REGRANEX® Gel contains becaplermin, a recombinant human platelet-derived growth factor (rhPDGF-BB) 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 poly-peptide chains that are bound together by disulfide bonds. Becaplermin Concentrate is produced by Novartis Vaccines and Diagnostics, Inc. and supplied to OMJ Pharmaceuticals under a shared manufacturing arrangement. REGRANEX Gel is a non-sterile, low biobur-den, preserved, sodium carboxymethylcellulose-based (CMC) topical gel, containing the active ingredient becaplermin and the following inactive ingredients: sodium chloride, sodium acetate trihydrate, glacial acetic acid, water for injection, and methyl-paraben, propylparaben, and m-cresol as preservatives and l-lysine hydrochloride as a stabilizer. Each gram of REGRANEX Gel contains 100 μg of becaplermin.

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. When used as an adjunct to, and not a substitute for, good ulcer care practices including initial sharp debridement, pressure relief and infection control, REGRANEX Gel increases the incidence of complete healing of diabetic ulcers.

The efficacy of REGRANEX Gel has not been established for the treatment of pressure ulcers and venous stasis ulcers (see Clinical Studies) 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.

The amount of REGRANEX Gel to be applied will vary depending 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 2, and to calculate the length of gel in centimeters, use the formula shown below in Table 3.

Table 2: Formula to Calculate Length of Gel in Inches to be Applied Daily

Using the calculation, each square inch of ulcer surface will require approximately ²/₃ inch length of gel squeezed from a 15g tube, or approximately 1¹/₃ inch length of the gel from a 2g tube. For example, if the ulcer measures 1 inch by 2 inches, then a 1¼ inch length of gel should be used for 15g tubes (1 X 2 X 0.6 = 1¼) and 2¾ inch gel length should be used for a 2g tube (1 X 2 X 1.3 = 2¾).

Table 3: Formula to Calculate Length of Gel in Centimeters to be Applied Daily

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 15g tube, or approximately a 0.5 centimeter length of gel from a 2g tube. For example, if the ulcer measures 4 cm by 2 cm, then a 2 centimeter length of gel should be used for a 15g tube [(4 X 2) ÷4 = 2] and a 4 centimeter length of gel should be used for a 2g tube [(4 X 2) ÷2 = 4].

The amount of REGRANEX Gel 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 Gel from 15g tubes is 0.65g per inch length and 0.25g per centimeter length.

To apply REGRANEX Gel, the calculated length of gel should be squeezed on to a clean measuring surface, e.g., wax paper. The measured REGRANEX Gel is transferred from the clean measuring surface using an application aid and then spread over the entire 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 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 second moist dressing (without REGRANEX Gel) for the remainder of the day. REGRANEX Gel 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 Gel should be reassessed. The step-by-step instructions for applying REGRANEX Gel for home administration are described under “Information for Patients”.

REGRANEX (becaplermin) Gel, supplied as a clear, colorless to straw-colored preserved gel containing 100μg of becaplermin per gram of gel, is available in multi-use tubes in the following sizes:

REGRANEX Gel is for external use only.

Storage

Store refrigerated, 2-8°C (36-46°F). DO NOT FREEZE. DO NOT USE THE GEL AFTER THE EXPIRATION DATE AT THE BOTTOM OF THE TUBE.

Manufactured by: OMJ Pharmaceuticals, Inc. San German, Puerto Rico 00683. Manufactured for: Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ 08869. Becaplermin Concentrate provided by: Novartis Vaccines and Diagnostics, Inc. Emeryville, CA 94608. Revised: May 2008. FDA revision date: 10/16/2008

Patients receiving REGRANEX (becaplermin) Gel, placebo gel, and good ulcer care alone had a similar incidence of ulcer-related adverse events such as infection, cellulitis, or osteomyelitis. However, erythematous rashes occurred in 2% of patients treated with REGRANEX Gel and placebo, and none in patients receiving good ulcer care alone. The incidence of cardiovascular, respiratory, musculoskeletal and central and peripheral nervous system disorders was not different across all treatment groups. Patients treated with REGRANEX Gel did not develop neutralizing antibodies against becaplermin.

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.

REGRANEX Gel contains becaplermin, a recombinant human platelet-derived growth factor, which promotes cellular proliferation and angiogenesis. (See CLINICAL PHARMACOLOGY). 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 in 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 0.6-12.8). 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 rate reported below may be underreported 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 0.7-1.9). 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 0.7- 4.9).
• 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 1.6-17.6). (See BOXED WARNING).

REGRANEX Gel is a non-sterile, low bioburden preserved product. Therefore, it should not be used in wounds that close by primary intention.

For external use only.

If application site reactions occur, the possibility of sensitization or irritation caused by parabens or m-cresol should be considered.

The effects of becaplermin on exposed joints, tendons, ligaments, and bone have not been established in humans. In preclinical studies, rats injected at the metatarsals with 3 or 10 μg/site (approximately 60 or 200 μg/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.

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.

Pregnancy: Category C

Animal reproduction studies have not been conducted with REGRANEX Gel. It is also not known whether REGRANEX Gel can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. REGRANEX Gel should be given to pregnant women only if clearly needed.

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.

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.

Pediatric Use

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

No information provided.

