XIAFLEX® (collagenase clostridium histolyticum, Auxilium Pharmaceuticals, Inc.) was recently approved by the US Food and Drug Administration (FDA) for the treatment of adults with Dupuytren’s contracture with a palpable cord. Pharmacists may have questions about Dupuytren’s disease and its treatment as well as the safety and efficacy profile of XIAFLEX®. In addition, pharmacists may not be aware of the Risk Evaluation and Mitigation Strategy (REMS) program for XIAFLEX® or provider requirements for accessing XIAFLEX®. We provide answers to commonly asked questions about Dupuytren’s contracture and XIAFLEX® use.
Q: What is Dupuytren’s contracture?
A: Dupuytren’s contracture is a progressive condition of the palmar fascia of the hand. Dupuytren’s contracture is characterized by increased collagen production and deposition in the fascia that leads to formation of a ropelike cord.1 The cord, over time, may cause the affected finger to permanently bend or contract toward the palm of the hand, which restricts the ability to fully extend the affected finger and reduces the range of motion. The ring and fifth fingers are most often affected and one or both hands can develop Dupuytren’s contracture.2 While Dupuytren’s contracture can occur in persons of both genders, any ethnic background, and at any age, the condition is more common in men and persons of Northern European descent. Dupuytren’s contracture can take months to years to develop and without treatment the disease progresses in about 90% of those affected.2 In later stages of the disease, simple activities of daily living such as washing, putting hands in pockets, wearing gloves, and shaking hands can be significantly affected.
Q: How is Dupuytren’s contracture treated?
A: The treatment of Dupuytren’s contracture depends on various factors such as the stage and severity of the cord, the patient’s age and general health, the patient’s occupation, the status of the skin of the palm, or the presence of bony deformity. Currently approved treatments are surgery and XIAFLEX®.2,3
Surgical management of Dupuytren’s contracture is usually considered when the contracture is at least 30º. Surgical options include fasciotomy, fasciectomy, or amputation.4 Fasciotomy is a procedure where the surgeon cuts the cords without taking out any of the diseased tissue. For subcutaneous fasciotomy, a scalpel is used to puncture the thickened fibrous bands across the palm to temporarily reduce tension in the cords. Needle aponeurotomy, another form of fasciotomy, is a blind procedure that involves puncturing and dividing the cords with a needle (instead of a scalpel) through the skin.
Fasciectomy is a procedure in which diseased tissue is removed through incisions in the palm and affected finger(s). Partial fasciectomy is done to remove only mature deformed tissue; it is often used in moderate to severe cases where 1 or 2 fingers are involved. Complete fasciectomy or radical fasciectomy is performed on a severe contracture that restricts joint motion and hand function. During this procedure, the bands of thickened, abnormal tissue under the skin are completely removed. Skin grafting may be needed for some cases when the remaining skin is insufficient to close the wound.
Amputation of the affected finger(s) is another option to treat Dupuytren’s contracture, however it is rarely performed.
Recently, XIAFLEX® injection was approved by the FDA as the first nonsurgical option for the treatment of adult patients with Dupuytren’s contracture with a palpable cord. Treatment with XIAFLEX® may be considered for patients in whom there is contracture at the metacarpophalangeal (MP) joint or proximal interphalangeal (PIP) joint of at least 20º.
Q: How does XIAFLEX® treat Dupuytren’s contracture?
A: XIAFLEX® contains a combination of 2 collagen enzymes, in a defined mass ratio, that have been isolated and purified from the fermentation of Clostridium histolyticum bacteria. When injected directly into a Dupuytren’s cord, these 2 types of collagenase work synergistically to enzymatically disrupt collagen.
Treatment consists of injections of XIAFLEX® into the Dupuytren’s cord, followed by a passive finger-extension procedure 24 hours later, if needed, to disrupt the cord. Additional XIAFLEX® injections may be necessary if the contracture remains after 4 weeks.
Q: How should XIAFLEX® be administered?
A: XIAFLEX® should be administered by a healthcare provider (HCP) experienced in injection procedures of the hand and in the treatment of Dupuytren’s contracture. XIAFLEX® is injected into the palpable cord of a Dupuytren’s contracture associated with the MP joint or a PIP joint. Treatment of cords associated with contractures of distal interphalangeal (DIP) joints or the joints of the thumb has not been evaluated in clinical trials.
XIAFLEX® 0.58 mg (0.25 mL of reconstituted solution for cords affecting an MP joint or 0.20 mL of reconstituted solution for cords affecting a PIP joint) should be prepared for injection into the cord. One-third of the solution should be injected directly into the cord, making sure to avoid injection of XIAFLEX® into tissues other than the cord. The needle tip should then be withdrawn from the cord and repositioned in a slightly more distal location (approximately 2 to 3 mm) to the initial injection in the cord and another one-third of the dose should be injected. Again the needle tip should be withdrawn from the cord and repositioned a third time proximal to the initial injection (approximately 2 to 3 mm) and the final portion of the dose should be injected into the cord. The treated hand should be wrapped with a soft, bulky, gauze dressing. The patient should be instructed to limit motion of the treated finger and to keep the injected hand elevated until bedtime. Unused reconstituted solution and diluent should be discarded. Vials containing the unused remnants of reconstituted XIAFLEX® solution or diluent should not be stored or pooled.
If the contracture remains the following day after the injection, passive finger extension procedure(s) may be performed to facilitate cord disruption. Four weeks after the injection and finger extension procedure(s), if an MP or PIP contracture remains, the cord may be re-injected with a single 0.58 mg dose of XIAFLEX®, and the finger extension procedure may be repeated. Injection and finger extension procedure(s) may be administered up to 3 times per cord at approximately 4-week intervals, only 1 cord at a time. For patients with multiple MP or PIP joint contractures with palpable cords, treatment of each cord should be undertaken in a sequential order with only 1 cord receiving XIAFLEX® at a time.
Q: Is there efficacy data to support the use of XIAFLEX® for Dupuytren’s contracture?
A: Multiple clinical trials have been conducted in subjects with Dupuytren’s contracture in the United States, Europe, and Australia. Results from 2 randomized, multicenter, double-blind, placebo-controlled clinical trials were key to FDA approval. The Collagenase Option for Reduction of Dupuytren’s (CORD) I study evaluated 308 patients (n = 204 for XIAFLEX®; n = 104 for placebo) with advanced Dupuytren’s and joint contractures.5 Collagenase injections with XIAFLEX® significantly reduced contractures to 0º–5º of normal (a return to complete or almost complete finger extension) 30 days after up to 3 injections compared with placebo injections (64% vs 6.8%, respectively; P < 0.001). The CORD II study consisted of 66 patients; 45 received XIAFLEX® and 21 received placebo.6 Significantly more patients receiving XIAFLEX® (44.4%) achieved a contracture reduction of the primary joint to 0º–5º of normal after the last injection compared with 4.8% in the placebo group (P < 0.001). No joint treated with XIAFLEX® had recurrence of contracture over the 12-month study period. Overall, XIAFLEX®-treated patients had a greater reduction in baseline contracture, a greater increase in range of motion of their treated fingers (a surrogate of functionality), and a shorter time to achieve clinical success of primary joint compared with those who received placebo.
Q: What adverse events have been associated with XIAFLEX® use?
A: The most frequently reported adverse drug reactions (≥ 25%) in XIAFLEX® clinical trials and at an incidence greater than placebo included edema peripheral (mostly swelling of the injected hand, 73% vs 5%), contusion (70% vs 3%), injection site hemorrhage (38% vs 3%), injection site reaction (35% vs 6%), and pain in the treated extremity (35% vs 4%). In the controlled portions of the clinical trials, a greater proportion of XIAFLEX®-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of XIAFLEX®-associated pruritus increased after more XIAFLEX® injections. Overall, more than 95% of XIAFLEX®-treated patients had an adverse event of the injected extremity after 3 injections; however, 81% of these local reactions resolved without intervention within 4 weeks of the injection.
