Evidence-Based Rationale

Transcription

1 Supplement to WOUNDS January 2014 Evidence-Based Rationale for Utilizing REGRANEX (becaplermin) Gel, 0.01% as an Adjunct to Standard of Care Indicated for Diabetic Foot Ulcers (DFUs) Please see Important Safety Information on page 5 and accompanying full Prescribing Information, including Boxed Warning and Medication Guide. This supplement was not subject to the peer-review process of WOUNDS. Supported by Smith & Nephew, Inc.

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3 Table of Contents Introduction... 4 About the authors... 4 Important Safety Information Burden of DFU Epidemiology of DFUs and associated morbidity Mortality associated with DFUs Financial burden Evaluation of diabetic foot ulcers Good ulcer care Unacceptably low healing rates with current standard of care Treatment guideline bibliography Pharmacology and biological action of growth factors in wound healing Role of growth factors in healing Role of PDGF in the healing process PDGF Its composition PDGF-BB Its role in healing REGRANEX (becaplermin) Gel, 0.01% Boxed Warning Contraindications/warnings and precautions/drug interactions/use in specific populations/ clinical pharmacology/toxicology/patient counseling information Clinical efficacy Phase 3 studies Adverse reactions Clinical trial summaries Dosage and administration Summary References

4 Introduction The number of people with diabetes is increasing in both the United States and around the world. It is estimated that, by 2030, approximately 366 million individuals will have diabetes, compared with 171 million in In the United States, the projections are staggering. There are currently 24 million people with diabetes in the US; this number is expected to increase to over 40 million diagnosed and undiagnosed people during the next 25 years. 2 Diabetic foot ulcers (DFUs) are a common complication of diabetes that often includes serious repercussions such as infection, amputation, and increased mortality risk. 3 The goal of this supplement is twofold: Highlight the societal impact of DFUs and current expert recommendations for good ulcer care Present the evidence-based rationale for the use of REGRANEX Gel, when appropriate, as standard adjunctive therapy (ie, in addition to good ulcer care practices) in the treatment of the lower extremity diabetic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. About the authors Eliot Mostow MD, MPH Dr. Eliot Mostow is a professor and chair of the Dermatology Section at Northeast Ohio Medical University (NEOMED) as well as associate professor of Clinical Dermatology at Case Western Reserve School of Medicine s Department of Dermatology. He began his focused interest in wound care working with Dr. David Steed at the Wound Healing and Limb Preservation Clinic at the University of Pittsburgh in 1992 as a faculty member of the Department of Dermatology. In 1993 he became a founding member of Wound Care Associates of Akron, Inc., which provided staffing at a newly formed multidisciplinary wound healing clinic at Akron General Medical Center. Since then, he has continued his association with Akron General and now runs the Clinical Research Program for the Wound Center. In that role he has coordinated programs in clinical research, health service research, and participated in industrysponsored trials including the current HP-802 trial with Smith & Nephew. Matthew Regulski DPM Dr. Matthew Regulski, a practicing foot and ankle surgeon, is the medical director of the Wound Care Institute of Ocean County. Dr. Regulski is also co-director of the Center for Wound Healing and Hyperbaric Medicine at Community Medical Center, as well as being involved at the Wound Care Center at the Kimball Institute. He has been the principal investigator for several clinical trials for chronic leg ulcers and diabetic foot ulcers and has authored several peer-reviewed articles for the treatment of chronic wounds. He is an accomplished speaker for several wound care conferences and is a wound care certified physician. Dr. Regulski is a fellow of the Academy of Physicians in Wound Healing and a fellow of the American Professional Wound Care Association. He is a national delegate for the Association for the Advancement of Wound Care and a member of the Wound Healing Society. 4

5 Important Safety Information WARNING: INCREASED RATE OF MORTALITY SECONDARY TO MALIGNANCY An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. REGRANEX Gel should only be used when the benefits can be expected to outweigh the risks. REGRANEX Gel should be used with caution in patients with known malignancy. Indications and usage: REGRANEX (becaplermin) Gel is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. REGRANEX Gel is indicated as an adjunct to, and not a substitute for, good ulcer care practices. Limitations of use: The efficacy of REGRANEX Gel has not been established for the treatment of pressure ulcers and venous stasis ulcers The effects of REGRANEX Gel on exposed joints, tendons, ligaments, and bone have not been established in humans REGRANEX Gel is a non-sterile, low bioburden preserved product that should not be used in wounds that close by primary intention REGRANEX Gel is contraindicated in patients with known neoplasm(s) at the site(s) of application. REGRANEX Gel is contraindicated in patients with known hypersensitivity to any component of the product (e.g., parabens). Malignancies distant from the site of application have been reported in both a clinical study and in postmarketing use. In clinical trials, erythematous rashes occurred in 2% of patients treated with REGRANEX Gel or placebo; none occurred in patients receiving good ulcer care alone. Burning sensation at the site of application and erythema have been reported during post-approval use of REGRANEX Gel. Please see accompanying full Prescribing Information, including Boxed Warning and Medication Guide. 5

