Episalvan - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Episalvan gel

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 g gel contains: 100 mg extract (as dry extract, refined) from birch bark from Betula pendula Roth, Betula pubescens Ehrh. as well as hybrids of both species (equivalent to 0.5–1.0 g birch bark), corresponding to 72–88 mg betulin.

Extraction solvent: n-Heptane

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Gel.

Colourless to slightly yellowish, opalescent.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Treatment of partial thickness wounds in adults. See section 4.4 and 5.1 with respect to type of wounds studied.

4.2 Posology and method of administration

Posology

The gel should be applied to the wound surface at a thickness of approximately 1 mm and covered by sterile wound dressing. The gel should be re-applied at each wound dressing change, until the wound is healed, for up to 4 weeks (see section 4.4 “wound size” and “duration of use”).

Special populations

Renal or hepatic impairment

No formal studies have been conducted with Episalvan in patients with renal or hepatic impairment.

No dose adjustment or special considerations are anticipated for patients with renal or hepatic impairment (see section 5.2).

Elderly

No dose adjustment is required.

Paediatric population

The safety and efficacy of Episalvan in children and adolescents under 18 years have not yet been established. No data are available.

Method of administration

For cutaneous application.

Fresh wounds should achieve haemostasis prior to application of Episalvan. If necessary, wounds (accidental wounds) should be cleaned according to standard procedure, using e.g. wound antiseptic solution, prior to application of Episalvan.

Episalvan is for single use only.

4.3 Contraindications

Hypersensitivity to the active substance or to the excipient listed in section 6.1.

4.4 Special warnings and precautions for use

Wound infection

Episalvan gel is sterile. However, wound infection is an important and serious complication that can occur during wound healing. In the case of infection, it is recommended to discontinue treatment with Episalvan. Additional standard treatment may be required (see section 4.5).

Wound size

The mean wound size treated with Episalvan in clinical studies in split-thickness skin graft donor site wounds was 40.7 cm2 (range 8–300 cm2). In the Grade 2a burn wound study, the mean wound size treated with Episalvan was 108 cm2 (range 23–395 cm2).

Duration of use

There is no information available on clinical use of Episalvan for more than 4 weeks.

Partial thickness burn wounds

Repeated critical assessment of burn depth and healing progression is needed. Wounds that are assessed as unable to heal within an acceptable time frame may need surgical measures (e.g., splitthickness skin grafting) to reduce the risk of hypertrophic scarring.

Other wound types

There is no clinical experience from the use of Episalvan for the treatment of chronic wounds, e.g. diabetic foot ulcers, venous leg ulcers or wounds in patients with epidermolysis bullosa.

Birch pollen allergy

Episalvan is safe to use for people who are allergic to birch pollen, as these allergens are not present in Episalvan.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Since the systemic exposure of Episalvan following cutaneous application is negligible no interaction with systemic treatments is expected. Interactions with topical products have not been investigated in clinical trials. Other topical products should not be concomitantly used together with Episalvan but rather sequentially or alternatively depending on the clinical need.

4.6 Fertility, pregnancy and lactation

Pregnancy

No studies in pregnant women have been conducted.

No effects during pregnancy are anticipated, since systemic exposure to Episalvan is negligible. Episalvan can be used during pregnancy.

Breast-feeding

No data are available to evaluate whether Episalvan is excreted into human milk.

No effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breastfeeding woman to Episalvan is negligible. Episalvan can be used during breast-feeding, unless the chest area is subject to treatment.

Fertility

Fertility studies have not been conducted. No effects on human fertility are anticipated, since the systemic exposure is negligible.

4.7 Effects on ability to drive and use machines

Episalvan has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most frequently observed adverse reactions were wound complication (in 2.9% of patients), pain of skin (2.5%) and pruritus (1.3%). Adverse reactions were administration site reactions only. Wound complication adverse reactions such as wound infection and wound necrosis are complications of healing of partial thickness skin wounds and can be serious (see section 4.4).

Tabulated list of adverse reactions

In the following table, adverse reactions are listed by MedDRA system organ class and preferred term. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The frequency of adverse reactions is defined as follows: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1: Adverse reactions reported in clinical trials

* Wound complication comprises different kinds of local complications such as post-procedural complications, wound necrosis, wound secretion, impaired healing, or inflammation of wound.

In addition, there is one case report of contact dermatitis reported from a literature in a patient after prolonged use of a topical birch bark extract containing cosmetic product.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

Overdosing with Episalvan is unlikely: in patients in which wound sizes >300 cm2 were repeatedly treated with Episalvan, no betulin plasma levels could be detected.

No data have been generated to study the effect of accidental ingestion of Episalvan.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Preparation for treatment of wounds and ulcers; ATC code: D03AX13.

Mechanism of action and pharmacodynamic effects

The active substance accelerated re-epithelialization in an in vitro wound scratch assay using human primary keratinocytes at the dosage of 1 gg/ml, and in a porcine ex vivo wound healing model at the dosage of 10 ^g/ml. The precise mechanism of action of the active substance in wound healing in humans is not known.

