Regranex Gel 0.01%

1 INDICATIONS AND USAGE REGRANEX 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, when used as an adjunct to, and not a substitute for, good ulcer care practices including initial sharp debridement, pressure relief and infection control. Limitations of Use: The efficacy of REGRANEX has not been established for the treatment of pressure ulcers and venous stasis ulcers [ see Clinical Studies ( 14.2 ) ] 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, International Association of Enterostomal Therapy (IAET) staging classification] or ischemic diabetic ulcers. The effects of becaplermin on exposed joints, tendons, ligaments, and bone have not been established in humans [ see Nonclinical Toxicology ( 13.2 ) ]. REGRANEX is not intended to be used in wounds that close by primary intention. REGRANEX is a human platelet-derived growth factor 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 is indicated as an adjunct to, and not a substitute for, good ulcer care practices. ( 1 ) Limitations of Use: The efficacy of REGRANEX has not been established for the treatment of pressure ulcers and venous stasis ulcers. ( 1 ) The effects of REGRANEX on exposed joints, tendons, ligaments, and bone have not been established in humans. ( 1 ) REGRANEX is not intended to be used in wounds that close by primary intention. ( 1 )

2 DOSAGE AND ADMINISTRATION REGRANEX is for topical use; it is not for oral, ophthalmic or intravaginal use. The amount of REGRANEX to be applied depends upon the size of the ulcer area. To calculate the length of gel to apply to the ulcer, measure the greatest length of the ulcer by the greatest width of the ulcer in either inches or centimeters. To calculate the length of gel in inches, use the formula shown below in Table 1, and to calculate the length of gel in centimeters, use the formula shown below in Table 2. Table 1: Formula to Calculate Length of Gel in Inches to Be Applied Daily Tube Size INCHES Formula 15 g tube length × width × 0.6 Using the calculation, each square inch of ulcer surface will require approximately 2/3 inch length of gel squeezed from a 15 g tube. For example, if the ulcer measures 1 inch by 2 inches, then a 1 1/4 inch length of gel should be used for 15 g tubes (1 x 2 x 0.6 = 1 1/4). Table 2: Formula to Calculate Length of Gel in Centimeters to Be Applied Daily Tube Size CENTIMETERS Formula 15 g tube length × width ÷ 4 Using the calculations for ulcer size in centimeters, each square centimeter of ulcer surface will require approximately a 0.25 centimeter length of gel squeezed from a 15 g tube. For example, if the ulcer measures 4 cm by 2 cm, then a 2 cm length of gel should be used for a 15 g tube [(4 x 2) ÷ 4 = 2]. The amount of REGRANEX to be applied should be recalculated by the physician or wound caregiver at weekly or biweekly intervals depending on the rate of change in ulcer area. The weight of REGRANEX from 15 g tubes is 0.65 g per inch length and 0.25 g per centimeter length. To apply REGRANEX, the calculated length of gel should be squeezed on to a clean measuring surface, e.g., wax paper, and measured to the correct length with a ruler. The measured REGRANEX is transferred from the clean measuring surface using an application aid and then spread over the entire cleaned ulcer area to yield a thin continuous layer of approximately 1/16 of an inch thickness. The site(s) of application should then be covered by a saline moistened gauze dressing and left in place for approximately 12 hours. The dressing should then be removed and the ulcer rinsed with saline or water to remove residual gel and covered again with a moist primary dressing (without REGRANEX gel) for the remainder of the day. REGRANEX should be applied once daily to the ulcer until complete healing has occurred. If the ulcer does not decrease in size by approximately 30% after 10 weeks of treatment or complete healing has not occurred in 20 weeks, continued treatment with REGRANEX should be reassessed. The step-by-step instructions for applying REGRANEX in a home care setting can be found in the FDA-approved Instructions for Use. For topical use; not for oral, ophthalmic or intravaginal use. ( 2 ) To calculate the length of REGRANEX to apply, measure the greatest length of the ulcer by greatest width of the ulcer in either inches or centimeters. ( 2 ) Formula to Calculate Length of Gel to Be Applied Daily Tube Size Formula 15 g Tube Inches: ulcer length x ulcer width x 0.6 15 g Tube Centimeters: ulcer length x ulcer width ÷ 4

5 WARNINGS AND PRECAUTIONS Malignancies distant from the site of application have been reported in both a clinical study and in postmarketing use. ( 5.1 ) The benefits and risks of REGRANEX treatment should be carefully evaluated before prescribing in patients with known malignancy. ( 5.1 ) 5.1 Risk of Cancer REGRANEX contains becaplermin, a recombinant human platelet-derived growth factor, which promotes cellular proliferation and angiogenesis [ see Clinical Pharmacology ( 12.1 ) ]. Malignancies distant from the site of application have occurred in REGRANEX users in a clinical study and in postmarketing use [ see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.3 ) ]. The benefits and risks of REGRANEX treatment should be carefully evaluated before prescribing in patients with known malignancy. 5.2 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 (e.g. patch testing) as dictated by clinical circumstances.

4 CONTRAINDICATIONS REGRANEX is contraindicated in patients with known neoplasm(s) at the site(s) of application. Known neoplasm(s) at the site(s) of application ( 4 )

7 DRUG INTERACTIONS It is not known if REGRANEX interacts with other topical medications applied to the ulcer site. The use of REGRANEX with other topical drugs has not been studied.

6 ADVERSE REACTIONS Erythematous rashes occurred in 2% of patients treated with REGRANEX. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch, or Lynch Regenerative Medicine, LLC at 1-888-576-7343 6.1 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. In clinical trials, erythematous rashes occurred in 2% of subjects treated with REGRANEX (and good ulcer care) or placebo (and good ulcer care), and none in subjects receiving good ulcer care alone. Subjects treated with REGRANEX did not develop neutralizing antibodies against becaplermin. In a retrospective follow-up study of 491 of 651 subjects (75%) from two randomized, controlled trials of another formulation of becaplermin gel 0.01%, the subjects were followed for a median of approximately 20 months to evaluate safety and recurrence of healed diabetic lower extremity ulcers. Eight of 291 subjects (2.7%) from the becaplermin gel 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 [CI], 0.6-12.8). The types of cancers varied and all were remote from the treatment site [see Warnings and Precautions ( 5.1 )] . 6.2 Postmarketing Experience 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. The following adverse reactions have been identified during post approval use of REGRANEX. Increased rate of death from systemic malignancies in patients dispensed 3 or more tubes of REGRANEX was observed in one of three retrospective postmarketing studies [ see Clinical Studies ( 14.3 ) ]. Burning sensation and erythema at the site of application have been reported.