Xiaflex (Collagenase Clostridium Histolyticum)
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Dupuytren’s contracture is a hand deformity that is characterized by progressive fibrosis of the palmar fascia leading to flexural contraction of the connective tissue. Fingers bend and cannot be straightened completely making it difficult to use the hand. Risk factors of Dupuytren’s contracture include age, gender, family history, tobacco and alcohol use, and diabetes. The prevalence of Dupuytren’s contracture is 3-6% in the general population. There are 3 stages in the fascia: proliferative phase: (1) local fascial fibroplasia and development of nodule (2) involutional phase: myofibroblasts align along tension lines within nodule and (3) residual phase: nodular tissue disappears leaving thick bands of collagen. This condition can be diagnosed through a physical exam and tabletop test, defined as the inability to simultaneously place the affected finger(s) and palm flat against table top. Nonpharmacological treatment options include steroid injection, needle fasciectomy, radiation therapy, needle aponeurotomy, physical therapy, splinting, or surgery. Surgery is reserved for patients who experience disability due to disease and when contraction is 20 degrees or more at the metacarpophalangeal joint and 30 degrees of more at the proximal interphalangeal joint.
Peyronie’s disease (PD) is a condition in which the penis has abnormal curvature during erection, which results in pain and unsatisfactory vaginal penetration during intercourse. The abnormal curvature is a result of fibrosis of the sheaths that cover the corpora cavernosa or vasculitis of the connective tissues, due to which the surface of the penis cannot lengthen with erection. The prevalence of PD is estimated to be 3%, and a significant proportion of men with PD are also found to have Dupuytren contractures, dyslipidemia and diabetes. Although not fully established, the risk factors that lead to PD may include vitamin E deficiency, use of beta-blockers, and elevated serotonin levels. Pharmacologic treatment options include vitamin E oral solution, potassium aminobenzoate (PABA), tamoxifen and colchicine, although some of them do not have strong evidence to support efficacy or may have intolerable side effects. Surgery is reserved for patients who are non-responders or intolerable to pharmacologic therapy, although this option carries the risk of decreased sensation, injury, and penile shortening.
Xiaflex (collagenase clostridium histolyticum) is a proteinase that hydrolyzes collagen in its native triple helical conformation, resulting in lysis of collagen deposits. In February 2010, Xiaflex was FDA-approved for the treatment of adult patients with Dupuytren’s contracture with a palpable cord. Xiaflex contains a purified collagenase clostridium histolyticum, containing Collagenase AUX-I and Collagenase AUX-II. The efficacy and safety of Xiaflex was studied in two randomized, double-blind, placebo-controlled, multi-centered trials in 374 adult patients (306 patients in CORD I and 66 patients in CORD II) with Dupuytren’s contracture. Patients were enrolled into the studied if they had a finger flexion contracture with a palpable cord of at least one finger of 20-100 degrees in a metacarpophalangeal joint or 20-80 degrees in a proximal interpahalangeal joint and a positive table top test. Patients were excluded if they had previous surgical treatment on the selected joints within 90 days before the first injection of study medication and patients could not have received anticoagulation medication (except for 150 mg of aspirin daily) within 7 days before the first injection of study medication. The cord of each affected joint was allowed to receive up to 3 injection of 0.58 mg of Xiaflex or placebo on days 0, 30 and 60. Twenty-four hours later, the investigator extended the treated finger and patients were fitted with a splint for up to 4 months. In the CORD I study, 64% of patients treated with Xiaflex achieved a reduction in contracture of the primary joint to 0-5 degrees after up to 3 injections per cord. In the CORD II study, 44% if patients treated with Xiaflex achieved a reduction in contracture of the primary joint to 0-5 degrees after up to 3 injections per cord. The proportion of patients treated with Xiaflex who achieved a contracture reduction of the primary joint to 0-5 degrees after the first injection was 39% in the CORD I study and 27% in the CORD II study. Adverse reactions occurring in ≥ 5% of Xiaflex treated patients included peripheral edema, contusion, injection site hemorrhage and pain at the injection site. Tendon ruptures were reported as a rare serious side effect. Also, it is advised to use extreme caution when receiving concomitant anticoagulants (except for aspirin).