In the controlled and uncontrolled portions of clinical trials (1082 patients; 2630 XIAFLEX® injections), a flexor tendon rupture of the treated finger (a rare but serious adverse event) occurred in 3 patients within 7 days of the XIAFLEX® injection.3 Injection of XIAFLEX® into collagen-containing structures such as tendons or ligaments of the hand may result in damage to those structures and possible permanent injury such as tendon rupture or ligament damage. An analysis of pooled safety data demonstrated a low incidence of tendon rupture (0.3% of 1082 patients) and ligament injury (< 0.1% of 1082 patients) following XIAFLEX® injection.7 To minimize the risk of tendon rupture or ligament damage, XIAFLEX® should be injected only into the collagen cord, and care should be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Other serious local adverse reactions in clinical trials include pulley rupture, ligament injury, complex regional pain syndrome (CRPS), and sensory abnormality of the hand. Although there were no severe allergic reactions observed in the XIAFLEX® studies (eg, those associated with respiratory compromise, hypotension, or end-organ dysfunction), severe reactions including anaphylaxis could occur following XIAFLEX® injections. Healthcare providers should be prepared to address severe allergic reactions following use of XIAFLEX®.
In clinical trials, 70% and 38% of XIAFLEX®-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively. The efficacy and safety of XIAFLEX® in patients receiving anticoagulant medications (other than low-dose aspirin) within 7 days prior to XIAFLEX® administration are not known. Therefore, XIAFLEX® should be used with caution in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin).
Q: What is being done to mitigate the risks associated with XIAFLEX® use?
A: At the request of the FDA, Auxilium has developed a training guide as part of the XIAFLEX® REMS program.1 The FDA-approved training guide informs HCPs about the risks associated with XIAFLEX® use, including tendon rupture and other serious adverse events of the injected extremity, and the possible risks of severe hypersensitivity events. It also provides instructions on the proper preparation and administration of XIAFLEX® to reduce the risks of serious adverse events. Physicians must complete the XIAFLEX® Xperience™ training and enrollment process before their healthcare facility may receive XIAFLEX® orders. For product-related questions, to report adverse events, or to enroll in the XIAFLEX® XperienceTM program, HCPs can contact 1-877-XIAFLEX (1-877-942-3539).
Q: What are the goals and elements (components) of the XIAFLEX® REMS program?
A: Currently there are over 130 REMS approved by the FDA.8 The goal of REMS is to inform patients and HCPs about the risks associated with a particular therapy. Many REMS require a medication guide and communication plan. Recently approved REMS that may be familiar to pharmacists are available for Androgel (testosterone gel),9 Testim 1% (testosterone gel),10 Chantix (varenicline),11 and Byetta (exenatide).12
The XIAFLEX® REMS program was designed to communicate the potential risks with XIAFLEX® to HCPs and patients. The specific goals of the XIAFLEX® REMS are (1) to inform HCPs about the risks of tendon rupture, serious adverse reactions affecting the injected extremity, and the potential risk of serious hypersensitivity reactions (including the potential for anaphylaxis) associated with XIAFLEX®; (2) to inform HCPs about how to properly inject XIAFLEX® and perform finger extension procedures; and (3) to inform patients about the serious risks associated with XIAFLEX®.13
The XIAFLEX® REMS program includes a medication guide and communication plan. The XIAFLEX® communication plan consists of the Dear Healthcare Provider Letter14 and educational materials (ie, training guide, procedure training video)1,15,16 available at www.XIAFLEX.com.
Q: Who has access to XIAFLEX® and how do I order XIAFLEX® for my healthcare site?
A: XIAFLEX® is only available through a managed distribution program called XIAFLEX® Xperience™ (available at https://www.XIAFLEXperience.com). This program was developed as part of Auxilium’s commitment to patient safety. Only enrolled, qualified HCPs who are experienced in injection procedures of the hand and the treatment of Dupuytren’s contracture may have access to XIAFLEX®. Physicians must complete the XIAFLEX® Xperience™ training and enrollment process before their healthcare facility may receive XIAFLEX® orders. Also, only enrolled healthcare sites may receive XIAFLEX® orders. Enrollment requires an authorized site representative (such as a pharmacist) to coordinate activities internally and ensure compliance with the program. For more information HCPs can call 1-877-XIAFLEX (1-877-942-3539) or visit www.XIAFLEX.com.