Clinical efficacy and safety

Three Phase III studies were conducted to assess the efficacy and safety of Episalvan in the treatment of partial thickness wounds of the skin: two studies which investigated split-thickness skin graft donor site wounds, which included a total of 219 patients (ITT: N=217), and one further study in 61 patients with Grade 2a burn wounds (ITT: N=57). Patients with deeper burn wounds (Grade 2b) were not included.

The 219 patients with split-thickness skin graft donor site wounds had a mean age of 53 years; their donor site mean wound size was 81.5 cm2. In the burn wound study with 61 patients, the mean study wound area was 216 cm2; the total burn injury of these patients was larger and affected 5.8% of the total body surface area.

The Phase III studies were blindly evaluated, prospective, intra-individually controlled, randomised, multicentre trials. The target wound area of each patient was divided into two treatment areas of approximately the same size; the treatment allocation to the two halves of the wound (distal vs. proximal) was determined by randomisation (in the burn trial, two similar wounds could be used). Episalvan plus wound dressing was applied to half of the wound area, and the same kind of nonadhesive wound dressing alone was applied to the other half as the control in the split-thickness skin graft donor site studies. In the Grade 2a burn wound study an octenidine containing antiseptic wound gel and fatty gauze dressing were used as control. Application was at each wound dressing change every third to fourth day until full wound closure up to 28 days for the split-thickness skin graft trials, and every other day up to 21 days for the Grade 2a burn trial. Photographs of the wound were taken at each visit for the blinded evaluation.

The primary endpoint for the two split-thickness skin graft trials was the intra-individual difference in time to wound closure (at least 95% epithelialisation) based on blinded photo evaluations. Median time to wound healing was 14 days. Wound halves treated with Episalvan healed faster than the wound halves treated with standard of care (mean 1.1 days according to primary endpoints, p<0.0001, two-sided paired t-test).

Table 2: Overview of efficacy results: intra-patient difference in time to wound closure

a Based on 2-sided paired t-test

Intention-to-treat (ITT) data set.

‘Primary’ vs. ‘secondary’ blinded read: In the primary blinded read evaluation a rigorous quality check was implemented to assure blinding of the observers. In consequence a substantial number of photographs were excluded and not presented in the primary blinded read because of apparent gel residues. The secondary blinded read was conducted with all photographs presented to the blinded observers.

’Very conservative calculation’ means that the first observation of wound closure was taken as time of wound closure. Difference in time to wound closure was set to 0 for photo series rated as ‘not evaluable’. If wound closure was not observed in a wound half photo series, it was calculated to have occurred one day after the last photograph in the series.

‘Less conservative calculation’ differs from the ‘very conservative calculation’ in one aspect: If wound closure was not observed in a wound half photo series, it was calculated to have occurred not one day, but approximately 3 days later (the mean time interval between wound dressing changes in the studies).

CI: 95% confidence interval; MTWDC: mean time to wound dressing change; N: number of patients in the analysis set; STSG Split-thickness skin graft

The primary endpoint for the Grade 2a burn wound trial was the percentage of patients with earlier healing (at least 95% epithelialisation) based on blinded photo evaluations. Median time to wound healing was 7.3 days. Of the patients with a between-treatment difference in wound healing (N=35), the percentage of patients who showed earlier healing (primary endpoint) of their Episalvan treated wound half (85.7% [95% CI: 69.7%, 95.2%]) was higher than those who showed earlier healing of their standard of care control treated wound half (14.3% [95% CI: 4.8%, 30.3%]) (p<0.0001, binomial test).

In follow-up visits at 3 months and 12 months after the day of surgery or of burn injury the treated wound halves were found to be equal in the majority of patients with regard to pigmentation, redness, texture and hair growth of the regenerated epidermis. For a subset of patients blinded photo-evaluation indicated better results for Episalvan treated wound halves compared to standard of care in pigmentation, redness and texture of the former wound areas.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Episalvan in one or more subsets of the paediatric population for the treatment of skin injuries (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Episalvan gel is administered topically to skin wounds and shows poor absorption. Based on data from three clinical studies with a total of 280 patients, application of Episalvan gel to open wounds did not lead to betulin plasma levels higher than natural background-levels originating e.g. from nutritional sources.

Since no biologically relevant levels of betulin were found in patients, no further studies related to distribution, biotransformation and elimination were performed.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, local tolerance, and phototoxicity. Repeated dose toxicity and local tolerance have been studied for up to 4 weeks. Toxicity studies of longer duration than 4 weeks have not been performed. The active substance was not genotoxic in in vitro assays.

Carcinogenicity and reproductive and developmental toxicity studies have not been performed.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sunflower oil, refined.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

Once opened, the product should be used immediately and be discarded after use.

6.4 Special precautions for storage

Store below 30°C.

6.5 Nature and contents of container

White collapsible aluminium tube, interior lacquered with epoxy phenolic coating, and with a sealing compound in the fold. The tubes are closed with a tamper-evident aluminium membrane and fitted with a white polypropylene screw cap. The tube is packed in a cardboard box.

Pack size: 1 tube containing 23.4 g gel.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Amryt GmbH

Streiflingsweg 11

75223 Niefem-Oschelbronn

Germany

tel +49 (0) 7233 9749 – 0

fax +49 (0) 7233 9749 – 210

Email:

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1069/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 January 2016

Date of latest renewal: