Stakehlder Perspectives in Men's Health August 2014 by Value-Based Cancer Care

STAKEHOLDER PERSPECTIVES IN

en’s Health AUGUST 2014 • PART 1 IN A SERIES

Peyronie’s Disease: An Underrecognized Men’s Health Condition By John A. Welz, MPH

s the US healthcare system continues to evolve, physicians in every state and specialty are attempting to comply with new rules, expectations, and costs, and must adapt to meet new healthcare demands. These changes are being driven by a combination of clinical and economic factors, including therapeutic innovation, improved diagnostic and surgical techniques, and perhaps most prominently, a policy environment where purchasers of healthcare are increasingly focused on accountability, quality, and value. For clinicians who manage conditions such as erectile dysfunction (ED), low testosterone, and Peyronie’s Disease (PD), these sweeping healthcare policy changes coincide with remarkable technological and pharmaceutical innovations, which have significantly improved outcomes for men with urologic conditions. Together, however, the combination of comprehensive healthcare reforms and fast-paced clinical advances has resulted in a challenging environment for urologists and other clinicians who treat these conditions. In order to continue to provide state-of-the-art, quality-driven, and cost-effective care for their patients, these specialists must reconsider both clinical and economic aspects of their practices. Business Challenges for Today’s Urology Practice In order to thrive in today’s healthcare environment, today’s urology practices must innovate. Many practices have consolidated to remain competitive, while others have sought to expand their coverage area and attract more new patients. Some of the approaches that have been implemented to mitigate risk, improve financial health, and maximize patient retention for urology practices include: • Increasing patient volume (workload): more patients per day, more surgeries per week, the addition of evening hours • Adding urology staff or consolidating private practices to broaden the catchment area

• Performing new procedures or prescribing newly available therapies • Maximizing referrals from primary care physicians • Partnering with local or regional hospital networks • Expanding the service line, including drug infusion services, pathology, diagnostic imaging, radiation, surgery, and/or clinical research.

Editor’s Note

Urology Practice Management is publishing a series of newsletters about selected men’s health topics that are of interest to the urology community. The newsletters provide relevant, up-to-date, evidence-based information on current topics of interest in a straightforward, concise manner. The series is specifically designed to raise awareness about new treatment approaches that may interest urologists and urology practice administrators from a business as well as a clinical perspective. The first issue of the newsletter focuses on Peyronie’s Disease, an underreported penile disorder (see the article on this page “Peyronie’s Disease: An Underrecognized Men’s Health Condition”). Until recently, treatment options were limited for patients with moderate to severe disease, and a substantial proportion of patients opted for surgery. Although surgery remains a mainstay of the treatment armamentarium, a less invasive option became available in 2013. This new option, XIAFLEX (collagenase clostridium histolyticum), is an injectable agent that has demonstrated the ability to reduce penile curvature deformity and patient bother in randomized clinical trials. This treatment option is explored in the article “XIAFLEX (collagenase clostridium histolyticum): A New Option for the Treatment of Peyronie’s Disease,” on page 6.

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2 I August 2014

FEATURES Peyronie’s Disease: An Underrecognized Men’s Health Condition..................................................1 In this article, clinical and economic considerations are explored for physicians who treat patients with Peyronie’s Disease.

XIAFLEX (collagenase clostridium histolyticum): A New Option for the Treatment of Peyronie’s Disease.................................6 This article addresses the efficacy, safety, and tolerability of XIAFLEX in the treatment of Peyronie’s Disease, and offers guidance on how to accurately code for treatment.

EDITORIAL ADVISORY BOARD Neil Baum, MD Practicing Urologist New Orleans, LA Cheris Craig, MBA, CMPE Chief Administrative Officer Urology of Greater Atlanta, LLC Atlanta, GA Michael deWitt Clayton, MD, FACS Urology Associates of San Luis Obispo, CA Rick Janss, MBA, CMPE Practice Administrator Clinical Urology Associates Gadsden, AL

John McMann, MS Administrator Advanced Urology Specialists, LLC Oxford, FL

James A. Sylora, MD Urologist AUS–Midwest Urology Evergreen Park, IL

Jonathan Oppenheimer, MD, FCAP Medical Director, Chief Pathologist Oppenheimer Urologic Reference Laboratory Nashville, TN

Sean M. Weiss, CCP-P, CCA-P, ACS-EM, CPC, CPC-P Vice President & Chief Compliance Officer DecisionHealth/ Professional Services Gaithersburg, MD

Jonathan Rubenstein, MD Director of Coding and Compliance Chesapeake Urology Baltimore, MD