In conclusion, XIAFLEX® is a safe and effective treatment for Dupuytren’s contracture. XIAFLEX® should be used by enrolled, qualified HCPs. To ensure the safe and effective use of XIAFLEX®, a REMS program, which includes communication and training, is available to HCPs. A medication guide is also available for patients. Additional resources are available to further assist pharmacists with answering questions from HCPs and patients (Table).
Table. Additional Resources for Pharmacists and Other Healthcare Providers
Drug Fact Sheet (http://www.XIAFLEX.com/docs/XIAFLEX%20Drug%20Fact%20Sheet.pdf)
Risk Evaluation and Mitigation Strategy (http://www.XIAFLEX.com/REMS_statement.jsp)
XIAFLEX Dear Healthcare Provider Letter (http://www.XIAFLEX.com/docs/dear_hcp_letter.pdf)
Dupuytren’s Disease Educational Brochure (http://www.XIAFLEX.com/docs/PatientEdBrochure.pdf)
XIAFLEX Patient Brochure (http://www.XIAFLEX.com/docs/XIAFLEX_patient_brochure.pdf)
Frequently asked questions about obtaining XIAFLEX and enrollment into the XIAFLEX Xperience™ Program (http://www.XIAFLEX.com/faq.jsp)
1. XIAFLEX® training for healthcare providers. Available at: www.XIAFLEX.com/procedure_training.jsp.
2. Trojian TH, Chu SM. Dupuytren’s disease: diagnosis and treatment. Am Fam Physician. 2007;76(1):86-89.
3. XIAFLEX® (collagenase clostridium histolyticum) for injection, for intralesional use [prescribing information]. Malvern, PA: Auxilium Pharmaceuticals, Inc. February, 2010.
4. Shaw RB, Jr., Chong AK, Zhang A, et al. Dupuytren’s disease: history, diagnosis, and treatment. Plast Reconstr Surg. 2007;120(3):44e-54e.
5. Hurst LC, Badalamente MA, Hentz VR, et al. Injectable collagenase clostridium histolyticum for Dupuytren’s contracture. N Engl J Med. 2009;361(10):968-979.
6. Gilpin D, Coleman S, Hall S, et al. Injectable collagenase clostridium histolyticum: A new nonsurgical treatment for Dupuytren’s contracture. J Hand Surg. 2010 (In Press).
7. Auxilium Pharmaceuticals, Inc. FDA briefing document. Data on file. 2009.
8. US Food and Drug Administration. Approved risk evaluation and mitigation strategies (REMS). Available at: http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm111350.htm.
9. NDA 21-015 Androgel (testosterone gel) 1% CIII drug class and formulation: testosterone gel products – Risk Evaluation and Mitigation Strategy (REMS). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021015s022REMS.pdf.
10. NDA 21-454 Testim 1% (testosterone gel) – Risk Evaluation and Mitigation Strategy (REMS). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021454s008REMS.pdf.
11. NDA 21-928 Chantix (varenicline) tablets nicotinic receptor partial agonist aid to smoking cessation – Risk Evaluation and Mitigation Strategy (REMS). Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM193309.pdf.
12. NDA 21-773, 21-919 Byetta (exenatide) injection (glucagon-like peptide [GLP]-1 receptor agonist) – Risk Evaluation and Mitigation Strategy (REMS). Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM193306.pdf.
13. XIAFLEX® (collagenase clostridium histolyticum) – Risk Evaluation And Mitigation Strategy (REMS). Available at: www.XIAFLEX.com/hcp/REMS_statement.jsp.
14. XIAFLEX® Dear Healthcare Provider letter. Available at: www.XIAFLEX.com/docs/dear_hcp_letter.pdf.
15. XIAFLEX® aquisition quick reference. Available at: https://www.XIAFLEX.com/docs/Quick%20Acquisition%20Guide.pdf.
16. XIAFLEX® (collagenase clostridium histolyticum) training guide for the administration of XIAFLEX. Malvern, PA: Auxilium Pharmaceuticals, Inc. 2010:1-32.