Xiaflex was also approved by the FDA for the treatment of Peyronie’s disease on December 6, 2013. The safety and efficacy of Xiaflex was studied in two, phase III, randomized, double-blind, placebo-controlled studies in 836 patients and enrolled in IMPRESS I and IMPRESS II trials. Patients were excluded from the study if they had mature Peyronie plaques which would prevent Xiaflex injection, and ventral curvature. Subjects were randomized to receive two Xiaflex 0.58 mg injections or placebo injections 24-72 hours apart, which were injected directly into the primary plaque at the point of maximal penile curvature abnormality. Treatment cycles were received every 6 weeks for up to 4 treatment cycles, unless the penile curvature reduced to less than 15 degrees after the first injection. The patients also underwent penile plaque remodeling in between treatment cycles. Plaque remodeling is a technique aimed at reducing abnormal curvature by applying steady pressure to elongate and stretch the penis for 30 seconds, repeated three times daily. The primary endpoints were significantly in the favor of Xiaflex at week 52, as patients showed 34% mean percent improvement in penile curvature abnormality compared to 18.2% in the placebo group (p<0.0001). The PD symptom bother score was also significantly improved in the Xiaflex group vs the placebo group (-2.8 vs -1.8, p=0.0037). Six men experienced treatment-related adverse events, including corporeal ruptures and hematoma. Most common adverse events (experienced by > 45% patients) included penile ecchymosis, penile swelling and penile pain.
In October 2014, the FDA approved a supplemental Biologics Application for Xiaflex for the treatment of up to two Dupuytren’s contracture joints in the same hand during a single treatment visit. Additionally, it allowed the finger manipulation procedure to be performed 24 to 72 hours following the injection(s). The sBLA was based on positive results from the global, multicenter Phase 3b MULTICORD trial that showed that two concurrent injections were safe to use in the treatment of one hand with multiple affected joints. The study also examined efficacy and safety of the finger extension procedure at 24, 48 or 72 hours post injection.
Xiaflex should be administered by a healthcare provider who is experienced in injection procedures of the hand and in the treatment of Dupuytren’s contracture. As per FDA labeling, the injection may be administered up to 3 times per cord per 4-week interval.
[INFORMATIONAL NOTE: Xiaflex packaging includes the following BOXED WARNINGS:
Corporal rupture was reported as an adverse reaction in 5 of 1044 patients treated with Xiaflex in clinical trials. In other trials with Xiaflex treated patients, a combination of penile ecchymoses or hematoma, sudden penile detumescene, and/or a penile “popping” sound or sensation was reported. Signs or symptoms that may reflect serious penile injury should be promptly evaluated to assess for corporal rupture or severe penile hematoma which may require surgical intervention.]
I. Xiaflex (collagenase clostridium histolyticum) must be prescribed by the treating physician.
II. Xiaflex (collagenase clostridium histolyticum) must be administered by:
a. a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren’s contracture.
b. a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of Xiaflex (collagenase clostridium histolyticum) in the treatment of Peyronie’s disease.
c. healthcare sites certified with the Xiaflex Risk Evaluation and Mitigation Strategy (REMS) Program and dispensed by certified prescribers
III. Xiaflex (collagenase clostridium histolyticum) is considered medically necessary for the FDA-approved indication of the treatment of adult patients with Dupuytren’s contracture with a palpable cord when all of the following are met:
a. The member is at least 18 years old AND
b. There is a palpable cord of at least one finger (other than thumb) in a metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joint of 20 degrees or greater
[INFORMATIONAL NOTE: In 2009, Hurst and colleagues published a randomized, double-blind placebo-controlled, multicenter trial (16 sites) of collagenase clostridium histolyticum for Dupuytren’s contracture with 308 subjects with joint contractures of 20 degrees or more. Joints were stratified according to type (metacarpophalangeal joints or proximal interphalangeal joint [PIP]) and severity of contracture and randomly assigned in a 2:1 ratio to receive up to 3 injections of either collagenase or placebo in the contracted collagen cord at 30-day intervals. Secondary and tertiary joints were identified for possible subsequent injections. Joints were manipulated one day after injection if necessary. The primary end point was reduction in contracture to 0-5 degrees of full extension 30 days after last injection. Twenty-six secondary end points were also evaluated. Recurrence of contracture was defined as an increase in joint contracture to ≥ 20 