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)andClinical 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.

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.

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.

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/cm 2) 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Becaplermin was not genotoxic in a battery of in vitroassays (including those for bacterial and mammalian cell point mutation, chromosomal aberration, and DNA damage/repair). Becaplermin was also not mutagenic in an in vivoassay 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.

14.1 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 T cpO 2> 30 mm Hg). In the four trials, 95% of the ulcers measured in area up to 10 cm 2, and the median ulcer size at baseline ranged from 1.4 cm 2to 3.5 cm 2.

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.

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).

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.

14.2 Lack of Efficacy in Pressure Ulcers and Venous Stasis Ulcers

In a randomized, double-blind study of REGRANEX (100 mcg/g once daily for 16 weeks) in subjects with Stage III or IV pressure ulcers, the incidence of complete ulcer closure was 15% (28/189) in the REGRANEX group and 12% (22/190) in the vehicle control group. This difference was not statistically significant.

In two small, randomized, double-blinded studies of REGRANEX (100 mcg/g once daily for 16 weeks) in subjects with venous stasis ulcers, the combined incidence of complete ulcer closure was 46% (30/65) in the REGRANEX group and 39% (26/67) in the vehicle control group. This difference was not statistically significant.

14.3 Observational Studies to Evaluate Cancer Development and Mortality

The observational studies described below do not involve random allocation of treatments. They are susceptible to bias and confounding.

A retrospective study using medical claims database to assess cancer incidence with up to 6 years of follow-up observed development of 28 cancers and 8 cancer deaths in the REGRANEX exposed cohort (n = 1,622) and 43 cancers and 8 cancer deaths in the matched comparator cohort not exposed to REGRANEX (n = 2,809). The rate ratio for incident cancer comparing the REGRANEX-exposed cohort to the unexposed comparator cohort was 1.2 (95% CI, 0.7 -1.9). The rate ratio for cancer mortality comparing the REGRANEX-exposed cohort to the unexposed comparator cohort was 1.8 (95% CI, 0.7 -4.9). The rate ratio comparing patients exposed to three or more tubes of REGRANEX to those not exposed was 5.2 (95% CI, 1.6 -17.6) [see Adverse Reactions (6.2)].

A retrospective study using medical claims from the Veteran Affairs health care database with up to 11 years of follow-up among patients withoutprior cancer observed 197 cancer deaths in the REGRANEX exposed cohort (n = 6,429) and 206 cancer deaths in the matched comparator cohort not exposed to REGRANEX (n = 6,429), resulting in a hazard ratio of 0.9 (95% CI, 0.8-1.2). The hazard ratio for cancer mortality comparing patients exposed to three or more tubes of REGRANEX to those not exposed was 1.0 (95% CI, 0.7 -1.5). The hazard ratio for incident cancer in a smaller cohort (1,507 REGRANEX-exposed and 1,507 unexposed patients) comparing patients exposed to REGRANEX to those not exposed was 1.1 (95% CI, 0.8-1.4).

A second retrospective study using medical claims from the Veteran Affairs health care database with up to 11 years of follow-up among patients withprior cancer observed 87 cancer deaths in the REGRANEX-exposed cohort (n = 477) and 340 cancer deaths in the matched comparator cohort not exposed to REGRANEX (n = 1,756), resulting in a hazard ratio of 0.9 (95% CI, 0.7-1.2). The hazard ratio for cancer mortality comparing patients exposed to three or more tubes of REGRANEX to those not exposed was 0.9 (95% CI, 0.6 -1.2).