Regranex - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gram of gel contains 100 pg of becaplermin.

Recombinant human Platelet Derived Growth Factor-BB (rhPDGF-BB) produced in Saccharomyces cerevisiae by recombinant DNA technology.

Excipients:

Each gram contains E218 (methyl parahydroxyben­zoate) 1.56 mg and E216 (propyl parahydroxyben­zoate) 0.17 mg, see section 4.4.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

REGRANEX is a clear colourless to straw-coloured gel.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

REGRANEX is indicated, in association with other good wound care measures, to promote granulation and thereby the healing of full-thickness, neuropathic, chronic, diabetic ulcers less than or equal to 5 cm2.

4.2 Posology and method of administration

Treatment with REGRANEX should be initiated and monitored by physicians (specialists or nonspecialists) who are experienced in the management of diabetic wounds.

REGRANEX should always be used in conjunction with good wound care consisting of initial debridement (to remove all the necrotic and/or infected tissue), additional debridement as necessary and a non-weight-bearing regimen to alleviate pressure on the ulcer.

REGRANEX should be applied as a continuous thin layer to the entire ulcerated area(s) once daily using a clean application aid. The site(s) of application should then be covered by a moist saline gauze dressing that maintains a moist wound-healing environment. REGRANEX should not be used in conjunction with occlusive dressings.

• – A tube of REGRANEX should be used on a single patient only.

• – Care should be taken during use to avoid microbial contamination and spoilage.

• – Hands should be washed thoroughly before applying REGRANEX.

• – The tip of the tube should not come into contact with the wound or any other surface.

• – The use of a clean application aid is recommended and contact with other parts of the body should

be avoided.

• – Before each application, the ulcer should be gently rinsed with saline or water to remove residual gel.

• – The tube should be closed tightly after each use.

REGRANEX should not be used for more than 20 weeks.

If during treatment with REGRANEX no meaningful healing progress is evident after the first ten weeks of continuous therapy, treatment should be re-evaluated, and factors known to compromise healing (such as osteomyelitis, ischaemia, infection) should be re-assessed. Therapy should be continued to the maximum of 20 weeks as long as healing progress is seen on periodic evaluations.

Special population

Paediatric population

Safety and effectiveness in children and adolescents below the age of 18 years have not been established.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Any known malignancies (See section 4.4).

In patients with clinically infected ulcers. (See section 4.4).

4.4 Special warnings and precautions for use

Malignancies distant from the site of application have occurred in becaplermin users in both clinical trial and in post-marketing use. In view of these data and since becaplermin is a growth factor, Regranex treatment is contraindicated in patients with any known malignancies.

Prior to the use of REGRANEX, related underlying conditions such as osteomyelitis and peripheral arteriopathy should be excluded or treated if present. Osteomyelitis should be assessed by X-ray examination. Peripheral arteriopathy should be excluded by assessment of the pedal pulses or other techniques. Ulcers with a suspicious appearance should be biopsied to exclude malignancy.

Wound infection should be treated prior to the use of REGRANEX. If a wound becomes infected during REGRANEX therapy, the product should be discontinued until the infection has cleared.

REGRANEX should not be used in patients with ulcers that are not of primarily neuropathic origin, such as those due to arteriopathy or other factors.

REGRANEX should not be used in ulcers of baseline surface area > 5 cm2, or for more than 20 weeks in any individual. There are insufficient data to support safe use of the product for more than 20 weeks (see 5.1 Pharmacodynamic properties). Efficacy has not been demonstrated for ulcers of baseline surface area > 5 cm2.

REGRANEX contains E218 (methyl parahydroxyben­zoate) and E216 (propyl parahydroxyben­zoate). These may cause allergic reactions (possibly delayed).

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Consequently, it is recommended that REGRANEX should not be applied to the ulcer site in conjunction with other topical medications.

4.6 Pregnancy and lactation

There are no adequate data from the use of becaplermin in pregnant women. Consequently, REGRANEX should not be used during pregnancy.