degrees and was considered an adverse event. Efficacy results were based on 306 primary joints: 203 injected with collagenase and 103 injected with placebo. In the collagenase treated group, 130 of 203 (64%) cords met the primary end point versus 7 of 103 (6.8%) placebo injected cords (P<0.001). More than half of the collagenase injected joints that did not meet the primary end point did not receive the maximum allowable number of injections, most commonly because a cord could not be palpated or the patient was satisfied with the result. Median time to reach the primary end point for collagenase treated joints was 56 days. At the 90-day visit, there was no recurrence of contracture in collagenase treated primary joints that had reached the primary end point. When analyzed by joint type, more collagenase treated joints achieved the primary end point than placebo (metacarpophalangeal 76.7% vs. 7.2% and proximal interphalangeal joint 40.9% vs. 5.9%) (P<0.001 for both comparisons). The mean change in contracture from baseline to 30 days after last injection was 48.0 to 7.2 degrees in the collagen-injected metacarpophalangeal joints and 45.4 to 43.1 degrees in the placebo-injected metacarpophalangeal joints. Thirty days after last injection 84.7% of collagenase injected joints versus 11.7% of placebo injected joints showed clinical improvement. Results were better in metacarpophalangeal joints than in interphalangeal joints: 94.0% versus 67.1% in the collagenase group and 11.6% versus 11.8% in the placebo group. Overall, 96.6% of patients who received collagenase reported at least one treatment related adverse event. They had significantly more injection- and manipulation-related events, such as contusion, hemorrhage, injection-site pain, upper extremity pain, and lymphadenopathy (P<0.02), than patients who received placebo injection. Most were mild or moderate in intensity, however 20 patients in the collagenase group and 2 in the placebo group reported events that were severe in intensity. Three severe adverse events were considered to be treatment related: a case of complex regional pain syndrome and 2 tendon ruptures, both requiring surgical procedures. The authors note that the timeframe of this study was insufficient to assess recurrence, and they could not make any claims about this outcome.
IV. Xiaflex (collagenase clostridium histolyticum) is also considered medically necessary for the FDA-approved indication of the treatment of Peyronie’s disease in combination with modeling when all of the following are met:
In a letter to the editor in response to publication of the study, Holzer and Holzer comment that successful treatment of Dupuytren’s disease correlates with the percentage of excised Dupuytren’s tissue and the extent of the intervention. They caution that the value of collagenase injection must be confirmed in a long-term follow-up study that focuses on the recurrence rate.
The evidence from one large clinical trial suggests that injectable clostridial collagenase provides short-term release of contracture in Dupuytren’s disease. However, longer term recurrence rates are not reported. A comparison of overall outcomes compared to surgical intervention may also be useful. Potentially serious adverse events also warrant further investigation.]
a. The member is at least 18 years old AND
b. There is a palpable plaque and curvature deformity of at least 30 degrees and less than 90 degrees at the start of therapy AND
c. The injection does not involve the penile urethra
[INFORMATIONAL NOTE: Xiaflex is contraindicated in the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure.
In 2013, Gelbard and colleagues published a post-hoc meta-analysis of two phase III, randomized, double-blind, placebo-controlled trials that assessed the efficacy of collagenase clostridium histolyticum (CCh) in improving penile curvature abnormality and Peyronie disease symptoms bother score in 800 patients diagnosed with Peyronie’s disease. Men were stratified by the degree of penile curvature abnormality (30-60 or 61-90 degrees), and randomized to CCh or placebo group in a 2:1 ratio. The point of maximal penile curvature was recorded as the distance from the corona to the maximum point of curvature after injecting prostaglandin E1 or trimix into a corpus cavernosum to induce erection. The primary direction of curvature was determined as right or left lateral, dorsolateral or dorsal, while ventral curvature was excluded from analysis. Each treatment cycle included 2 injections of CCh or placebo, which were directly injected into the primary plaque at the point of maximal penile curvature abnormality with an interval of approximately 24-72 hours between each injection. The treatment cycle was repeated after 6 weeks for up to 4 treatment cycles. If after the first treatment, the penile curvature was reduced to less than 15 degrees, subsequent treatments were not administered as further treatment was not clinically indicated.
