture of 2 microbial collagenases, collagenase AUX-I (clostridial type I collagenase) and collagenase AUX-II (clostridial type II collagenase), in a fixed ratio.1 2 7

  • Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiologic conditions resulting in lysis of collagen deposits.1 7

  • Injection may result in enzymatic disruption of Dupuytren’s cord (comprised mostly of collagen).1 8 10

  • 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

  • Importance of clinicians counseling patients about potential risks associated with treatment.5 6 7

  • Risk of tendon rupture or serious ligament damage in the treated hand that may require surgical correction.1 6

  • 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 informing patients to contact their clinician immediately if signs of allergic reactions (e.g., hives, facial swelling, difficulty breathing, chest pain) develop following injection.1 6

  • Importance of informing patients to avoid flexing or extending fingers of the affected hand following injection to reduce drug extravasation from the cord.1 6

  • Importance of informing patients to avoid finger extension and disruption of the injected cord by self manipulation.1 6

  • Importance of informing patients to keep the injected hand elevated until bedtime on day of injection.1 6

  • Importance of informing patients to return to their clinician’s office the day following injection for follow-up examination and possible finger extension procedure to disrupt the cord.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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of collagenase clostridium histolyticum is restricted.7 9 14 (See Restricted Distribution Program under Dosage and Administration.)

Collagenase Clostridium Histolyticum

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for intralesional use

0.9 mg

Xiaflex

Auxilium

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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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