6 PART 1 Burden of DFUs 1.1 Epidemiology of DFUs and associated morbidity People living with diabetes are at risk of developing serious complications foot ulcerations are one of the most common. 4 The decreased or complete inability to perceive excessive pressure or pain and altered foot mechanics combine to make the weight-bearing portions of the foot at risk for ulcers. 5 Advanced glycation end products, which are sugar-derived molecules, accumulate on a cellular level in people with diabetes and may adversely affect extracellular matrix production, cell function, and cytokine production, and also prevent prompt wound healing. 6,7 Deformity, callus, trauma, large vessel atherosclerosis with underlying ischemia of varying severity, and peripheral neuropathy are major contributing factors to ulcer occurrence and the chronic nonhealing nature of a DFU. 8 Discomfort and disability are not the only consequences of ulceration; a DFU can lead to other types of morbidity in a significant number of individuals. 3 Lower extremity amputations and osteomyelitis are the two most frequent serious consequences of a DFU. 3 The rate of amputations in individuals with diabetes is approximately 4.1 per 1,000 person-years compared with 3 per 10,000 personyears in the general population. 9 Figure 1. Estimated Number of People at Risk of Developing a DFU: 2009 and ,6 Figure 1: Among people with diabetes, 15% will experience a DFU in their lifetime. In 2009, there were 23.7 million Americans with diagnosed and undiagnosed diabetes. That number is expected to rise to 44.1 million by This means that, in 2009, 4 million people with diabetes had a lifetime risk of developing a DFU. By 2034, that number will rise to almost 7 million. 2,6 Figure 2. Lower Extremity Complications in a Diabetes Disease Management Program 13 Overall, individuals with diabetes have a 15% lifetime risk of developing a DFU, with an annual incidence rate of 1% to 6.84%, and an estimated community prevalence of 2% to 5%. 3,10 In 2009, the estimates for people in the US with a lifetime risk of developing a DFU totaled about 4 million people. By 2034, this estimate is expected to rise to nearly 7 million people. 2,6 Compared with the general population, the risk of developing a lower extremity ulceration is much greater for individuals with type 2 diabetes. 11 In a study of 1,077 people with diabetes who were age- and sexmatched with 480 individuals without diabetes, having type 2 diabetes was associated with an almost 3 times greater risk of developing foot ulceration (odds ratio of 2.94 [95% CI ]; P<0.001). 11 As the number of people with diabetes increases, DFUs and resulting complications will increase significantly as well. 12 Study design: This study evaluated screening results and clinical outcomes for the first 1,666 patients enrolled in a diabetes disease management program for a period of 24 months (50.3% men, aged 69.1 ±11.1 years). Although the study compared Mexican Americans to non-hispanic whites, combined results for both groups are presented here. 13 6

7 1.2 Mortality associated with DFUs In addition to causing serious complications for people living with diabetes, DFUs and a history of foot ulceration have been shown to be an independent predictor of mortality. 3 In a population-based analysis, 92,434 individuals were mailed a questionnaire and invited to a health examination. A total of 65,604 individuals responded, of whom 155 individuals reported having a history of foot ulceration (HFU); 1,339 individuals reported having diabetes but no HFU; and 63,632 individuals did not have diabetes. A total of 65,126 individuals were followed for up to 10 years with mortality as the endpoint in this prospective analysis of lower extremity ulcers. During that time, 49% of the 155 individuals with an HFU died, compared with 35.2% of the 1,339 individuals with diabetes and no HFU, and 10.5% of the 63,632 individuals who did not have diabetes. After adjustment for confounding risk factors, diabetic individuals with and without an HFU had a significantly higher mortality rate (HR 2.29 [95% CI ]) than individuals without diabetes (HR 1.70 [95% CI ]). And among individuals with diabetes, an HFU increased mortality risk by 47%. 14 Moreover, consensus recommendations describe a study that estimated the 5-year mortality rate at 45% for patients with neuropathic DFUs and diabetes-related amputations, which further demonstrates that DFUs are a marker of mortality for patients with diabetes. 3 Figure 3. Risk of Mortality Increases Among Individuals With Diabetes and a History of Foot Ulcers 14 Study design: The purpose of this study (N=65,126) was to compare mortality rates for individuals with diabetes reporting a history of foot ulceration (HFU) with those for individuals without an HFU and the nondiabetic population. These issues were investigated in the Nord-Trøndelag Health population-based sample of men and women from a well-defined geographic area. During the follow-up period (up to 10 years, with mortality as the endpoint), 49% of the 155 diabetic individuals with an HFU died compared with 35.2% of the 1,339 diabetic individuals without an HFU and 10.5% of the 63,632 nondiabetic individuals. 14 7