MISSION STATEMENT Urology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the high-quality care urology patients deserve, providers must master the ever-changing business of urology. Urology Practice Management offers process solutions for members of the urology care team—medical, surgical, and radiation urologists, as well as executives, administrators, and coders/billers—to assist them in reimbursement, staffing, electronic health records, REMS, and compliance with state and federal regulations. Urology Practice Management™, ISSN (requested), is published 6 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Urology Practice Management™ is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Urology Practice Management™ do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Urology Practice Management™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/ or damage to persons or property arising out of or related to any use of the material mentioned in this publication. POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Urology Practice Management™, 1249 South River Road, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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Despite past communication challenges with payers (typically regarding contracting, prior authorization requirements, and step-edit restrictions), private urology practices now recognize that their financial objectives are increasingly aligned with the payer community. At the same time, payers now appreciate that supporting independent physician practices (relative to hospital-based care settings) has meaningful consequences in terms of the cost, and perhaps also the quality, of patient care. In a recent engagement of urologists and urology practice administrators, participants noted the positive consequences of including payers’ medical directors, whom one dubbed “the voice of [clinical] reason,” in contract negotiation meetings. In addition to more fair contracts, such meetings were said to lay the groundwork for constructive future collaborations with the payer. Panelists believed that quantitative data regarding differences in patient satisfaction, as well as the cost of care, between office- and hospital-based sites of care will enhance the likelihood that these productive payer–practitioner relationships will continue.1 Central Role of the Urologist in Treating Men’s Health Issues One can argue that there are disparities between men’s and women’s healthcare. The gynecologic and obstretric specialties were developed specifically to address women’s health needs, and men do not have a corresponding specialty devoted to gender-specific health issues. Men have higher rates of physical inactivity, poor nutrition, and excessive alcohol consumption than women. In addition, studies have shown that men are more resistant to engaging with the healthcare system or participating in preventive health practices than women. Ongoing research has revealed an association between metabolic dysfunction and urologic disorders such as lower urinary tract symptoms, low testosterone, and ED.2 Timely treatment of disorders such as ED and low testosterone may have important health implications for men who are affected. More than 50% of premature male deaths in the United States are a result of chronic but preventable medical conditions. ED and low testosterone are often associated with comorbidities of a chronic nature, but these urologic disorders can also precede a major medical event, such as a heart attack or stroke, by several years. This association may well offer an opportunity for early detection and prevention of life-threatening eventualities.3 To address these issues, the urology community has begun to take a more active leadership role in men’s health. In 2009, the American Urological Association created the Committee on Male Health. The Committee was charged with developing a comprehensive approach to address issues of men’s health, in-

cluding education, community outreach, research, integration with other specialties, and support of local and national men’s health initiatives.2 Ultimately, the urology community is best positioned to lead the consolidation of men’s health concerns and the means to address those concerns. It is possible that, through their role in providing specialized care for a wide range of men’s health needs, the urologist may emerge as the authority and coordinator of care for the majority of men as they navigate their way through the healthcare system.2

ED and low testosterone are often associated with comorbidities of a chronic nature, but these urologic disorders can also precede a major medical event, such as a heart attack or stroke, by several years. Peyronie’s Disease: An Underrecognized Disorder PD is a good example of a condition that calls for the expertise of a specialist in men’s healthcare. For a man with PD, healthcare needs can range from medication and physical therapy to a variety of surgical interventions to psychological and psychosocial support. The urologist with heightened awareness of the ramifications of this condition can take a proactive role in treating these patients and coordinating their care and their access to the variety of services and support needed to treat the whole man. PD is one of several gender-specific disorders experienced by men that place a substantial physical and psychological burden on sufferers. PD is a wound-healing disorder of the penis characterized by the formation of fibrous, inelastic plaques located in the tunica albuginea, the fibrous sheath surrounding the corpora cavernosa of the penis. The formation of these plaques results in penile deformities during erection, including curvature, shortening, narrowing, and bending (also known as the hinge effect). The disease does not generally resolve without treatment.4-6 Prevalence estimates for PD vary widely, and it is believed to be underreported for a number of reasons. A web-based survey of a large (N = 11,420) probability-based panel of research subjects representative of the full US population estimated the prevalence of PD to range from 0.5% (the percentage of surveyed subjects with PD diagnosis) to 13% (percentage with diagnosis, treatment, or penile symptoms of PD).7 In another claims-based market research analysis of men with PD in the United States, an estimated 118,182 men with PD Stakeholder Perspectives in Men’s Health I 3

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(6.4% of all men with the condition) sought treatment for their deformity. An estimated one-third of these men (n = 38,646) had moderate to severe curvature deformity of at least 30°.8 The Burden of Peyronie’s Disease Men with PD experience significant anxiety and psychological distress, and related effects may include depression, emotional distress, reduced quality of life because of PD-related pain and discomfort, and diminished self-esteem. These factors have been reported to negatively impact sexual relationships, restrict intimacy, and cause social isolation and stigmatization.4

The etiology of PD has not been well characterized. A leading hypothesis postulates that trauma is the most likely trigger for PD, activating an abnormal response to local injury in a man who has a genetic predisposition to abnormal scar formation and healing. Psychosocial function and sexual function are important issues for men with PD. In a series of interviews, patients with PD indicated that they experienced significant issues with PD-related pain and discomfort, physical appearance and self-image, sexual performance and function, and social stigmatization and isolation. In this analysis, the major themes and patterns of response were consistent across the groups of men with PD.9 Sustained depression is relatively common among men with

PD. In a survey of 92 men with diagnosed PD, 48% were classified as clinically depressed based on their scores on the Center for Epidemiological Studies Depression Scale. Furthermore, the percentage of these patients with depression did not change significantly with time since diagnosis, suggesting lack of mental adjustment to the diagnosis of PD. Given the high initial rate of depression, the authors concluded that all men with PD should be screened for mental illness.10 Etiology, Pathophysiology, and Natural History of Peyronie’s Disease The etiology of PD has not been well characterized. A leading hypothesis postulates that trauma is the most likely trigger for PD, activating an abnormal response to local injury in a man who has a genetic predisposition to abnormal scar formation and healing. Specifically, repeated mechanical stress and microvascular trauma of the penis resulting from excessive bending or single blunt trauma to the erect penis causes bleeding into the subtunical spaces and subsequent tissue damage.4,6,11 In these individuals, collagen synthesis is thought to increase abnormally, and resulting plaque formations interfere with the elasticity of the tunica albuginea. Although the specific mechanisms have not been elucidated, it is thought that changes in elastin fibers and collagen types can contribute to the formation of penile deformities. Fibrin deposits in the injured tissue may initiate an inflammatory wound healing response with resultant recruitment of macrophages, neutrophils, and fibroblasts.4,6,11 First symptoms of PD vary. In about half (52%) of men with the disorder, the first noticeable symptom is a penile deformity.

KEY POINTS In order to thrive in today’s healthcare environment, urology practices must innovate to maintain financial health; this may involve consolidation, expanding coverage areas, or taking steps to attract new patients. ➤ Urologists play a central role in treating men’s health issues. In 2009, the American Urological Association created the Committee on Male Health as a comprehensive approach to men’s healthcare. ➤ Peyronie’s Disease (PD) is an underrecognized disorder that affects 0.5% to 13% of men within the United States; however, its prevalence is believed to be underreported. ➤ Men with PD experience significant anxiety and psychological distress, and related effects may include depression, emotional distress, and reduced quality of life. ➤ The etiology of PD has not been well characterized. A leading hypothesis postulates that trauma is the most likely trigger for PD, activating an abnormal response to local injury. ➤ Effective treatment options for PD are limited. In treating PD, a number of nonsurgical interventions are used in clinical practice, including oral and topical treatments (vitamin E, tamoxifen, pentoxifylline, potassium para-aminobenzoate, colchicine) and intralesional injections (corticosteroids, interferons, verapamil). ➤

4 I August 2014

The first presenting symptom is penile pain or a lump in about 40% and 21% of men, respectively.12 The natural history of PD involves acute and chronic phases. The acute phase, which generally lasts 12 to 18 months, is characterized by progression in plaque size and progression in curvature deformity, often with pain at the site of the plaque and painful erections that are caused by inflammation. Plaque size and curvature deformity stabilize during the chronic phase and inflammation and pain are not characteristic of this phase of the disease.5,6,13 Treatment of Peyronie’s Disease Effective treatment options for PD are limited. In treating PD, a number of nonsurgical interventions are used in clinical practice, including oral and topical treatments (vitamin E, tamoxifen, pentoxifylline, potassium para-aminobenzoate, colchicine) and intralesional injections (corticosteroids, interferons, verapamil). Although the aforementioned treatments may result in some improvement in PD signs, such as penile curvature deformities and psychosocial symptoms, none have been approved by the US Food and Drug Administration (FDA) as safe and effective for the treatment of PD. Furthermore, most historically available, minimally invasive treatments have little in the way of controlled data demonstrating efficacy.4,5,7,14 Some men with symptomatic PD may opt for surgery. International Society for Sexual Medicine guidelines indicate that to be eligible for surgery, patients should have stable disease and a compromised ability or an inability to engage in coitus, have extensive plaque calcification, or desire a rapid and reliable result. Surgical procedures include tunica albuginea plication, plaque incision or partial excision of the plaque with

grafting, and implantation of a penile prosthesis with straightening maneuvers.5 However, surgery may be reserved for severe cases of PD because of serious complications that include penile shortening, ED, neurovascular injury, infection, and decreased sexual sensation.5,14,15 References

1. Raedler LA, Welz JA. Business challenges and opportunities for today’s urology practices. Urol Pract Manag. 2013;2:7-8. 2. Elterman DS, Kaplan SA, Pelman RS, Goldenberg SL. How ‘male health’ fits into the field of urology. Nat Rev Urol. 2013;10:606-612. 3. Grauer NA. Treating the whole man. Dome. 2013;64:7. 4. Levine LA. The clinical and psychosocial impact of Peyronie’s disease. Am J Manag Care. 2013;19:S55-S61. 5. Ralph D, Gonzalez-Cavadid N, Mirone V, et al. The management of Peyronie’s disease: evidence-based 2010 guidelines. J Sex Med. 2010;7:2359-2374. 6. Miner MM, Seftel AD. Peyronie’s disease: epidemiology, diagnosis, and management. Curr Med Res Opin. 2014;30:113-120. 7. DiBenedetti DB, Nguyen D, Zografos L, Ziemiecki R, Zhou X. A population-based study of Peyronie’s disease: prevalence and treatment patterns in the United States. Adv Urol. 2011;2011:282503. 8. Data on file. Auxilium Pharmaceuticals, Inc. 9. Rosen R, Catania J, Lue T, et al. Impact of Peyronie’s disease on sexual and psychosocial functioning: qualitative findings in patients and controls. J Sex Med. 2008;5: 1977-1984. 10. Nelson CJ, Diblasio C, Kendirci M, Hellstrom W, Guhring P, Mulhall JP. The chronology of depression and distress in men with Peyronie’s disease. J Sex Med. 2008;5:1985-1990. 11. Moreland RB, Nehra A. Pathophysiology of Peyronie’s disease. Int J Impot Res. 2002; 14:406-410. 12. Pryor JP, Ralph DJ. Clinical presentations of Peyronie’s disease. Int J Impot Res. 2002; 14:414-417. 13. Kadioglu A, Küç ükdurmaz F, Sanli O. Current status of the surgical management of Peyronie’s disease. Nat Rev Urol. 2011;8:95-106. 14. Gelbard M, Goldstein I, Hellstrom WJG, et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of Peyronie’s disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol. 2013;190: 199-207. 15. Wespes E, Hatzimouratidis K, Eardley I, et al; European Association of Urology. Guidelines on penile curvature. European Association of Urology website. www.uroweb. org/gls/pdf/16%20Penile%20Curvature_LR.pdf. Published February 2012. Accessed May 9, 2014.

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XIAFLEX (collagenase clostridium histolyticum): A New Option for the Treatment of Peyronie’s Disease By John A. Welz, MPH

ollagenase clostridium histolyticum (CCH), a purified mixture of 2 microbial collagenases, is a minimally invasive intervention recently approved by the FDA for the treatment of PD, under the brand name XIAFLEX.1,2 XIAFLEX is indicated for the treatment of adult men with PD with a palpable plaque and curvature deformity of at least 30° at the start of therapy. To ensure that the benefits of the drug outweigh its risks, the FDA has required that XIAFLEX be made available for the treatment of PD only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX REMS Program.2 XIAFLEX is also approved by the FDA, Health Canada, and European Medicines Agency (as XIAPEX) for use in adults who have Dupuytren’s contracture with a palpable cord. In these patients, XIAFLEX/XIAPEX is injected into the Dupuytren cord, and a finger extension procedure is performed to further Figure 1. XIAFLEX Mechanism of Action

Source: XIAFLEX website.4

6 I August 2014

disrupt the cord, which may have been enzymatically weakened by the procedure.1 Injection of XIAFLEX into a Peyronie’s plaque, which is comprised mostly of collagen, may result in enzymatic disruption of the plaque, as shown in Figure 1. Following disruption of the plaque, penile curvature deformity and patient bother caused by PD are reduced.2 XIAFLEX injection requires a specific procedure, and should only be performed by a trained physician, who is experienced in the treatment of male urological diseases, and who has completed required training for use of XIAFLEX in the treatment of PD.2 XIAFLEX is injected into a PD plaque. If more than 1 plaque is present, injection should be administered into the plaque causing the curvature deformity. A XIAFLEX treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of 2 injection procedures and 1 penile modeling procedure. The interval between cycles is approximately 6 weeks. If the curvature deformity is less than 15° 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.2 Efficacy data The efficacy of XIAFLEX in subjects with PD was evaluated in 2 large double-blind, randomized, placebocontrolled phase 3 studies (IMPRESS [Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies] I and II). The objective of these studies was to evaluate the safety and effectiveness of CCH intralesional injections administered twice per treatment cycle for up to 4 treatment cycles in men with PD.1,2 The studies included patients with stable disease and curvature deformity of at least 30°. Conversely, patients with ventral curvature deformity, an isolated hourglass deformity, or a calcified plaque that could have interfered with the injection technique, were excluded from the studies. At baseline, penile pain was either not present or was mild in most (98%) patients.1,2

Figure 2. XIAFLEX Efficacy: Mean Percent Change in Penile Curvature Deformity from Baseline Study 2

Placebo n=104

-5%

XIAFLEX n=199

-10% -15%

-17.8%

-20% -25%

P<0.01

-30% -35%

-35.0%

Last injection

-40% Treatment cycles 1 2 3 4

Placebo n=107

-5%

XIAFLEX n=202

-10% -15% -20%

-21.8%

-25%

P<0.01

-30% -35%

-33.2%

Last injection

-40% Treatment cycles 1 2 3 4

Follow-up period

0 6 12 18 24

Mean % change in penile curvature deformity

Study 1

Weeks

Follow-up period

0 6 12 18 24

Weeks

Sources: XIAFLEX [prescribing information] and XIAFLEX website.2,4

Patients were randomized 2:1 to receive either CCH (0.58 mg) or placebo injections plus penile remodeling. In addition, patients were stratified into 2 groups by degree of penile curvature: 30° to 60° and 61° to 90°. The duration of each study was 52 weeks.1,2 There were 2 coprimary end points, which measured the change from baseline to week 521-3: • Percentage change in penile curvature deformity • Change in Peyronie’s Disease Questionnaire (PDQ) bother domain score, whose components include concern about erection pain, erection appearance, impact of PD on intercourse, and impact of PD on frequency of intercourse. 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 at intervals of 24 to 72 hours between injections. Approximately 24 to 72 hours after the second injection of each treatment cycle, subjects underwent investigator penile plaque modeling.1,2 Baseline characteristics included mean age, mean duration of PD, history of ED, mean penile curvature deformity, and mean patient-reported PDQ bother domain score. These characteristics were similar across active treatment and control groups in both IMPRESS I and IMPRESS II studies.1,2 As shown in Figure 2, in both pivotal studies, XIAFLEX treatment significantly improved penile curvature deformity in patients with PD compared with placebo. Furthermore, the improvement in curvature deformity was numerically similar among subjects with baseline curvature deformity from 30° to 60° and those with curvature deformity from 61° to 90°.

Likewise, the mean change in the PDQ bother domain score was significantly improved in the XIAFLEX group versus the placebo group, as shown in Figure 3.1,2 All data for penile curvature deformity and patient-reported bother are from a modified intent-to-treat, last-observation-carried-forward (LOCF) analysis at week 52. P values are based on an LOCF analysis at week 52 and an analysis of variance with factors for drug, stratum of baseline penile curvature deformity, and their interaction.2,4

In both pivotal studies, XIAFLEX treatment significantly improved penile curvature deformity in patients with PD compared with placebo. Safety and tolerability data In pivotal studies, most patients completed all 4 cycles of treatment (8 injections total), including 434 of 551 XIAFLEXtreated men (78.8%) and 247 of 281 men who received placebo (87.9%). The majority of XIAFLEX-treated men and those who received placebo (92% and 61%, respectively) experienced at least 1 adverse reaction (AE).1,2 Most AEs were local events of the penis and groin and the majority were of mild or moderate severity. Of these events, 79% resolved without intervention within 14 days of the injection. The AE profile was similar after each injection; no cumulative effects were observed.2,4 Stakeholder Perspectives in Men’s Health I 7

Moving Toward Individualized Care of Patients with Type 2 Diabetes

da, in rd. he ed ti-

is upon her

nd peho he 1

he ates. d1 is an

Figure 3. XIAFLEX Efficacy: Mean Change in Patient-Reported Bother Figure 3. XIAFLEX Efficacy: Mean Change in Patient-Reported Bother Study 1 Mean change in patient-reported bother domain score from baseline to week 52

ed lly DA .1,2 PD 0° ug be reon

XIAFLEX n=199

Placebo n=104

Study 2 XIAFLEX n=202

Placebo n=107

-1.5

-1.6 -2.6

-2.8 P <.05

P <.05

Mean change from baseline expressed as % of mean baseline

-37.3%

-21.6%

-35.1%

-18.3%

Sources: XIAFLEX [prescribing information] and XIAFLEX website.2,4

Coding for Peyronie’s Disease XIAFLEX should only be administered by a physician who is experienced in the treatment of male urological diseases and who has completed required training for use of XIAFLEX in the treatment of PD. A treatment course consists of a maximum of 4 treatment cycles; a treatment cycle consists of 2 injection procedures and a penile modeling procedure.2 The ICD-9 diagnosis code for PD is 607.85.6 The following CPT® codes are used to bill for the injection procedure7: • 54235: Injection of corpora cavernosa with pharmacologic agent(s) to induce erection (eg, papaverine, phentolamine). This is necessary to determine where to inject XIAFLEX • 54200: Initial injection procedure for PD in a treatment cycle • 54200-58: Second injection procedure for PD in a treatment cycle. Use of the -58 modifier indicates a staged or related procedure or service by the same physician during the postoperative period. The correct drug code is J0775, which represents 0.01 mg of XIAFLEX.8 Because a single-use vial contains 0.90 mg,2 XIAFLEX is billed at 90 units.

In the XIAFLEX group, 30 patients did not receive all injec-

2 should not be administered. tions because of an AE and 44 patients did not receive all injec-

Conclusion PD is believed to be a wound-healing disorder that occurs in tions because their penile curvature deformity was less than 15° genetically susceptible men and results in penile curvature deafter one of the treatment cycles. Additional reasons patients Efficacy data formity.9,10 Typically, PD does not resolve without clinical did not receive all injections included inability to attend visits, The efficacy of XIAFLEX in subjects with PD was evaluated treatment refusal, and consent withdrawal.5 intervention.11 in 2Table large1 double-blind, randomized, placebo controlled phase shows the treatment-related AEs that occurred in Only a small percentage of men with PD seek treatment 3≥1% studies (IMPRESS for occurred Maximalat Peyronie’s of patients treated [Investigation with XIAFLEX and a (approximately 118,000 in the United States). Within this greater incidence in the group than in the population of men who seek treatment, 38,646 (32.7%) have Reduction Efficacy andtreatment Safety Studies] I and II).placebo The objective 5 The most frequently AEs (≥45.0%) XIAFLEXmoderate ofgroup. these studies was to reported evaluate the safety in and effectiveness of to severe curvature deformity of ≥30°. treated men included penile hematoma, penile swelling, and Effective treatment options for PD are limited. Most historiCCh intralesional injections administered twice per treatment penile pain.2 cally available, minimally invasive treatments have neither 1,2 cycle for up to 4 treatment cycles in men with PD. substantial data from controlled trials showing efficacy nor FDA In the controlled and uncontrolled clinical studies of XIAFLEX The studies included patients with stable disease and curvaapproval as safe and effective for the treatment of PD. Surgical in PD, 1044 patients received a total of 7466 XIAFLEX injecmay correct curvature deformity, but is associated tions.deformity There wereofserious AEs. FiveConversely, of 1044 (0.5%) patientswithintervention ture at least 30°. patients venwith complications such as penile shortening, ED, neurovascureported corporal rupture as an AE after XIAFLEX injection. In tral curvature deformity, an isolated hourglass deformity, or a lar injury, infection, and decreased sexual sensation.9,10 other XIAFLEX-treated patients (9 of 1044; 0.9%), a combinacalcified plaque that could have interfered with the injection tion of penile ecchymosis or hematoma, sudden penile detumesXIAFLEX injection is FDA approved as effective for the technique, were excluded from the studies. At baseline, penile cence, and/or a penile “popping” sound or sensation was treatment of PD in men with a palpable plaque and curvature pain wasand, either notcases, present or was mild inrupture most (98%) reported, in these a diagnosis of corporal deformity of at least 30° at the start of therapy, and represents patients. cannot be1,2excluded. These patients were managed without an alternative to surgical intervention in appropriate patients.2 surgical intervention, but the long-term are unIn today’s challenging healthcare environment for providers, Patients were randomized 2:1 toconsequences receive either CCh (0.58 known. Severe penile hematoma was reported as an AE in 39 treatment mg) or placebo injections plus penile remodeling.2 In addition, of PD with XIAFLEX promises to be an important of 1044 patients (3.7%) who were treated with XIAFLEX. therapeutic innovation for the practices of urologists and others

patients were stratified into 2 groups by degree of penile curvature: 30° to 60° and 61° to 90°. The duration of each study 1,2 8 I August 2014 was 52 weeks. There were 2 coprimary end points, which measured the

Table. Adverse Events Reported in ≥1% of XIAFLEX-Treated Patients in Pivotal Trials XIAFLEX N=551

Placebo N=281

All adverse reactions

84.2%

36.3%

Penile hematomaa

65.5%

19.2%

Penile swellingb

55.0%

3.2%

45.4%

9.3%

Penile ecchymosis

14.5%

6.8%

Blood blister

4.5%

Penile blister

3.3%

Pruritus genital

3.1%

Painful erection

2.9%

Erectile dysfunction

1.8%

0.4%

Skin discoloration

1.8%

Procedural pain

1.6%

0.7%

Injection site vesicles

1.3%

Localized edema

1.3%

Dyspareunia

1.1%

Injection site pruritus

1.1%

Nodule

1.1%

Suprapubic pain

1.1%

Adverse Reaction

Penile pain

c d

Includes: injection site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of subjects. Includes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection site edema. c Includes: injection site pain, penile pain, and injection site discomfort. d Includes: contusion, ecchymosis, penile hemorrhage, and injection site hemorrhage. Source: XIAFLEX website.4 b

who treat men’s urological conditions. Not only can XIAFLEX fulfill an unmet clinical need in treating appropriate patients with PD, but it also represents a potential business opportunity for urologists who are interested in expanding their service offerings to support the provision of comprehensive men’s healthcare. References

1. Gelbard M, Goldstein I, Hellstrom WJG, et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of Peyronie’s disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol. 2013;190: 199-207. 2. XIAFLEX [prescribing information]. Chesterbrook, PA: Auxilium Pharmaceuticals, Inc; 2013. 3. Auxilium Pharmaeuticals. Peyronie’s Disease Questionnaire (PDQ)—US Version. 2013.

4. XIAFLEX website. https://peyronies-disease.xiaflex.com/hcp/how-xiaflex-works.php. Accessed May 16, 2014. 5. Data on file. Auxilium Pharmaceuticals, Inc. 6. Buck CJ. 2012 ICD-9-CM for Physicians, Volumes 1 & 2, Professional Edition. St. Louis, MO: Saunders, an imprint of Elsevier, Inc; 2012. 7. American Urological Association. Coding for new medical treatment of Peyronie’s disease. Health Policy Brief. 2014;21. American Urological Association website. www. auanet.org/publications/hpbrief/view.cfm?i=2857&a=5645. Accessed May 19, 2014. 8. Center for Medicare & Medicaid Services. Alpha-Numeric HCPCS codes: 2014 Table of Drugs. Center for Medicare & Medicaid Services website. http://www.cms.gov/Medicare/Coding/HCPCSReleaseCodeSets/Downloads/DRUG2014.pdf. Updated November 25, 2013. Accessed May 20, 2014. 9. Ralph D, Gonzalez-Cavadid N, Mirone V, et al. The management of Peyronie’s disease: evidence-based 2010 guidelines. J Sex Med. 2010;7:2359-2374. 10. Wespes E, Hatzimouratidis K, Eardley I, et al; European Association of Urology. Guidelines on penile curvature. European Association of Urology website. www.uroweb. org/gls/pdf/16%20Penile%20Curvature_LR.pdf. Published February 2012. Accessed May 9, 2014. 11. Levine LA. The clinical and psychosocial impact of Peyronie’s disease. Am J Manag Care. 2013;19:S55-S61.

Stakeholder Perspectives in Men’s Health I 9

XIAFLEX® (collagenase clostridium histolyticum) for injection, for intralesional use Brief Summary of Prescribing Information For complete information, see the full prescribing information for XIAFLEX. WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE’S DISEASE Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX-treated patients in clinical studies. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX-treated patients [see Warnings and Precautions]. 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 [see Warnings and Precautions]. Because of the risks of corporal rupture or other serious penile injury, XIAFLEX is available for the treatment of Peyronie’s disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX REMS Program [see Warnings and Precautions]. INDICATIONS AND USAGE XIAFLEX is indicated for the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. CONTRAINDICATIONS XIAFLEX is contraindicated in: • the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure. • patients with a history of severe allergic reaction to XIAFLEX or to collagenase used in any other therapeutic application or application method [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Corporal Rupture (Penile Fracture) or Other Serious Injury to the Penis in the Treatment of Peyronie’s Disease Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX treated patients in the controlled and uncontrolled clinical trials in Peyronie’s disease. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture can not be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie’s disease [see Adverse Reactions]. Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to

assess for corporal rupture or severe penile hematoma, which may require surgical intervention. Injection of XIAFLEX into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, XIAFLEX should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis. XIAFLEX REMS Program Because of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie’s disease, XIAFLEX is available only through the XIAFLEX REMS Program [see Warnings and Precautions]. Required components of the XIAFLEX REMS Program include the following: • Prescribers must be certified with the program by enrolling and completing training in the administration of XIAFLEX treatment for Peyronie’s disease. • Healthcare sites must be certified with the program and ensure that XIAFLEX is only dispensed for use by certified prescribers. Further information is available at www.XIAFLEXREMS.com or 1-877-313-1235. Allergic Reactions In the double-blind, placebo-controlled portions of the clinical trials in Peyronie’s disease (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered. Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Although there were no severe allergic reactions observed in the XIAFLEX clinical studies (e.g., allergic reactions associated with respiratory compromise, hypotension, or end-organ dysfunction), an anaphylactic reaction was reported in a post-marketing clinical study in a patient who had previous exposure to XIAFLEX for the treatment of Dupuytren’s contracture, demonstrating that severe reactions including anaphylaxis can occur following XIAFLEX injections. Some patients with Dupuytren’s contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive XIAFLEX injections. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. The safety of more than one treatment course of XIAFLEX is not known. Risk of Bleeding in Patients with Abnormal Coagulation In the XIAFLEX controlled trials in Peyronie’s disease (Studies 1 and 2), 65.5% of XIAFLEX-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis (see Adverse Reactions Table). Patients with abnormal coagulation (except for patients taking low-dose aspirin, e.g., up to 150 mg per day) were excluded from participating in these studies. Therefore, the efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to XIAFLEX administration is not known. In addition, it is recommended to avoid use of XIAFLEX in patients with coagulation disorders,

