1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

For topical use; not for oral, ophthalmic or intravaginal use.

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 1, and to calculate the length of gel in centimeters, use the formula shown below in Table 2.

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 1 1/3 inch length of the gel from a 2g tube (physician sample). For example, if the ulcer measures 1 inch by 2 inches, then a 1 1/4 inch length of gel should be used for 15g tubes (1 × 2 × 0.6 = 1 1/4) and 2 3/4 inch gel length should be used for a 2g tube (1 × 2 × 1.3 = 2 3/4).

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 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 × 2) ÷ 4 = 2] and a 4 centimeter length of gel should be used for a 2g tube [(4 × 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 "Patient Counseling Information". [see Patient Counseling Information (17)]

3 DOSAGE FORMS AND STRENGTHS

Gel: 0.01%; clear, colorless to straw-colored gel

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS

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.

8 USE IN SPECIFIC POPULATIONS

10 OVERDOSAGE

There are no data on the effects of becaplermin overdose.

11 DESCRIPTION

REGRANEX Gel 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 Gel 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 Gel contains 100 mcg of becaplermin.

12 CLINICAL PHARMACOLOGY

13 NONCLINICAL TOXICOLOGY

14 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 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 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 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 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.

15 REFERENCES

1. J. Enterostomal Ther 15:4, 1988
2. Decubitis 2:24, 1989

16 HOW SUPPLIED/STORAGE AND HANDLING

REGRANEX Gel 0.01% is available in a multi-use tube in the following size:

REGRANEX Gel 0.01% is for external use only.

17 PATIENT COUNSELING INFORMATION

[See FDA-approved patient labeling (Medication Guide)]

Counsel patients to review and discuss any questions or concerns with their healthcare provider before starting REGRANEX and at regular intervals while receiving REGRANEX.

Patients should be advised that:

• they should read the medication guide;
• 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 REGRANEX Gel;
• REGRANEX Gel should only be applied once a day in a carefully measured quantity [see Dosage and Administration (2)]. 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 onto a clean, firm, nonabsorbable 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 REGRANEX Gel;

  –

  REGRANEX Gel should not be used after the expiration date on the bottom, crimped end of the tube.

MEDICATION GUIDE
REGRANEX® (REʹ–GRAN–IX)
(becaplermin)
Gel

Read this Medication Guide before you start using REGRANEX and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

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

People who use 3 or more tubes of REGRANEX may have an increased risk of death from cancer.

• You should talk with your healthcare provider about the possible benefits and risks to you if you use more than 3 tubes of REGRANEX.
• If you already have cancer, you and your healthcare provider should carefully consider whether you will use REGRANEX.

If you decide to use REGRANEX, your healthcare provider will tell you how to use REGRANEX. See the section "How should I use REGRANEX?" below.

What is REGRANEX?

REGRANEX is a man-made protein medicine that is used with other ulcer care practices (such as good wound care) to treat 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.

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.

Who should not use REGRANEX?

Do not use REGRANEX if you have a skin tumor at the area where you apply REGRANEX.

What should I tell my healthcare provider before using REGRANEX?

Before you use REGRANEX tell your healthcare provider if you:

• have cancer
• have poor blood flow to your lower legs and feet
• have allergies to any of the ingredients in REGRANEX. See the end of this Medication Guide for a complete list of ingredients in REGRANEX.
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if REGRANEX will harm your unborn baby.
• are breast-feeding or plan to breast-feed. It is not known if REGRANEX passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you apply other medicines to diabetic ulcers of your legs or feet.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use REGRANEX?

• Use REGRANEX together with good ulcer care, as prescribed by your healthcare provider. This includes following your healthcare provider's instructions about not putting weight on the affected leg and foot (non-weight bearing).
• Use REGRANEX exactly as your healthcare provider tells you to use it.
• REGRANEX is for use on skin ulcers only. Do not use REGRANEX in your mouth, eyes, or vagina.
• REGRANEX comes as a gel. Your healthcare provider should tell you how often to use REGRANEX and how much REGRANEX to use.
• Your healthcare provider should check the size of your ulcer every 1 to 2 weeks.
• Your healthcare provider may change the amount of REGRANEX to be applied to your ulcer as the size of your ulcer changes. So, the amount of REGRANEX to be squeezed from the tube may change as the size of your ulcer changes.
• Close your REGRANEX tube tightly after each use.
• Put the REGRANEX tube back in the refrigerator after each use.
• Use a cotton swab, tongue depressor, or other application aid when you apply your REGRANEX. Do not let the tip of your REGRANEX tube touch the ulcer or any other surface.
• Apply REGRANEX one time each day.

Apply REGRANEX as follows:

• Wash your hands well before you apply REGRANEX.
• Carefully measure the amount of REGRANEX that your healthcare provider tells you to use.
• Squeeze the amount of REGRANEX needed for your ulcer on to a clean, firm, non-absorbable surface, such as wax paper.
• Use a clean cotton swab, tongue depressor, or similar application aid, to spread the REGRANEX gel in a thin even layer over the surface of the ulcer on your foot or leg.
• Cover the area with a saline-moistened gauze dressing.
• After about 12 hours, gently rinse the ulcer with saline or water to remove the rest of the REGRANEX. Cover the ulcer with a new saline-moistened gauze dressing. Do not apply any more REGRANEX.

What are the possible side effects of REGRANEX?

REGRANEX may cause serious side effects.

• See the section, "What is the most important information I should know about REGRANEX?"
• Common side effects of REGRANEX include:
  • Red skin rash
  • Burning at the application site

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of REGRANEX gel. For more information, ask your doctor or pharmacist.

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 Ortho-McNeil at 1-888-734-7263.

How should I store REGRANEX?

• Store REGRANEX in the refrigerator at 36°F to 46°F (2°C to 8°C).
• Do not freeze REGRANEX.
• Do not use REGRANEX after the expiration date on the bottom (sealed end) of the tube.
• Throw away your REGRANEX that is out of date or no longer needed for your treatment.

Keep REGRANEX and all medicines out of the reach of children.

General information about REGRANEX

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.

This Medication Guide summarizes the most important information about REGRANEX. If you would like more information about REGRANEX, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about REGRANEX that is written for health professionals.

What are the ingredients in REGRANEX?

Active ingredient: becaplermin

Inactive ingredients: carboxymethylcellulose sodium, glacial acetic acid, l-lysine hydrochloride, m-cresol, methylparaben, propylparaben, sodium acetate trihydrate, sodium chloride, and water for injection.

Manufactured by:
OMJ Pharmaceuticals, Inc.
U.S. License No. 1196
San German, Puerto Rico 00683

Manufactured for:
Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Raritan, NJ 08869

Becaplermin Concentrate provided by: Novartis NPC
2010 Cessna Dr.
Vacaville, CA 95688
U.S. License No. 1244

Revised: 05/2011

This Medication Guide has been approved by the U.S. Food and Drug Administration.

PRINCIPAL DISPLAY PANEL - 15g Tube Carton

NDC 0045-0810-15

REGRANEX®
(becaplermin)
GEL
0.01%

For Topical Use Only
Multi-dose tube

NET WT. 15g

Attention Pharmacist: Dispense the
accompanying Medication Guide to
each patient.

Dosage and Administration: See package insert.

STORE REFRIGERATED, 2° - 8°C (36° - 46°F).
DO NOT FREEZE.

Warning: Keep out of reach of children.

Rx only.