Boxed Warning, increased rate of cancer mortality (5.11) Removed 11/2018

Warnings and Precautions, cancer mortality (5.11) Removed 11/2018

Revised inactive ingredient names Revised 11/2022

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.

The efficacy of REGRANEX has not been established for the treatment of pressure ulcers and venous stasis ulcers [see Clinical Studies /14.2)1 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 11, 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 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 lo 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.

INCHES

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Tube Size Formula

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15 g tube length x width x 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 l / 4 inch length of gel should be used for

15 g tubes 11 x 2 x 0.6 = 1 1/4).

CENTIMETERS

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Tube Size Formula

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15 g tube length x 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 [14 x 21 + 4 = 21. 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 0.65g per inch length and 0.25 g per centimeter length.

To apply REGRANEX, the calculated length of gel should be squeezed on to a ciean 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.

Gel: 0.01%; Clear, colorless to straw-colored.

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

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.

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.

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.

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.

To report SUSPECTED ADVERSE REACTIONS contact FDA at 1-800-322-1088 or www.fda.gov/medwatch, or Smith & Nephew, Inc. at 1-800-441-8227.

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.

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.

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.

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

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 ln=341 to determine whether they respond differently from younger subjects.

here are no data on the effects of REGRANEX overdose.

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 IPDGF) into the yeast,

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, acetic acid, lysine hydrochloride, metacresol, methylparaben, propylparaben, sodium acetate, sodium chloride, and purified water. Each gram of REGRANEX contains 100 mcg of becaplermin.

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.

Clinical pharmacodynamic studies have not been conducted.

Ten subjects with Stage Ill or IV [as defined in the International Association of Enterostomal Therapy IIAETI 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 17 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.

Becaplermin was not genotoxic in a battery of

In nonclinical studies, rats injected at the metatarsals with 3 orl0 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.

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 Ill 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 TcpO2 > 30 mm Hg). In the four trials, 95% of the ulcers measured in area up to 10 cm

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=123I was 50% versus 36% for REGRANEX 0.003% (n=132) and 35% for placebo gel (n=127I. 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=70I compared to good ulcer care alone (n=681. 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=128I (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.

In a randomized, double-blind study of REGRANEX 1100 mcg/g once daily for 16 weeks) in subjects with Stage Ill 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 1100 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.

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% Cl, 0.7 -1.9). The rate ratio for cancer mortality comparing the REGRANEX-exposed cohort to the unexposed comparator cohort was l.8 (95% Cl, 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% Cl, 1.6 -17.61 [see Adverse Reactions /6.2/J. A retrospective study using medical claims from the Veteran Affairs health care database with up to 11 years of follow-up among patients without prior 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% Cl, 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% Cl, 0.7 -1.5). The hazard ratio for incident cancer in a smaller cohort 11,507 REGRANEX-exposed and 1,507 unexposed patients) comparing patients exposed to REGRANEX to those not exposed was 1.1 (95% Cl, 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 with prior 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% Cl, 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% Cl, 0.6 -1.2).

REGRANEX (0.01%) is clear, colorless to straw-colored and is available in multi-use tubes in the following size:

15 g tube NOC 50484-810-15

Store refrigerated at 2° - 8° C (36 ° - 46 ° F). Do not freeze.

What is the most important information I should know about REGRANEX?

REGRANEX may cause serious side effects, including:

REGRANEX is a prescription medicine that is used with good ulcer care practice for the treatment of diabetic sores (ulcers) of your legs or feet that are deeper than just your skin, in people who have good blood supply to the legs and feet.

It is not known if REGRANEX is effective for the treatment of pressure ulcers or ulcers that are due to poor blood flow (circulation).

It is not known if REGRANEX is safe and effective in children under 16 years of age.

REGRANEX may cause serious side effects.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Smith & Nephew, Inc. at 1-800-441-8227.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use REGRANEX for a condition for which it was not prescribed. Do not give REGRANEX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about REGRANEX that is written for health professionals.