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  • CLASSES

    All Other Wound Healing Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant human platelet-derived growth factor (rhPDGF)
    Topical wound healing for lower extremity, neuropathic, diabetic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply
    Not adequately studied for ulcers that do not extend into the subcutaneous tissue; efficacy not established for ischemic diabetic ulcers, venous stasis ulcers, or pressure ulcers

    COMMON BRAND NAMES

    Regranex

    HOW SUPPLIED

    Regranex Topical Gel: 0.01%

    DOSAGE & INDICATIONS

    For the treatment of lower extremity diabetic neuropathic ulcers (e.g., diabetic foot ulcer) that extend into the subcutaneous tissue or beyond and have an adequate blood supply.
    NOTE: Becaplermin is used as an adjunct to good ulcer care practices including initial sharp debridement, pressure relief, and infection control.
    NOTE: The safety and efficacy of becaplermin treatment beyond 20 weeks have not been determined.
    NOTE: The diabetic ulcers had failed to heal after at least 8 weeks of other treatment, and the median ulcer size at baseline ranged from 1.4 to 3.5 cm2; 95% of the ulcers measured in area up to 10 cm2.
    Topical dosage
    Adults and Adolescents at least 16 years of age

    The recommended dose is one application left in place for 12 hours once daily. The amount of gel to be used is determined by ulcer size; measure the greatest length by the greatest width. If the ulcer width and length are measured in centimeters, use ulcer length x ulcer width divided by 4 for a 15 g tube. If the ulcer width and length are measured in inches, use ulcer length x ulcer width x 0.6 for a 15 g tube. If the ulcer does not decrease in size by approximately 30% after 10 weeks of treatment or if complete healing does not occur in 20 weeks, reassess continued treatment with becaplermin.

    For wound management† of full thickness, single, fingertip injuries with a wound area of at least 1.5 cm2 with or without phalangeal exposure; distal to the distal interphalangeal joint; and not involving the flexor tendon insertion.
    For surgical, abdominal wound dehiscence†.
    Topical dosage
    Adults

    One application once daily in conjunction with twice daily dressing changes starting the day after the wound opened led to wound closure in 35 +/- 15 days. In contrast, receipt of placebo gel with similar pH and osmotic activity as becaplermin gel led to wound closure in 54 +/- 26 days. Wound closure was defined as a wound volume of less than 1 cm3.

    Topical dosage
     Adults

    One application once daily in conjunction with saline-moistened gauze until complete wound closure led to complete re-epithelialization in 25 +/- 3 days. In contrast, graft/flap stability occurred in 35 +/- 7 days in patients who had reconstruction with either a skin graft or local soft tissue flap. Further, the calculated functional impairment defined as cold intolerance, grip strength, and total active motion after patients had reached maximum medical improvement was 10% +/- 4% with becaplermin as compared with 22% +/- 6% with surgery.

    For the treatment of chronic, full thickness decubitus ulcer† in combination with good wound care.
    NOTE: The efficacy of becaplermin has not been established for the treatment of pressure ulcers.
    Topical dosage
    Adults

    One application once daily in conjunction with twice daily dressing changes until complete healing or for 16 weeks led to complete healing in 23% of 31 ulcers as compared with 0% of 31 ulcers treated with a placebo (sodium carboxymethylcellulose) gel. Further, 58% of becaplermin-treated ulcers had at least 90% healing whereas 29% of placebo-treated ulcers met the endpoint. Greater efficacy was not achieved with the use of a 0.03% becaplermin gel as compared with 0.01% gel.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    One application over 12 hours/day.

    Geriatric

    One application over 12 hours/day.

    Adolescents

    16 years or older: One application over 12 hours/day.
    15 years or younger: Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Each gram of the gel contains 100 mcg of becaplermin. The weight of becaplermin gel from a 15 g tube is 0.65 g per inch of length and 0.25 g per centimeter of length. The gel is clear and colorless or straw-colored.

    Topical Administration

    For topical use only.

    Other Topical Formulations

    Gel Formulations
    The amount to be applied will vary depending on the size of the ulcer area (see Dosage). The physician or wound care giver needs to recalculate the needed amount of gel at weekly or biweekly intervals depending on the rate of change in ulcer area.
    Thoroughly wash your hands before applying the gel. Squeeze the calculated length of gel on to a clean, firm, non-absorbable surface such as wax paper. Do not touch the tip of the tube to the ulcer or to any other surface. Tightly recap the tube after each use.
    Use a clean cotton swab, tongue depressor, or similar application aid to evenly spread the measured amount of gel over the ulcer surface. A thin, continuous layer of gel that is approximately 1/16 of an inch in thickness is needed. Cover the ulcer with a saline moistened gauze dressing.
    After approximately 12 hours, gently rinse the ulcer with saline or water to remove residual gel. Cover the ulcer with a saline-moistened gauze dressing for the remaining 12 hours of the day.

    STORAGE

    Regranex:
    - Do not freeze
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Becaplermin gel is a non-sterile, low bioburden preserved product. Therefore, it should not be used in wounds that close by primary intention.
     
    The effects of becaplermin on exposed joints, tendons, ligaments, and bone have not been established in humans.