8 1.3 Financial burden of DFUs DFUs and the resulting complications are a tremendous financial burden to the healthcare system and society. 8 A total of 85% of lower-extremity amputations are associated with diabetic complications, and almost all of these are preceded by a foot ulcer. In 2004, approximately 71,000 nontraumatic lower-limb amputations in the United States were performed on patients with diabetes. 15 In 2007, the treatment of diabetes and its complications in the US generated at least $116 billion in direct costs (2007 US dollars) with at least 33% of the costs linked to treatment of foot ulcers. Compared to patients with diabetes but without foot ulcers, the cost of care for patients with diabetes and a foot ulcer is approximately 5.4 times higher in the year after the first ulcer episode and 2.8 times higher in the second year. 16 In 2001, the costs of diabetes-related amputations were estimated to be $38,077 per amputation. The average costs for foot ulcer care in the United States were estimated to be $13,179 per episode, with costs increasing with severity of ulceration. 15 If current trends continue, the CDC estimates that 1 in 3 Americans will develop a foot ulcer in their lifetime, highlighting the need for foot ulcer prevention programs in people living with diabetes, in order to reduce the risk of unnecessary amputations Evaluation of DFUs Recently, consensus recommendations were published to assist clinicians in advancing the treatment of neuropathic DFUs through straightforward and practical approaches to good ulcer care. 3 These recommendations provide a comprehensive framework for optimum management of a DFU, beginning with a complete evaluation of the patient, including medical history, comorbidities that influence wound healing, glycemic control, and issues specific to the ulcer. 3 The recommendations also state that an evaluation should include a physical examination with neurologic, musculoskeletal, vascular, and laboratory assessment, as well as a review of nutritional status. Additional attention should be paid to factors that may have led to wound formation or that may impair healing. 3 The consensus recommendations state that the evaluation must consider dermatological changes, ulcer characteristics, wound edges, wound bed, wound base, periwound skin, exudate, presence of necrosis, and any associated pain, as well as a probe for sinus tracts or a positive probe-to-bone test. 3 The classic signs and symptoms of infection heat, pain, redness, and swelling are not always present or may be diminished due to a decreased immune response with diabetes. 3 Therefore, the guidelines recommend observing the ulcer for secondary signs of infection such as exudate, delayed healing, friable or discolored granulation tissue, foul odor, and pocketing at wound base. 3 8

9 Figure 4: The initial evaluation of the diabetic foot ulcer must be comprehensive and systematic to ascertain the parameters that might have led to its onset and to determine the presence of factors that can impair wound healing. 17 From Frykberg RG, Zgonis T, Armstrong DG, et al. J Foot Ankle Surg. 2006;45(5 Suppl):S-19. Reprinted and adapted with permission from Elsevier. 9

10 1.5 Good ulcer care Several classification systems exist for staging foot ulcers. Although no single system has been universally adopted, the 3 classification systems used most often are the Wagner system, the University of Texas San Antonio (UTSA) system, and the PEDIS system. 17 Specific to the treatment of DFUs, the recommendations include comprehensive good ulcer care with sharp debridement at frequent intervals, infection control, local pressure off-loading, provision of a moist interactive wound-healing environment, and, depending on response to these treatments, consideration of advanced therapy. 3 A critical component of good wound care is patient adherence to the multiple aspects of care, including dietary compliance for good glycemic control and following prescribed regimens for medications. 6 Table 1. Components of Good Wound Care 3 Debridement: Cold steel surgical debridement initially and then as needed based on condition of the wound (maintenance) Infection control: Bacterial colonization infection Infection is diagnosed from clinical findings whenever possible. Purulent secretions are present or >two or at least two principal symptoms of inflammation (eg, redness, warmth, swelling, and pain or tenderness) Given that patients with diabetes are typically immunocompromised, clinicians should also look for secondary signs of infection including exudate, delayed healing, friable granulation tissue, discolored granulation tissue, foul odor, pocketing at the wound base, and wound breakdown Culture: Levine swab technique Quantitative biopsy (for bone only) Testing (not universally available) via polymerase chain reaction assay, oligonucleotide array Off-loading: Total contact cast (TCC) Instant TCC Advanced therapies: Use 4-week treatment endpoint to assess need for advanced therapies If wound is not progressing toward healing (percent wound area reduction <50%), then advanced techniques should be considered All previous assessment and treatment standards should continue to be utilized From Snyder RJ, Kirsner RS, Warriner RA, Lavery LA, Hanft JR, Sheehan P. Ostomy Wound Manage. 2010;56(suppl 4):S19. Used with permission. DEBRIDEMENT The chronic wound environment differs from the acute wound, which, in a nonimmunocompromised host, will usually heal. 18 In addition to the decreased immune response in an individual with diabetes, chronic wounds fail to heal for multiple reasons, including local ischemia, necrotic tissue, and overwhelming bacterial load, any of which can lead to prolonged inflammatory response and delayed healing. The noxious cellular and molecular environment that results from prolonged inflammation prohibits healthy healing through growth factor deficiencies, faulty receptor site function, and poor cell proliferation. 3 Therefore, good ulcer care of a DFU requires that the chronic wound environment be addressed first through debridement. Debridement may be surgical/sharp, enzymatic (eg, collagenase), autolytic (eg, occlusive), mechanical (wet-to-dry dressing, lavage), or biologic (larval). 3 10

11 If surgical debridement is the method of choice, it may not need to be weekly, but should be often enough to prevent the accumulation of necrotic or fibrinous tissues. Frequent debridement changes the wound physiology by removing nonviable tissue, matrix metalloproteinases, and biofilm, and promotes a healthy wound environment with a greater production of growth factors. 3 Dressings that maintain a moist wound but control excess exudations are important in promoting a healthy wound environment. 19 INFECTION CONTROL DFUs that are potentially infected require additional evaluation, according to guidelines developed by the Infectious Diseases Society of America (IDSA). 19 The recommendations for a patient with a suspected infected DFU include assessment of the patient s overall health and examination of the affected foot or limb, as well as the infected wound. Osteomyelitis should be considered as a potential complication of any infected deep or large foot ulcer, especially one that is chronic or overlies a bony prominence. 19 Magnetic resonance imaging is the most specific and sensitive imaging test for osteomyelitis. 3 The IDSA guidelines recommend that all infected DFUs be treated with antibiotic therapy, but caution that antibiotics without the use of comprehensive good wound care are not likely to be effective. 19 OFF-LOADING True off-loading that decreases pressure and strain rates is critical in improving the healing of a DFU. The more aggressive off-loading techniques, such as total contact casts and cast walkers, have been shown to produce significantly better healing rates than pads or shoe insoles, but effective off-loading can be obtained with an ankle brace or similar device fixed to the foot bed, if the patient adheres to the regimen. Bed rest, wheelchairs, or crutches have not been shown to improve healing rates Unacceptably low healing rates with current standard of care Good wound care is vital in the management of a DFU but does not always result in complete healing. 3,20 Statistically, despite good ulcer care, about half of all diabetic foot ulcers may still fail to heal. 20 Unfortunately, wounds that do not show a progression toward closure in the first few weeks of standard ulcer care have demonstrated a low probability for successful healing. 21 Even in the controlled setting of clinical trials aimed at healing persistent DFUs, the current standard of care results in low rates of healing. 3 In a meta-analysis of 10 control groups from clinical trials where the controls received good standard wound care, 24.2% of DFUs healed over 12 weeks (19.5%-28.8%) and 30.9% over 20 weeks (26.6%-35.1%). 22 Several adjunctive therapies have been investigated in an effort to improve the healing rate of DFUs and prevent the costly and debilitating complications of a chronic ulcer. Clinically, advanced therapies are often reserved for an advanced and poorly healing DFU. However, because clinical trials have shown that becaplermin, as well as two living-skin equivalents, accelerate DFU healing, the consensus recommendations state that advanced therapies should be considered as options early in the management of a DFU Treatment guideline bibliography Snyder RJ, Kirsner RS, Warriner RA, Lavery LA, Hanft JR, Sheehan P. Consensus recommendations on advancing the standard of care for treating neuropathic foot ulcers in patients with diabetes. Ostomy Wound Manage. 2010;56(4Suppl):S1-S24. Snyder RJ, Hanft JR. Diabetic foot ulcers effects on quality of life, costs, and mortality and the role of standard wound care and advanced-care therapies in healing: a review. Ostomy Wound Manage. 2009;55: Lipsky BA, Berendt AR, Cornia PB, et al. Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54(12):e132-e173. Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen. 2006;14:

12 PART 2 Pharmacology and biological action of growth factors in wound healing 2.1 Role of growth factors in healing Growth factors are required at each phase of healing (hemostasis, inflammation, proliferation, and remodeling) and are important during reestablishment of the integrity of the extracellular matrix, angiogenesis, and reepithelialization. 23,24 Analysis of wound fluid from chronic wounds, as compared with acute surgical wounds, demonstrates increased protease levels, increased proinflammatory cytokine levels, and a reduction in growth factor levels. 5 The prolonged inflammatory response in chronic wounds and an inflammatory cell population that differs from the cell population associated with acute injury impede cell proliferation and repair. 18 A series of multiple mechanisms, including decreased cell and growth factor response, leads to diminished peripheral blood flow and decreased endothelial cell proliferation, and contributes to the lack of wound healing in diabetes Role of PDGF in the healing process All phases of wound healing are controlled and regulated by growth factors. 23,26 Growth factors are released by cells that are important to wound healing, including platelets, macrophages, endothelial cells, keratinocytes, smooth muscle cells, and fibroblasts. Platelet-derived growth factor (PDGF) is an integral part of this healing process. In order for PDGF to affect would healing, it has to be present at the site of the wound, and the cells in the wound area must express PDGF receptors. Early observations revealed that PDGF is released by platelets and secreted by activated macrophages, thrombin-stimulated endothelial cells, smooth muscle cells of damaged arteries, activated fibroblasts, as well as by epidermal keratinocytes, suggesting that PDGF is indeed present in the wounded area. PDGF acts on several cell types involved in wound healing. It stimulates mitogenicity and chemotaxis of fibroblasts and smooth muscle cells and chemotaxis of neutrophils and macrophages. It also stimulates macrophages to produce and secrete other growth factors of importance for various phases in the healing process. Moreover, PDGF has been shown to stimulate production of several matrix molecules, such as fibronectin, collagen, proteoglycans, and hyaluronic acid. PDGF may also be of importance at later stages of wound healing because it stimulates contraction of collagen matrices in vitro, implicating a role in wound contraction in vivo. Moreover, PDGF stimulates the production and secretion of collagenase by fibroblasts, suggesting a role in the remodeling phase of wound healing

13 Table 2. Role of PDGF in the 4 Phases of Healing 23,24, PDGF Its composition PDGF is found in human platelets and is sequestered within specialized alpha granules. These alpha granules release PDGF from the platelet during clot formation or when the platelet comes in contact with a wettable surface. 28 PDGF is a dimeric protein of approximately 25 kda and composed of 2 disulfide-linked polypeptide chains. PDGF exists in 3 different isoforms: PDGF-AA (2 alpha chains), PDGF-AB (an alpha and a beta chain), and PDGF-BB (2 beta chains). 29 PDGF-AA induces αα-receptor homodimers, PDGF-AB induces ααreceptor homodimers or αβ-receptor heterodimers, and PDGF-BB induces all 3 dimeric combinations of α- and β-receptors. Because there are differences between α- and β-receptors in their binding specificity of PDGF isoforms and in the signals they transduce, the response of a cell to PDGF stimulation will be determined by which of the two receptor types the cell expresses PDGF-BB Its role in healing Activation of the β-receptor stimulates chemotaxis in cell types such as fibroblasts and smooth muscle cells, which, in turn, express both α- and β-receptors, but tend to express higher levels of β-receptors. In keeping with this understanding, the homodimer PDGF-BB has been shown in preclinical studies to promote the formation of granulation tissue at the wound site and to stimulate wound healing. 29 PDGF-BB initiates several steps of the healing process, including the stimulation of cell division, chemotaxis of fibroblasts and smooth muscle cells, chemotaxis of neutrophils and macrophages, and stimulation of macrophages to produce and secrete other growth factors necessary in the healing of chronic wound environments

14 PART 3 REGRANEX (becaplermin) Gel, 0.01% REGRANEX (becaplermin) Gel, 0.01% is a human platelet-derived growth factor that is indicated as an adjunct to good ulcer care for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and that have an adequate blood supply. 30 Becaplermin is a recombinant human PDGF-BB isoform in a sodium carboxymethylcellulose gel. 29 The efficacy of REGRANEX Gel has not been established for the treatment of pressure ulcers and venous stasis ulcers and has not been evaluated for the treatment of diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue (Stage I or II, IAET staging classification) or ischemic diabetic ulcers. 30 The effects of REGRANEX Gel on exposed joints, tendons, ligaments, and bone have not been established in humans. 30 Figure 5. A schematic representation of the PDGF-BB protein molecule 31 REGRANEX Gel is a non-sterile, low bioburden preserved product. Therefore, it should not be used in wounds that close by primary intention. 30 An analysis of DFU healing rates synthesized from the reported results of 4 clinical trials of becaplermin determined that administration of becaplermin gel, in conjunction with good wound care, increased the probability of healing by 39% compared with placebo gel (50% vs 36%) Please see Important Safety Information on page 5 and accompanying full Prescribing Information, including Boxed Warning and Medication Guide.

15 PART 4 Boxed Warning As with all growth factors, there is a potential risk for cell proliferation. In a retrospective study of a medical claims database, cancer rates and overall cancer mortality were compared between 1,622 patients who used REGRANEX Gel and 2,809 matched comparators. Estimates of the incidence rates reported below maybe under-reported due to limited follow-up for each individual. The incidence rate for all cancers was 10.2 per 1,000 person years for patients treated with REGRANEX Gel and 9.1 per 1,000 person years for the comparators. Adjusted for several possible confounders, the rate ratio was 1.2 (95% confidence interval ). Types of cancer varied and were remote from the site of treatment. The incidence rate for mortality from all cancers was 1.6 per 1,000 person years for those who received REGRANEX Gel and 0.9 per 1,000 person years for the comparators. The adjusted rate ratio was 1.8 (95% confidence interval ). 30 As a result, the FDA required the addition of the following Boxed Warning to the product information 30 : WARNING: INCREASED RATE OF MORTALITY SECONDARY TO MALIGNANCY An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. REGRANEX Gel should only be used when the benefits can be expected to outweigh the risks. REGRANEX Gel should be used with caution in patients with known malignancy. Indications and usage: REGRANEX (becaplermin) Gel is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. REGRANEX Gel is indicated as an adjunct to, and not a substitute for, good ulcer care practices. Limitations of use: The efficacy of REGRANEX Gel has not been established for the treatment of pressure ulcers and venous stasis ulcers The effects of REGRANEX Gel on exposed joints, tendons, ligaments, and bone have not been established in humans REGRANEX Gel is a non-sterile, low bioburden preserved product that should not be used in wounds that close by primary intention REGRANEX Gel is contraindicated in patients with known neoplasm(s) at the site(s) of application. REGRANEX Gel is contraindicated in patients with known hypersensitivity to any component of the product (e.g., parabens). Malignancies distant from the site of application have been reported in both a clinical study and in postmarketing use. In clinical trials, erythematous rashes occurred in 2% of patients treated with REGRANEX Gel or placebo; none occurred in patients receiving good ulcer care alone. Burning sensation at the site of application and erythema have been reported during post-approval use of REGRANEX Gel. 15

16 PART 5 Contraindications/warnings and precautions/drug interactions/ use in specific populations/clinical pharmacology/toxicology/patient counseling information 30 CONTRAINDICATIONS REGRANEX Gel is contraindicated in patients with known neoplasm(s) at the site(s) of application. WARNINGS AND PRECAUTIONS Cancer and Cancer Mortality REGRANEX Gel contains becaplermin, a recombinant human platelet-derived growth factor, which promotes cellular proliferation and angiogenesis. The benefits and risks of becaplermin treatment should be carefully evaluated before prescribing. Becaplermin should be used with caution in patients with a known malignancy. Malignancies distant from the site of application have occurred in becaplermin users in both a clinical study and postmarketing use, and an increased rate of death from systemic malignancies was seen in patients who have received 3 or more tubes of REGRANEX Gel. In a follow-up study, 491 (75%) of 651 subjects from two randomized, controlled trials of becaplermin gel 0.01% were followed for a median of approximately 20 months to identify malignancies diagnosed after the end of the trials. Eight of 291 subjects (3%) from the becaplermin group and two of 200 subjects (1%) from the vehicle/standard of care group were diagnosed with cancers during the follow-up period, a relative risk of 2.7 (95% confidence interval ). The types of cancers varied and all were remote from the treatment site. In a retrospective study of a medical claims database, cancer rates and overall cancer mortality were compared between 1,622 patients who used REGRANEX Gel and 2,809 matched comparators. Estimates of the incidence rates reported below may be under-reported due to limited follow-up for each individual. The incidence rate for all cancers was 10.2 per 1,000 person years for patients treated with REGRANEX Gel and 9.1 per 1,000 person years for the comparators. Adjusted for several possible confounders, the rate ratio was 1.2 (95% confidence interval ). Types of cancers varied and were remote from the site of treatment. The incidence rate for mortality from all cancers was 1.6 per 1,000 person years for those who received REGRANEX Gel and 0.9 per 1,000 person years for the comparators. The adjusted rate ratio was 1.8 (95% confidence interval ). The incidence rate for mortality from all cancers among patients who received 3 or more tubes of REGRANEX Gel was 3.9 per 1,000 person years and 0.9 per 1,000 person years in the comparators. The adjusted rate ratio for cancer mortality among those who received 3 or more tubes relative to those who received none was 5.2 (95% confidence interval ). Application Site Reactions If application site reactions occur, the possibility of sensitization or irritation caused by parabens or m-cresol should be considered. Consider interruption or discontinuation and further evaluation (eg, patch testing) as dictated by clinical circumstances. 16 Please see Important Safety Information on page 5 and accompanying full Prescribing Information, including Boxed Warning and Medication Guide.

17 DRUG INTERACTIONS It is not known if REGRANEX Gel interacts with other topical medications applied to the ulcer site. The use of REGRANEX Gel with other topical drugs has not been studied. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women treated with REGRANEX Gel. REGRANEX Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with REGRANEX Gel. Nursing Mothers It is not known whether becaplermin is excreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when REGRANEX Gel is administered to nursing women. Pediatric Use Safety and effectiveness of REGRANEX Gel in pediatric patients below the age of 16 years have not been established. Geriatric Use Among patients receiving any dose of REGRANEX Gel in clinical studies of diabetic lower extremity ulcers, 150 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients <65 years of age and patients 65 years of age. The number of patients aged 75 and older were insufficient (n=34) to determine whether they respond differently from younger patients. CLINICAL PHARMACOLOGY Mechanism of Action REGRANEX Gel has biological activity similar to that of endogenous platelet-derived growth factor, which includes promoting the chemotactic recruitment and proliferation of cells involved in wound repair and enhancing the formation of granulation tissue. Pharmacokinetics Ten patients with Stage III or IV (as defined in the International Association of Enterostomal Therapy (IAET) guide to chronic wound staging) lower extremity diabetic ulcers received topical applications of becaplermin gel 0.01% at a dose range of μg/kg (7 μg/cm 2 ) daily for 14 days. Six patients had non-quantifiable PDGF levels at baseline and throughout the study, two patients had PDGF levels at baseline, which did not increase substantially, and two patients had PDGF levels that increased sporadically above their baseline values during the 14- day study period. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Becaplermin was not genotoxic in a battery of in vitro assays (including those for bacterial and mammalian cell point mutation, chromosomal aberration, and DNA damage/repair). Becaplermin was also not mutagenic in an in vivo assay for the induction of micronuclei in mouse bone marrow cells. Carcinogenesis and reproductive toxicity studies have not been conducted with REGRANEX Gel. Animal Toxicology and/or Pharmacology In nonclinical studies, rats injected at the metatarsals with 3 or 10 mcg/site (approximately 60 or 200 mcg/kg) of becaplermin every other day for 13 days displayed histological changes indicative of accelerated bone remodeling consisting of periosteal hyperplasia and subperiosteal bone resorption and exostosis. The soft tissue adjacent to the injection site had fibroplasia with accompanying mononuclear cell infiltration reflective of the ability of PDGF to stimulate connective tissue growth. Pharmacodynamics Clinical pharmacodynamic studies have not been conducted. 17

18 PATIENT COUNSELING INFORMATION Counsel patients to review and discuss any questions or concerns with their healthcare provider before starting REGRANEX Gel and at regular intervals while receiving REGRANEX Gel. Patients should be advised that they should read the medication guide; hands should be washed thoroughly before applying REGRANEX Gel; the tip of the tube should not come into contact with the ulcer or any other surface; the tube should be recapped tightly after each use; a cotton swab, tongue depressor, or other application aid should be used to apply REGRANEX Gel; REGRANEX Gel should only be applied once a day in a carefully measured quantity. The measured quantity of gel should be spread evenly over the ulcerated area to yield a thin continuous layer of approximately 1/16 of an inch thickness. The measured length of the gel to be squeezed from the tube should be adjusted according to the size of the ulcer. The amount of REGRANEX Gel to be applied daily should be recalculated at weekly or biweekly intervals by the physician or wound care giver. Step-by-step instructions for application of REGRANEX Gel are as follows: Squeeze the calculated length of gel onto a clean, firm, nonabsorbable surface (eg, wax paper). With a clean cotton swab, tongue depressor, or similar application aid, spread the measured REGRANEX Gel over the ulcer surface to obtain an even layer. Cover with a saline moistened gauze dressing. After approximately 12 hours, the ulcer should be gently rinsed with saline or water to remove residual gel and covered with a saline-moistened gauze dressing (without REGRANEX Gel); It is important to use REGRANEX Gel together with a good ulcer care program, including a strict non-weight-bearing program; Excess application of REGRANEX Gel has not been shown to be beneficial; REGRANEX Gel should be stored in the refrigerator. Do not freeze REGRANEX Gel; REGRANEX Gel should not be used after the expiration date on the bottom, crimped end of the tube. Important Safety Information An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. 18 Please see Important Safety Information on page 5 and accompanying full Prescribing Information, including Boxed Warning and Medication Guide.

19 PART 6 Clinical efficacy 6.1 Phase 3 studies The importance of utilizing advanced therapies is well documented. Sometimes, however, clinicians use these therapies as a last resort, and may not be sure how soon to use them in the wound healing process. 3 The effects of REGRANEX Gel on the incidence of and time to complete healing in lower extremity diabetic ulcers were assessed in 4 randomized controlled studies. Of 922 patients studied, 478 received either REGRANEX Gel 0.003% or 0.01%. All study participants had lower extremity diabetic neuropathic ulcers that extended into the subcutaneous tissue or beyond (Stages III and IV of the IAET guide to chronic wound staging). A total of 93% of the patients enrolled in these 4 trials had foot ulcers. The remaining 7% of the patients had ankle or leg ulcers. The diabetic ulcers were of at least 8 weeks duration and had an adequate blood supply. In the 4 trials, the median ulcer size at baseline ranged from 1.4 cm 2 to 3.5 cm 2. All treatment groups received a program of good ulcer care consisting of initial complete sharp debridement, a nonweight-bearing regimen, systemic treatment for woundrelated infection if present, moist saline dressings changed twice a day, and additional debridement as necessary. Patients were treated until complete healing, or for a period of up to 20 weeks. Patients were considered a treatment failure if their ulcer did not show an approximately 30% reduction in initial ulcer area after 8 to 10 weeks of REGRANEX Gel therapy. The primary endpoint was incidence of complete ulcer closure within 20 weeks for all treatment arms. In each study, REGRANEX Gel in conjunction with good ulcer care was compared to placebo gel plus good ulcer care or good ulcer care alone. 30 Figure 6. Incidence of Complete Healing With REGRANEX Gel vs Placebo Gel Across 4 Studies 30 19

20 The following summaries in this section highlight the details from the becaplermin phase 3 studies. Summary of Steed DL et al. J Vasc Surg Steed and colleagues randomized 118 patients from 10 treatment centers in the US to receive either topical becaplermin 30 mcg/g or placebo gel. Participants had to have at least one infection-free ulcer with a surface area between 1 and 100 cm 2. One to 2 weeks before randomization, the target ulcer was given a complete sharp debridement to remove all callus, necrotic tissue, and chronic granulation tissue. For participants in both groups, further surgical debridement was performed on ulcers as required throughout the treatment period. Becaplermin gel or placebo gel was applied to the target ulcer every 24 hours at a dose equivalent to approximately 2.2 mcg of becaplermin per square centimeter of ulcer surface area for at least 20 weeks or until complete wound healing was achieved, whichever occurred first. Complete healing was the primary endpoint and defined as 100% wound closure, no drainage present, and no dressing required. Patients (or caregivers) were instructed on the procedure for study gel application, dressing changes, and good wound care, and were then followed as outpatients. Sixty-one patients were randomized to receive becaplermin and 57 patients were randomized to receive placebo. There were no statistically significant differences between the 2 groups with respect to race, duration of ulcer, area of ulcer, and transcutaneous partial pressure of oxygen at the dorsum and wound edge. Fourteen of 61 (23%) becaplermin-treated patients and 18 of 57 (31.6%) placebo-treated patients discontinued the study before complete wound healing or 20 weeks of treatment. 32 Complete wound healing was significantly greater in patients randomized to receive becaplermin compared with patients who received treatment with placebo. Twenty-nine of 61 (48%) patients in the becaplermin treatment group achieved complete wound healing during the study compared with only 14 of 57 (25%) patients in the placebo treatment group (P=0.01). The median reduction in wound area in the treatment group was 98.8% compared with 82.1% in the group given placebo (P=0.09), and the rate of healing was significantly faster in the becaplermin treatment group compared to the placebo treatment group. From approximately Day 68 through the trial end, the becaplermin group demonstrated a 30- to 40-day decreased difference in time to complete wound healing compared with the placebo treatment group (P=0.01). 32 When comparing the 2 treatment groups, there was no statistical difference in the number of times debridement was performed. A trend toward a greater recurrence rate of the target ulcer in the placebo treatment group (46%) compared with the becaplermin treatment group (26%) after a mean follow-up of 8.6 weeks did not reach statistical significance. 32 Summary of Wieman TJ et al. Diabetes Care A multicenter, double-blind, placebo-controlled trial by Wieman and colleagues evaluated 2 concentrations of becaplermin gel, 30 mcg/g and 100 mcg/g against a placebo gel in a randomized phase 3 trial. A total of 382 patients with lower extremity ulcers who met the inclusion criteria from 23 treatment centers in the US participated in the study. Prior to randomization, sharp debridement was performed to remove all nonviable tissue and callus. Following debridement, patients were excluded if osteomyelitis was present or if the target ulcer was less than 1 cm, greater than 40 cm, or had a surface area greater than 100 cm 2. Standard good wound care, including sharp debridement, was provided as needed to all participants throughout the study period. Patients were randomized to 1 of 3 parallel treatment groups with one group (n=124) treated with becaplermin 30 mcg/g, a second group (n=132) treated with becaplermin 100 mcg/g, and a third group (n=127) treated with a gel formulation that was identical to the one containing becaplermin. The primary efficacy endpoint was the percentage of patients with complete ulcer healing at the end of the 20-week study period, and the secondary endpoint was the time to achieve complete healing. 33 Important Safety Information An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. 20 Please see Important Safety Information on page 5 and accompanying full Prescribing Information, including Boxed Warning and Medication Guide.

21 Of the 382 patients originally randomized to 1 of the 3 treatment groups, 309 (81%) completed the study, and there were no clinically significant differences among the demographics of the 3 treatment groups. Comparisons between the placebo treatment group and the becaplermin 100 mcg/g treatment group demonstrated a significant increase in complete wound closure of 43% (50 vs 35%, P=0.007). The time to achieve complete wound closure in the becaplermin 100 mcg/g treated group was an average of 86 days compared with an average of 127 days for the patients in the placebotreated group. This was a significant decrease in the time to achieve complete wound closure of 32% (estimated 35th percentile, P=0.013) for the higher concentration of becaplermin compared with placebo. 33 Figure 7. Average Healing Time of Becaplermin Gel vs. Placebo Gel in Pivotal Study 33 Study design: The efficacy and safety of REGRANEX Gel were studied in 382 patients with type 1 or type 2 diabetes in a multicenter, double-blind, parallel-group, placebo-controlled trial. Patients had at least one full-thickness chronic ulcer of the lower extremity. After sharp debridement of the ulcer, patients were randomized to receive REGRANEX Gel or placebo gel, in conjunction with good ulcer care, until complete wound closure was achieved or for a maximum of 20 weeks. To assess rate of closure, study visits were scheduled weekly for Visits 2-6 and every other week after Visit Summary of d Hemecourt PA et al. Wounds A 10-center, parallel-group study was conducted by d Hemecourt in 172 patients who were randomized using a 2:2:1 ratio to receive a standardized regimen of good wound care alone (n=68), good wound care plus an aqueous gel (n=70), or good wound care plus becaplermin gel 100 mcg/g (n=34). The aqueous gel treatment group and the becaplermin treatment group were double-blinded, and the group that received good wound care alone was blinded to the evaluator by a third party. In the becaplermin gel 100 mcg/g and aqueous gel treatment groups, a thin layer of the corresponding gel was applied once daily at the morning dressing change for a maximum of 20 weeks or until the target ulcer was completely healed. The study was designed to assess safety and efficacy. The primary efficacy endpoint was percent of patients achieving complete wound closure without drainage or need for dressing. Secondary efficacy measures included time to achieve complete wound closure and relative size of ulcer area from baseline to endpoint. Of the 172 intent-to-treat population randomly assigned, the demographic and baseline target ulcer characteristics were similar for all 3 treatment groups. Of the 68 patients receiving good wound care alone, 15 (22%) achieved complete wound closure at endpoint compared with 25 (36%) of patients treated with the aqueous gel, and 15 (44%) of the 34 patients receiving becaplermin. Time to achieve complete wound closure was shortest for the becaplermin treatment group (85 days), followed by the aqueous gel treatment group (98 days), and longest for the good wound care alone treatment group (>141 days). 34 Summary of Smiell JM. Wound Repair Regen The fourth clinical trial results were reported by Smiell and colleagues who conducted a combined analysis of the 3 trials discussed above (n=922), with the results of a fourth multicenter, randomized, parallel-group study (n=250). Comparison groups were those treated with a standardized regimen of good ulcer care alone, good ulcer care plus placebo gel, good ulcer care plus becaplermin gel 30 mcg/g, or good ulcer care plus becaplermin gel 100 mcg/g, with various combinations 21

22 of these regimens among the 4 studies. Statistical techniques were used in the combined analysis to establish homogeneity of treatment comparisons across studies. The primary outcome was a more precise assessment of the efficacy of becaplermin gel, with a focus on the difference between becaplermin 100 mcg/g and placebo gel. 29 Homogeneity of treatment responses across the 4 studies was established for intent-to-treat population who had a baseline ulcer area of less than 10 cm 2. (n=874; 95%), and subsequent combined analyses were based on this population subgroup. The higher concentration of becaplermin of 100 mcg/g compared with placebo gel demonstrated a significantly greater probability of complete healing (P=0.007). Treatment with becaplermin gel 100 mcg/g significantly decreased the time to heal, with the 35th percentile of time to healing 30% faster compared with treatment with placebo gel (14.1 weeks vs 20.1 weeks, respectively; Kaplan-Meier estimates) Adverse reactions Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 30 In a follow-up study from two randomized, controlled trials, an increased rate of cancer remote from the becaplermin treatment site was observed in subjects treated with REGRANEX Gel. 30 In clinical trials, erythematous rashes occurred in 2% of patients treated with REGRANEX Gel (and good ulcer care) or placebo (and good ulcer care), and none in patients receiving good ulcer care alone. Patients treated with REGRANEX Gel did not develop neutralizing antibodies against becaplermin. 30 Clinical trial data also indicate that treatment with becaplermin gel was associated with adverse events that were similar in incidence and severity across all study groups. In a pivotal clinical trial, 382 patients were evaluated for safety, including patients receiving becaplermin 100 mcg/g, becaplermin gel 30 mcg/g, and placebo gel. All patients also received standard good wound care. Treatment-emergent adverse events were generally related to the DFU or the patients diabetes, and the most common events were infection, cellulitis, skin ulceration, and osteomyelitis. 33 Postmarketing Experience An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. Burning sensation and erythema have been reported during post-approval use of REGRANEX Gel. Because post-approval adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. 30 Important Safety Information An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. 22 Please see Important Safety Information on page 5 and accompanying full Prescribing Information, including Boxed Warning and Medication Guide.