REGRANEX (becaplermin) Gel is contraindicated in patients with:

• known hypersensitivity to any component of this product (e.g., parabens);
• known neoplasm(s) at the site(s) of application.

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, J. Enterostomal Ther 15:4, 1988 and Decubitis 2:24, 1989) lower extremity diabetic ulcers received topical applications of becaplermin gel 0.01% at a dose range of 0.32-2.95 μg/kg (7μg/cm²) 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.

Systemic bioavailability of becaplermin was less than 3% in rats with full thickness wounds receiving single or multiple (5 days) topical applications of 127 μg/kg (20.1 μg/cm²of wound area) of becaplermin gel.

Clinical Studies

The effects of REGRANEX Gel on the incidence of and time to complete healing in lower extremity diabetic ulcers were assessed in four 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). Ninety-three percent of the patients enrolled in these four 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 (defined as TcpO₂ > 30 mm Hg). In the four trials, ninety-five percent of the ulcers measured in area up to 10 cm², and the median ulcer size at baseline ranged from 1.4 cm²to 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 debride-ment as necessary. REGRANEX Gel 0.003% or 0.01% or placebo gel 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. 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 eight to ten weeks of REGRANEX Gel therapy.

The primary endpoint, incidence of complete ulcer closure within 20 weeks, for all treatment arms is shown in Figure 1. 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.

In Study 1, a multicenter, double-blind, placebo controlled trial of 118 patients, the incidence of complete ulcer closure for REGRANEX Gel 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 patients, the incidence of complete ulcer closure for REGRANEX Gel 0.01% (n=123), was 50% versus 36% for REGRANEX Gel 0.003% (n=132), and 35% for placebo gel (n=127). Only REGRANEX Gel 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 patients, 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 Gel 0.01% arm. Incidences of complete ulcer closure were 44% for REGRANEX Gel, 36% for placebo gel and 22% for good ulcer care alone.

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

Figure 1: Incidence of Complete Healing

In general, where REGRANEX Gel 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 1).

Table 1: Life Table Estimates of the Incidence (%) of Complete Healing Over Time for Study 2

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 Gel (100 mcg/g once daily for 16 weeks) in patients with Stage III or IV pressure ulcers, the incidence of complete ulcer closure was 15% (28/189) in the becaplermin 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 Gel (100 mcg/g once daily for 16 weeks) in patients with venous stasis ulcers, the combined incidence of complete ulcer closure was 46% (30/65) in the becaplermin group and 39% (26/67) in the vehicle control group. This difference was not statistically significant.

Patients should be advised that:

• 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 RE-GRANEX Gel;
• REGRANEX Gel should only be applied once a day in a carefully measured quantity (see DOSAGE AND ADMINISTRATION section). 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 on to a clean, firm, non-absorbable surface, e.g., 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 REGRANEXGel;
  • REGRANEX Gel should not be used after the expiration date on the bottom, crimped end of the tube.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

BECAPLERMIN GEL - TOPICAL

(beh-CAP-ler-min)

COMMON BRAND NAME(S): Regranex

WARNING: Discuss the risks and benefits of using this medication with your doctor. Before using this medication, tell your doctor if you have cancer or a history of cancer.

USES: This medication is used to treat certain foot/leg ulcers in people with diabetes. It is used along with good foot/leg care (e.g., keeping pressure off the wound) to help the ulcer heal completely. Becaplermin works by attracting certain natural substances to the ulcer that help wound healing.

HOW TO USE: Wash hands thoroughly before applying this medicine. To avoid contaminating the container tip, do not touch it to the skin or any other surface. Learn all preparation and usage instructions in the product package. If any of the information is unclear, consult your doctor or pharmacist.

The amount of the medication applied is based on the size of the ulcer. Your doctor or wound specialist should adjust your dose every 1 to 2 weeks.

Squeeze the prescribed amount of medication onto a clean, firm, and non-absorbent surface (e.g., waxed paper). Use a clean applicator (e.g., cotton swab, tongue depressor) to apply a thin layer of the medication evenly over the ulcer, usually once daily or as directed by your doctor.

Cover the ulcer with wound dressing as directed by your doctor. After 12 hours, remove the dressing, rinse the ulcer, and apply new dressing on the ulcer. Do not apply more medication at this time.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time each day. Use this medication until the ulcer heals completely.

Do not apply a thick layer of the medication or use more of the medication than directed. This will not increase the effects of the medication or help the wound heal faster and may increase the risk of side effects. Talk to your doctor for more details.

Tell your doctor if your condition worsens, does not improve after 10 weeks, or does not heal completely after 20 weeks.

SIDE EFFECTS: Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: See also Warning section.

Before using becaplermin, tell your doctor or pharmacist if you are allergic to it; or to other ingredients in this product (e.g., parabens); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: cancer in the ulcer area.

Before using this medication, tell your doctor or pharmacist your medical history.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This medication may be harmful if swallowed. If overdose or swallowing is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current wound only. Do not use it later for another wound unless told to do so by your doctor. A different medication may be necessary in that case.

Good foot care can help reduce the chances of foot ulcers. Wash your feet daily and check for cuts, sores, or blisters. Keep your toenails neat and trimmed. Choose shoes that are well-fitting, and always wear socks with your shoes.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store in the refrigerator at 36-46 degrees F (2-8 degrees C). Do not freeze. Keep tube tightly closed. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.