    Mortality, neoplastic disease, new primary malignancy

    Becaplermin promotes cellular proliferation and angiogenesis; therefore, use is contraindicated in patients with known neoplastic disease at the site of application. Further, healthcare providers are advised to consider the potential risks and benefits of prescribing becaplermin to patients with any type of known cancer, as the drug has been associated with new primary malignancy distant from the site of application. Using a health insurance medical claims database, the incidence of cancer development and cancer deaths among becaplermin-exposed and non-exposed patients were examined in 1 retrospective study. Data from this study found the rate ratio incidence for cancer development and the rate ratio for cancer mortality in becaplermin-exposed as compared to the unexposed comparator cohort to be 1.2 (95% CI 0.7 to 1.9) and 1.8 (95% CI, 0.7 to 4.9), respectively. However, among patients exposed to 3 or more tubes of becaplermin the incidence of cancer mortality as compared to the unexposed cohort was 5.2 (95% CI, 1.6 to 17.6).[49355]

    Pregnancy

    No adequate or well-controlled studies have been conducted to evaluate the use of becaplermin during pregnancy. It is not known whether the drug can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Becaplermin gel should be given to pregnant women only if clearly needed.[49355]

    Breast-feeding

    It is not known whether becaplermin is excreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when becaplermin is administered to breast-feeding women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and efficacy of becaplermin have not been established in neonates, infants, children, and adolescents less than 16 years of age.

    Corticosteroid therapy, infection

    Patients with infection at the ulcer site or patients on corticosteroid therapy may have a poorer response to becaplermin gel as compared to results obtained from the 4 randomized, controlled studies of the effects of becaplermin on the incidence of and time to complete healing in lower extremity diabetic ulcers. Patients taking corticosteroids in these trial were excluded from participation. In the clinical trials, all patients also had a non-weight-bearing regimen and systemic treatment for wound-related infection, if present. All ulcers also had an initial complete, sharp debridement; moist saline dressings changed twice a day; and additional debridement, as needed. Corticosteroid therapy could impair wound healing and impair the immune response, which could lead to infection. Necrotic and nonviable tissue is also likely to harbor dangerous organisms; debridement helps keep the wound in an acute versus chronic state. Becaplermin treatment increases the incidence of complete healing of diabetic ulcers when used as an adjunct to good ulcer care practices, which includes initial sharp debridement, pressure relief, and infection control. Becaplermin is not a substitute for good ulcer care.

    Peripheral vascular disease

    Patients with an inadequate arterial blood supply such as patients with peripheral vascular disease may have a poor response to becaplermin gel. The efficacy of becaplermin has not been established for the treatment of ischemic diabetic ulcers, venous stasis ulcers, or for diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue. Becaplermin is only indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. In clinical trials, all ulcers had to have an adequate blood supply, which was defined as TcpO2 > 30 mm Hg.

    ADVERSE REACTIONS

    Severe

    new primary malignancy / Delayed / Incidence not known

    Moderate

    erythema / Early / 2.0-2.0

    Mild

    rash / Early / 2.0-2.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Becaplermin, rh-PDGF products.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate or well-controlled studies have been conducted to evaluate the use of becaplermin during pregnancy. It is not known whether the drug can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Becaplermin gel should be given to pregnant women only if clearly needed.[49355]

    It is not known whether becaplermin is excreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when becaplermin is administered to breast-feeding women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Becaplermin and endogenous platelet-derived growth factor (PDGF) have similar activity such as the promotion of chemotactic recruitment and proliferation of cells involved in wound repair and the enhancement of granulation tissue formation. Platelet-derived growth factor-AA (short form) and PDGF-BB appear to be the predominant isoforms in maturing granulation tissue, and PDGF-AA (long form) and PDGF-AA (short form) are present in less mature granulation tissue. For example, little PDGF-BB was present in chronic pressure ulcers one week after daily application of becaplermin 1 mcg/cm2. However, PDGF-BB was expressed at higher levels in fibroblasts than other isoforms of PDGF after 4 weeks of treatment. Theoretically, becaplermin may stimulate wound repair by direct stimulation of fibroblasts. Fibroblasts in normal skin and granulation tissue express PDGF-beta receptors. Also, vascular PDGF-beta receptor staining was often colocalized with endothelial EN-4 staining, which suggests that microvascular endothelial cells contain PDGF-beta receptors. PDGF-beta receptor staining in granulation tissue showed the same pattern as observed in normal skin.

    PHARMACOKINETICS

    Becaplermin is applied topically to the skin.
     
    The mean time to complete wound closure was 86 days with becaplermin 0.01% gel. In contrast, the mean time to complete wound closure was 127 days with placebo treatment; all ulcers were treated with good ulcer care. Differences in the numbers of ulcers that completely healed with either the placebo or becaplermin 0.01% gel became more apparent after 10 weeks of treatment. For example, of 123 ulcers that were treated with becaplermin 0.01% gel, 9% were completely healed at week 6, 23% at week 10, 43% at week 16, and 50% at week 20. In contrast, of 127 ulcers that were treated with placebo gel, 6% were completely healed at week 6, 18% at week 10, 33% at week 16, and 37% at week 20. The higher number of ulcers with complete healing after becaplermin treatment was not associated with a higher rate of ulcer recurrence. The incidence of ulcer recurrence was approximately 30% in all treatment groups over a 3-month follow-up period where no standardized regimen of preventive care was utilized.

    Topical Route

    Ten patients with Stage III or IV lower extremity diabetic ulcers as defined in the International Association of Enterostomal Therapy guide to chronic wound staging received 0.32—2.95 mcg/kg (7 mcg/cm2) of becaplermin 0.01% gel daily to the ulcer for 14 days. Six patients had non-quantifiable platelet-derived growth factor (PDGF) concentrations at baseline and throughout the study, 2 patients had PDGF concentrations at baseline that did not increase substantially, and 2 patients had PDGF concentrations that increased sporadically above their baseline values over the 14 days.