With regards to primary efficacy endpoints, CCh –treated patients showed a mean percent improvement in penile curvature abnormality of 34%, compared to 18.2% improvement in the placebo group (p<0.0001). The mean change in the PD symptom bother score was also significantly improved in the CCh group vs the placebo group (-2.8 vs -1.8, p=0.0037) Secondary endpoints that were assessed included percent of global responders, PDQ psychological and physical symptoms, IIEF overall satisfaction, percent of composite responders, and plaque consistency, all of which showed consistent trends toward greater improvement in CCh-treated mean compared to those treated with placebo.
Treatment-related adverse events local to the penis were found in 84.2% patients treated with CCh compared to 36.3% treated with placebo. The adverse events included penile ecchymosis, penile swelling, and penile pain. Six men reported treatment-related serious AE’s, including corporeal rupture and penile hematoma.
Xiaflex should be administered under the appropriate Risk Evaluation and Mitigation Strategy (REMS) program for its intended indications. ]
V. When medically necessary, Xiaflex (collagenase clostridium histolyticum) will be approved as follows:
a. Dupuytren’s disease: 12 weeks at the FDA-approved dose of 0.58 mg per injection into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint for a total of three doses per cord given at 4-week intervals.
b. Peyronie’s disease: 6 weeks at FDA approved dose of 2 injections (0.58 mg per injection) into primary plaque at the point of maximal penile curvature abnormality with an interval of 24-72 hours between each injection.
VI. Continued use of Xiaflex (collagenase clostridium histolyticum) will be approved for Peyronie’s disease only every 6 weeks at the FDA recommended dose of 2 injections (0.58 mg per injection) 24-72 hours apart for up to 4 treatment cycles if:
VII. Xiaflex (collagenase clostridium histolyticum) is considered investigational including, but not limited to, the following condition:
[INFORMATIONAL NOTE: Dupuytren’s disease: 24 to 72 hours after injection, a finger extension procedure should be performed if a contracture persists to facilitate cord disruption Four weeks following initial injection and finger extension procedure, if a MP or PIP contracture remains, re-injection with a single dose of 0.58 mg with subsequent finger extension procedure is indicated. A total of 3 injections per cord at 4-week intervals may be administered.
- Penile curvature is greater than 15 degrees
- Member is not experiencing toxicities associated with Xiaflex (e.g. penile fracture)
According to FDA-approved labeling, two palpable cords affecting two joints may be injected or one palpable cord affecting two joints in the same finger may be injected at two locations during a treatment visit. If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with XIAFLEX at other treatment visits approximately 4-week apart
Pivotal studies used for FDA approval did not study dosing beyond a total of 3 injections every 4 weeks.
Peyronie’s disease: 24-72 hours after second injection, patients should undergo penile plaque modeling. This technique is performed by using the plaque as a fulcrum point and applying firm, steady pressure for 30 seconds to elongate and stretch the penis. This procedure should be repeated three times daily during the 6-week period between treatment cycles. The treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures.
If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered.]
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Collagenase Clostridium Histolyticum (Xiaflex)
Xiaflex (Collagenase Clostridium Histolyticum)
Dupuytren's Contracture, Xiaflex for
Peyronie’s Disease, Xiaflex for
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9. National Institutes of Health. Clinical Trials Database. Available at http://clinicaltrials.gov/ct2/show/NCT00755222?term=peyronie%27s+disease&rank=1 Accessed March 2010.
10. Hellstrom WJ. Medical management of Peyronie’s disease. J Androl 2009; 30(4):397-405.
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12. Cooper CS, Joudi FN, Williams RD. Chapter 38. Urology. In: Doherty GM, ed. CURRENT Diagnosis & Treatment: Surgery. 13th ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content.aspx?aID=5312459. Accessed December 17, 2013.
13. Gelbard M, Goldstein I, Hellstrom WG et al. Clinical Efficacy, Safety and Tolerability of Collagenase Clostridium Histolyticum for the Treatment of Peyronie Disease in 2 Large Double-Blind, Randomized, Placebo Controlled Phase 3 Studies. J Urology 2013;190:199-207.
14. Nehra A, Alterowitz R. American Urological Association. Peyronie’s Disease: AUA Guideline. Apr 2015. Available from: https://www.auanet.org/education/guidelines/peyronies-disease.cfm
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