including patients receiving concomitant anticoaguincluding patients receiving concomitant anticoagulants (except low-dose aspirin). lants (except forfor low-dose aspirin). ADVERSE REACTIONS following serious adverse reactions patients TheThe following serious adverse reactions in in patients with Peyronie’s disease discussed in greater with Peyronie’s disease areare discussed in greater de-deelsewhere in the labeling: tailtail elsewhere in the labeling: Corporal rupture (penile fracture) severe • •Corporal rupture (penile fracture) andand severe pe-pehematoma [see Warnings Precautions] nilenile hematoma [see Warnings andand Precautions] In other XIAFLEX-treated patients, a combination • •In other XIAFLEX-treated patients, a combination of penile ecchymoses or hematoma, sudden of penile ecchymoses or hematoma, sudden pe-pedetumescence, and/or a penile “popping” nilenile detumescence, and/or a penile “popping” sound sensation was reported, these sound or or sensation was reported, andand in in these cases, a diagnosis of corporal rupture cannot cases, a diagnosis of corporal rupture cannot be be excluded excluded [see Warnings and Precautions] ClinicalStudies StudiesExperience Experiencein inPatients Patientswith with Clinical Peyronie’s Disease Peyronie’s Disease Because clinical studies conducted under widely Because clinical studies areare conducted under widely varying conditions, adverse reaction rates observed varying conditions, adverse reaction rates observed clinical studies a drug cannot directly in in thethe clinical studies of of a drug cannot be be directly compared rates clinical studies another compared to to rates in in thethe clinical studies of of another drug may reflect rates observed in pracdrug andand may notnot reflect thethe rates observed in practice. tice. controlled uncontrolled clinical studies In In thethe controlled andand uncontrolled clinical studies XIAFLEX Peyronie’s disease, 1044 patients of of XIAFLEX in in Peyronie’s disease, 1044 patients re-received a total of 7466 XIAFLEX injections. ceived a total of 7466 XIAFLEX injections. Corporal Rupture and Other Serious Penile Injury Corporal Rupture and Other Serious Penile Injury Corporal rupture was reported adverse • •Corporal rupture was reported as as an an adverse reaction after XIAFLEX injections 5 of 1044 reaction after XIAFLEX injections in in 5 of 1044 (0.5%) XIAFLEX treated patients. (0.5%) XIAFLEX treated patients. other XIAFLEX-treated patients 1044; • •In In other XIAFLEX-treated patients (9 (9 of of 1044; 0.9%), a combination penile ecchymoses 0.9%), a combination of of penile ecchymoses or or hematoma, sudden penile detumescence, and/ hematoma, sudden penile detumescence, and/ a penile “popping” sound sensation was or or a penile “popping” sound or or sensation was reported, in these cases, a diagnosis of correported, andand in these cases, a diagnosis of corporal rupture cannot excluded. These patients poral rupture cannot be be excluded. These patients were managed without surgical intervention, were managed without surgical intervention, butbut long-term consequences unknown. thethe long-term consequences areare unknown. Severepenile penilehematoma hematomawas wasalso alsoreported reported • •Severe adverse reaction 1044 patients as as an an adverse reaction in in 3939 of of 1044 patients (3.7%) in the controlled uncontrolled clinical (3.7%) in the controlled andand uncontrolled clinical trials Peyronie’s disease [see Adverse Reactrials in in Peyronie’s disease [see Adverse Reactions]. tions]. data described below based idenTheThe data described below areare based on on twotwo identical,pooled, pooled,randomized, randomized,double-blind, double-blind,placeboplacebotical, controlled, multi-center trials through controlled, multi-center trials through DayDay 365365 in in patients with Peyronie’s disease (Studies 1 and patients with Peyronie’s disease (Studies 1 and 2).2). These trials included patients of whom These trials included 832832 patients of whom 551551 andand received XIAFLEX placebo, respectively. 281281 received XIAFLEX andand placebo, respectively. In In these trials, patients were given 4 treatment these trials, patients were given up up to to 4 treatment cycles XIAFLEX placebo. In each cycle, cycles of of XIAFLEX or or placebo. In each cycle, twotwo in-injections of XIAFLEX or two injections of placebo were jections of XIAFLEX or two injections of placebo were administered 1 to 3 days apart. A penile modeling administered 1 to 3 days apart. A penile modeling procedure was performed study procedure was performed at at thethe study sitesite on on pa-patients 1 to 3 days after second injection tients 1 to 3 days after thethe second injection of of thethe cycle. treatment cycle was repeated approxicycle. TheThe treatment cycle was repeated at at approximately 6-week intervals to three additional times, mately 6-week intervals up up to three additional times, a maximum 8 total injection procedures forfor a maximum of of 8 total injection procedures andand 4 total modeling procedures [see Clinical Studies 4 total modeling procedures [see Clinical Studies in in Prescribing Information] thethe fullfull Prescribing Information]. majority Peyronie’s patients experienced TheThe majority of of Peyronie’s patients experienced at at least adverse reaction (92% XIAFLEX-treated least oneone adverse reaction (92% XIAFLEX-treated patients, 61% placebo-treated). Most adverse reacpatients, 61% placebo-treated). Most adverse reactions were local events penis groin tions were local events of of thethe penis andand groin andand majority these events were mild moderthethe majority of of these events were of of mild or or moderseverity, most (79%) resolved within days ateate severity, andand most (79%) resolved within 1414 days injection. adverse reaction profile was of of thethe injection. TheThe adverse reaction profile was similar after each injection, regardless of the number similar after each injection, regardless of the number of injections administered. of injections administered. most frequently reported adverse drug reactions TheThe most frequently reported adverse drug reactions 25%) in the XIAFLEX clinical trials in patients with (≥ (≥ 25%) in the XIAFLEX clinical trials in patients with Peyronie’sdisease diseasewere werepenile penilehematoma, hematoma,penile penile Peyronie’s

swelling, and penile pain. The Adverse Reactions Table below shows the incidence of adverse reactions that were reported in greater than or equal to 1% of XIAFLEXtreated patients and at a frequency greater than placebotreated patients after up to 8 injections in the pooled placebo-controlled trials through Day 365. Adverse Reactions Occurring in ≥ 1% of XIAFLEX-Treated Patients with Peyronie’s disease and at a Greater Incidence than Placebo After Up to Four Treatment Cycles in Studies 1 and 2 Combined XIAFLEX N=551