It is not known whether becaplermin is excreted in human milk. Therefore, REGRANEX should not be used during breastfeeding.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

The safety of REGRANEX Gel was evaluated in 1883 adult patients who participated in 17 clinical trials of REGRANEX and placebo and/or standard therapy (saline dressing). These 1883 patients had at least one topical administration of REGRANEX and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (>5% incidence) adverse drug reactions (ADRs) were (with % incidence) infected skin ulcer (12.3), cellulitis (10.3), and osteomyelitis (7.2). Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of REGRANEX from either clinical trial or postmarketing experiences.

The displayed frequency categories use the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available clinical trial data).

Adverse Drug Reactions Reported in Clinical Trials and Postmarketing Experience

1. The bundled term burning sensation consists of the preferred terms burning sensation, skin rning sensation, and application site irritation, all of which referred specifically to burning at e application site.

fers to erythema at the application site.

There are limited data on the effects of becaplermin overdose. Since there was no consistent increase in plasma platelet-derived growth factor-BB concentrations above pre-treatment concentrations, following 14 consecutive daily topical applications to ulcers, no untoward systemic events are expected.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Preparation for treatment of wounds and ulcers, ATC code: D 03 AX06 REGRANEX contains becaplermin, a recombinant human Platelet Derived Growth Factor-BB (rhPDGF-BB). Becaplermin is produced by insertion of the gene for the B chain of human platelet derived growth factor into the yeast, Saccharomyces cerevisiae. The biological activity of becaplermin includes promoting the chemotactic recruitment and proliferation of cells involved in wound repair. Thus it helps the growth of normal tissue for healing. In animal wound models, the predominant effect of becaplermin is to enhance the formation of granulation tissue. From data combined from 4 clinical trials conducted over a 20 week treatment phase for ulcers of baseline surface area less than or equal to 5 cm2, 47% of ulcers treated with becaplermin 100 pg/g gel completely healed, compared to 35% which were treated with placebo gel alone. Subjects recruited into these studies were diabetic adults aged 19 years or over who were suffering from at least one stage III or IV diabetic ulcer of at least 8 weeks duration.

5.2 Pharmacokinetic properties

Absorption

Clinical absorption studies were conducted in patients with a mean diabetic ulc (range 2.3 – 43.5 cm2). Following 14 consecutive daily topical applications of REGRANEX, there was no consistent increase in plasma platelet-derived growth factor-BB concentrations above pre-treatment concentrations.

5.3 Preclinical safety data

Becaplermin was not mutagenic in a battery of in vitro and in vivo tests. Since there was no consistent increase in plasma platelet-derived growth factor-BB concentrations above pre-treatment concentrations, following 14 consecutive daily topical applications to ulcers in man, carcinogenesis and reproductive toxicity studies have not been conducted with REGRANEX. In the process of healing the wound, becaplermin induces cell proliferation.

In a preclinical study designed to determine the effects of PDGF on exposed bone, rats injected at the metatarsals with 3 or 10 pg/site (concentration of 30 or 100 pg/ml/site) of becaplermin every other day for 13 days displayed histological changes indicative of accelerated bone remodelling 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.

Preclinical absorption studies through full-thickness wounds were conducted in rats with a wound area of 1.4 – 1.6 cm2. Systemic absorption of a single dose and multiple applications for 5 consecutive days of becaplermin to those wounds was insignificant.

6.1

6. PH

EUTICAL PARTICULARS

carmellose sodium (E466) sodium chloride sodium acetate glacial acetic acid (E260)

methyl parahydroxybenzoate (methylparaben) (E218) propyl parahydroxybenzoate (propylparaben) (E216) metacresol

lysine hydrochloride

water for injections

6.2 Incompatibilities

There are no known incompatibilities.

6.3 Shelf life

1 year.

Use within 6 weeks after first opening.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Close tightly after each use.

6.5 Nature and contents of container

6.6 Special precautions for disposal

After treatment is completed, any unused gel should be discarded in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

JANSSEN-CILAG INTERNATIONAL NV

Turnhoutseweg, 30

B-2340 Beerse

Belgium

8. MARKETING AUTHORISATION NUMBER(S)