REGRANEX (Page 2 of 4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on REGRANEX use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with REGRANEX.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

There are no data on the presence of becaplermin in human milk, the effects on the breastfed infant, or the effects on milk production after topical application of REGRANEX to lactating women. The developmental and health benefits of breastfeeding should be considered along with the lactating woman’s clinical need for REGRANEX and any potential adverse effects on the breastfed child from becaplermin.

8.4 Pediatric Use

Safety and effectiveness of REGRANEX in pediatric patients below the age of 16 years have not been established.

8.5 Geriatric Use

Among subjects receiving any dose of REGRANEX in clinical studies of diabetic lower extremity ulcers, 150 subjects were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. The number of subjects aged 75 and older was insufficient (n=34) to determine whether they respond differently from younger subjects.

10 OVERDOSAGE

There are no data on the effects of REGRANEX overdose.

11 DESCRIPTION

REGRANEX contains becaplermin, a recombinant human platelet-derived growth factor, for topical administration. Becaplermin is produced by recombinant DNA technology by insertion of the gene for the B chain of platelet-derived growth factor (PDGF) into the yeast, Saccharomyces cerevisiae.

Becaplermin has a molecular weight of approximately 25 kD and is a homodimer composed of two identical polypeptide chains that are bound together by disulfide bonds. REGRANEX is a non-sterile, low bioburden, preserved, sodium carboxymethylcellulose-based (CMC) topical gel, containing the active ingredient becaplermin and the following inactive ingredients: carboxymethylcellulose sodium, glacial acetic acid, l-lysine hydrochloride, m-cresol, methylparaben, propylparaben, sodium acetate trihydrate, sodium chloride, and water for injection. Each gram of REGRANEX contains 100 mcg of becaplermin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

REGRANEX 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.

12.2 Pharmacodynamics

Clinical pharmacodynamic studies have not been conducted.

12.3 Pharmacokinetics

Ten subjects 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 0.32–2.95 mcg/kg (7 mcg/cm2) daily for 14 days. Six subjects had non-quantifiable PDGF levels at baseline and throughout the study, two subjects had PDGF levels at baseline which did not increase substantially, and two subjects had PDGF levels that increased sporadically above their baseline values during the 14-day study period.

13 NONCLINICAL TOXICOLOGY

13.1 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.

13.2 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.

14 CLINICAL STUDIES

14.1 Efficacy in Diabetic Lower Extremity Ulcers

The effects of REGRANEX on the incidence of and time to complete healing in lower extremity diabetic neuropathic ulcers were assessed in four randomized controlled studies (Studies 1-4). Of 922 subjects studied, 478 received either REGRANEX 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 International Association of Enterostomal Therapy (IAET) guide to chronic wound staging]. Ninety-three percent of the subjects enrolled in these four trials had foot ulcers. The remaining 7% of the subjects had ankle or leg ulcers. The diabetic ulcers were of at least 8 weeks duration and had an adequate blood supply (defined as Tc pO2 > 30 mm Hg). In the four trials, 95% of the ulcers measured in area up to 10 cm2 , and the median ulcer size at baseline ranged from 1.4 cm2 to 3.5 cm2.

All treatment groups received a program of good ulcer care consisting of initial complete sharp debridement, a non-weight-bearing regimen, systemic treatment for wound-related infection if present, moist saline dressings changed twice a day, and additional debridement as necessary. REGRANEX 0.003% or 0.01% or placebo was applied once a day and covered with a saline moistened dressing. After approximately 12 hours, the gel was gently rinsed off and a saline moistened dressing was then applied for the remainder of the day. Subjects were treated until complete healing, or for a period of up to 20 weeks. Subjects were considered a treatment failure if their ulcer did not show an approximately 30% reduction in initial ulcer area after eight to ten weeks of therapy.

Results of the primary endpoints from 4 independent studies, shown as incidence of complete ulcer closure within 20 weeks, for all treatment arms are given in Figure 1. In each study, REGRANEX in conjunction with good ulcer care was compared to placebo gel plus good ulcer care or good ulcer care alone.

In Study 1, a multicenter, double-blind, placebo-controlled trial of 118 subjects, the incidence of complete ulcer closure for REGRANEX 0.003% (n=61) was 48% versus 25% for placebo gel (n=57; p=0.02, logistic regression analysis).

In Study 2, a multicenter, double-blind, placebo-controlled trial of 382 subjects, the incidence of complete ulcer closure for REGRANEX 0.01% (n=123) was 50% versus 36% for REGRANEX 0.003% (n=132) and 35% for placebo gel (n=127). Only REGRANEX 0.01% was significantly different from placebo gel (p=0.01, logistic regression analysis).

The primary goal of Study 3, a multicenter controlled trial of 172 subjects, was to assess the safety of vehicle gel (placebo; n=70) compared to good ulcer care alone (n=68). The study included a small (n=34) REGRANEX 0.01% arm. Incidences of complete ulcer closure were 44% for REGRANEX, 36% for placebo gel and 22% for good ulcer care alone.

In Study 4, a multicenter, evaluator-blind, controlled trial of 250 subjects, the incidences of complete ulcer closure in the REGRANEX 0.01% arm (n=128) (36%) and good ulcer care alone (n=122) (32%) were not statistically different.

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In general, where REGRANEX was associated with higher incidences of complete ulcer closure, differences in the incidence first became apparent after approximately 10 weeks and increased with continued treatment (Table 3).

Table 3: Life Table Estimates of the Incidence (%) of Complete Diabetic Lower Extremity Ulcer Healing over Time of Study 2

REGRANEX

Gel 0.01%

(%)

Placebo

(%)

Week 2

1

0

Week 4

6

2

Week 6

9

6

Week 8

16

14

Week 10

23

18

Week 12

34

25

Week 14

37

28

Week 16

43

33

Week 18

46

34

Week 20

50

37

In a 3-month follow-up period where no standardized regimen of preventative care was utilized, the incidence of ulcer recurrence was approximately 30% in all treatment groups, demonstrating that the durability of ulcer closure was comparable in all treatment groups.

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