Placebo N=281

84.2%

36.3%

Penile hematomaa

65.5%

19.2%

Penile swelling

55.0%

3.2%

45.4%

9.3%

Adverse Reaction All Adverse Reactions b

Penile painc Penile ecchymoses

14.5%

6.8%

Blood blister

4.5%

Penile blister

3.3%

Pruritus genital

3.1%

Painful erection

2.9%

Erectile dysfunction

1.8%

0.4%

Skin discoloration

1.8%

Procedural pain

1.6%

0.7%

Injection site vesicles

1.3%

Localized edema

1.3%

Dyspareunia

1.1%

Injection site pruritus

1.1%

Nodule

1.1%

Suprapubic pain

1.1%

Includes: injection site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of subjects. b Includes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection site edema. c Includes: injection site pain, penile pain, and injection site discomfort. d Includes: contusion, ecchymoses, penile hemorrhage, and injection site hemorrhage. Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of XIAFLEXtreated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined. Reports of penile “popping” sounds or sensations A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking”, and sometimes accompanied by detumescence, hematoma and/or pain, were reported in 73/551(13.2%) a

XIAFLEX-treated patients and 1/281 (0.3%) placebotreated patients. There were no clinically meaningful differences in the incidence of adverse events following treatment with XIAFLEX based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use. XIAFLEX was not associated with shortening of penile length in clinical trials in the treatment of Peyronie’s disease. Immunogenicity During clinical studies in Dupuytren’s contracture and Peyronie’s disease, patients were tested at multiple time points for antibodies to the protein components of XIAFLEX (AUX-I and AUX-II). In the Peyronie’s disease clinical studies, at 6 weeks after the first treatment cycle of XIAFLEX 0.58 mg, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of XIAFLEX, >99% of XIAFLEX-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested. In patients treated for these two indications, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions. Since the protein components in XIAFLEX (AUX-I and AUX-II) have some sequence homology with human matrix metalloproteinases (MMPs), anti-product antibodies could theoretically interfere with human MMPs. In vitro studies showed no evidence of crossreactivity between anti-drug-antibody positive patient sera and a series of relevant MMPs. In addition, no clinical safety concerns related to the inhibition of endogenous MMPs have been observed. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to collagenase clostridium histolyticum with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS Anticoagulant drugs: XIAFLEX should be used with caution in patients receiving concomitant anticoagulants (except for low-dose aspirin) [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of XIAFLEX in pregnant women. Because animal repro-

duction studies are not always predictive of humanresponse, XIAFLEX should be used during pregnancy only if clearly needed. Risk Summary Based on animal data, XIAFLEX is not predicted to increase the risk for major developmental abnormalities in humans. Human Data Human pharmacokinetic studies showed that XIAFLEX levels were not quantifiable in the systemic circulation following injection into a Dupuytren’s cord. Low levels of XIAFLEX were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of XIAFLEX into the penile plaque of subjects with Peyronie’s disease [see Clinical Pharmacology in the full Prescribing Information]. Almost all patients develop anti-product antibodies (anti-AUX-I and anti-AUX-II) after treatment with XIAFLEX, and the clinical significance of anti-product antibody formation on a developing fetus is not known [see Adverse Reactions]. Animal Data Reproduction studies have been performed in rats with intravenous exposures up to approximately 11 times the maximum recommended human dose (MRHD) of XIAFLEX on a mg/m2 basis, and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum. Nursing Mothers It is not known whether collagenase clostridium histolyticum is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when XIAFLEX is administered to a nursing woman. Pediatric Use The safety and effectiveness of XIAFLEX in pediatric patients less than 18 years old have not been established. Geriatric Use Of the 551 XIAFLEX-treated patients in the doubleblind, placebo-controlled, clinical trials in Peyronie’s disease (Studies 1 and 2), 100 (18%) were 65 years of age or older and 5 (0.9 %) were 75 years of age or older. No overall differences in safety or effectiveness of XIAFLEX were observed between these patients and younger patients. OVERDOSAGE The effects of overdose of XIAFLEX are unknown. It is possible that multiple simultaneous or excessive doses of XIAFLEX may cause more severe local effects than the recommended doses including serious adverse reactions in the injected area (e.g., tendon ruptures or corporal ruptures dependent on the injection site). Supportive care and symptomatic treatment are recommended in these circumstances. Manufactured and distributed by: Auxilium Pharmaceuticals, Inc. Chesterbrook, PA 19087 This Brief Summary is based on PL-0108-001.e Revised 12/2013

For the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy

For men with Peyronie’s disease, there’s good news: the only FDA-approved treatment option. XIAFLEX

Important Safety Information WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE’S DISEASE Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX-treated patients in clinical studies. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX-treated patients. 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. Because of the risks of corporal rupture or other serious penile injury, XIAFLEX is available for the treatment of Peyronie’s disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX REMS Program. • XIAFLEX is contraindicated in the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure and in patients with a history of severe allergic reaction to XIAFLEX or to collagenase used in any other therapeutic application or application method • Injection of XIAFLEX into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, XIAFLEX should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis • In the double-blind, placebo-controlled portions of the clinical trials in Peyronie’s disease, a greater proportion of XIAFLEX-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered • Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Although there were no severe allergic reactions observed in the XIAFLEX clinical studies (eg, those associated with respiratory compromise, hypotension, or end-organ dysfunction), an anaphylactic reaction was reported in a post-marketing clinical study in a patient who had previous exposure to XIAFLEX for the treatment of Dupuytren’s contracture, demonstrating that severe reactions including anaphylaxis can occur following XIAFLEX injections. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. The safety of more than one treatment course of XIAFLEX is not known • In the XIAFLEX controlled trials in Peyronie’s disease, 65.5% of XIAFLEX-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis. Patients with abnormal coagulation (except for patients taking low-dose aspirin, eg, up to 150 mg per day) were excluded from participating in these studies. Therefore, the efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than low-dose aspirin, eg, up to 150 mg per day) within 7 days prior to XIAFLEX administration is not known. In addition, it is recommended to avoid use of XIAFLEX in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin) • In the XIAFLEX clinical trials for Peyronie’s disease, the most frequently reported adverse drug reactions (≥25%) and at an incidence greater than placebo included: penile hematoma, penile swelling, and penile pain

Please visit XIAFLEX.com/hcp