FILSUVEZ gel medication leaflet

Filsuvez gel

1 g of gel contains 100 mg of extract (as dry extract, refined) from Betula pendula Roth, Betulapubescens Ehrh. as well as hybrids of both species, cortex (equivalent to 0.5-1.0 g birch bark),including 84-95 mg triterpenes calculated as the sum of betulin, betulinic acid, erythrodiol, lupeol andoleanolic acid. Extraction solvent: n-Heptane.

For the full list of excipients, see section 6.1.

Colourless to slightly yellowish, opalescent, non-aqueous gel.

Treatment of partial thickness wounds associated with dystrophic and junctional epidermolysis bullosa(EB) in patients 6 months and older.

The gel should be applied to the wound surface at a thickness of approximately 1 mm and covered bya sterile non-adhesive wound dressing or applied to the dressing so that the gel is in direct contact withthe wound. The gel should not be applied sparingly. It should not be rubbed in. The gel should bereapplied at each wound dressing change. The maximum total wound area treated in clinical studieswas 5,300 cm2 with a median total wound area of 735 cm2. If symptoms persist or worsen after use, orif wound complications occur, the patient’s condition should be fully clinically assessed prior tocontinuation of treatment, and regularly re-evaluated thereafter.

No studies have been conducted with Filsuvez in patients with renal or hepatic impairment. No doseadjustment or special considerations are anticipated for patients with renal or hepatic impairment (seesection 5.2).

No dose adjustment is required.

The posology in paediatric patients (6 months and older) is the same as in adults.

The safety and efficacy of Filsuvez in children aged less than 6 months have not been established. Nodata are available.

For cutaneous application only.

Filsuvez should be applied to cleansed wounds. This medicinal product is not for ophthalmic use andshould not be applied to mucous membranes.

Each tube is for single use only. The tube should be discarded after use.

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

Hypersensitivity has occurred in patients treated with Filsuvez (see section 4.8). If signs andsymptoms of local or systemic hypersensitivity occur, Filsuvez should be discontinued immediatelyand appropriate therapy should be initiated.

The gel is sterile. However, wound infection is an important and serious complication that can occurduring wound healing. In the case of infection, it is recommended to interrupt treatment. Additionalstandard treatment may be required (see section 4.5). Treatment may be re-initiated once the infectionhas resolved.

Squamous cell carcinoma and other skin malignancies

Patients with dystrophic EB (DEB) and junctional EB (JEB) may be at increased risk of developmentof squamous cell carcinoma. While there has been no increased risk of skin malignancies associatedwith Filsuvez to date, a theoretical increased risk of skin malignancies associated with use of Filsuvezcannot be ruled out. In the case of diagnosis of squamous cell carcinoma or other skin malignancies,treatment to the affected area should be discontinued.

Use in dominant dystrophic EB (DDEB) and junctional EB (JEB)

The quantity of clinical data from use of Filsuvez in patients with DDEB and JEB is limited (seesection 5.1). The patient’s condition should be regularly evaluated to assess the benefit of continuedtreatment.

Birch pollen allergy

Filsuvez is safe to use for people who are allergic to birch pollen, as these allergens are not present inthis medicinal product.

Accidental eye exposure

In the case of exposure to eyes product should be removed by eye irrigation.

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

There are no data from the use of Filsuvez in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to reproductive toxicity (see section 5.3). No effects duringpregnancy are anticipated, since systemic exposure to Filsuvez is negligible. Filsuvez can be usedduring pregnancy.

It is unknown whether birch bark extract/metabolites are excreted in human milk. No effects on thebreastfed newborn/infant are anticipated since the systemic exposure of the breastfeeding woman to

Filsuvez is negligible. Filsuvez can be used during breast-feeding, unless the chest area is subject totreatment.

No adverse effects on fertility were observed in male and female rats administered birch bark extract.

No effects on human fertility are anticipated, since the systemic exposure is negligible.

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

The most frequently observed adverse reactions were wound complication (in 11.6% of EB patientsand 2.9% of patients with other partial thickness wounds (PTW)), application site reaction (in 5.8% of

EB patients), wound infections (in 4.0% of EB patients), pruritus (in 3.1% of EB patients and 1.3% ofpatients with other PTW), pain of skin (in 2.5% of patients with other PTW) and hypersensitivityreactions (in 1.3% of EB patients). There were no clinically relevant differences in the reactionsreported in EB patients compared to patients with other PTW.

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), notknown (cannot be estimated from the available data).

Table 1 lists all adverse reactions reported across clinical studies.

Table 1: Adverse reactions

System organ class Very common Common Uncommon

Infections and infestations Wound infections

Immune system disorders Hypersensitivityreactions*

Wound complication* Pruritis

Skin and subcutaneous Dermatitisatissue disorders Rash pruritica

Purpuraa

General disorders and Application site Painaadministration site reactions*conditions (e.g. application sitepain and application sitepruritis)

Injury, poisoning and Wound complication*a Wound secretionprocedural complications

* see Description of selected adverse reactionsa adverse reactions observed in studies of patients with grade 2a burn wounds or split-thickness skingrafts

Common cases of hypersensitivity-like reactions have been observed during clinical trials in EBpatients. These reactions include rash, urticaria and eczema which were mild in 1.3% of patients andsevere in 0.4% of patients. For specific recommendations, see section 4.4.

Application site reactions

Mild or moderate application site reactions are common and include application site pain andapplication site pruritis.

Wound complication

In studies with EB patients, wound complication comprised different kinds of local complications suchas increase in wound size, wound re-opening, wound pain and wound haemorrhage.

In studies in patients with burn wounds or split-thickness skin grafts, wound complications compriseddifferent kinds of local complications such as post-procedural complications, wound necrosis, woundsecretion, impaired healing, or inflammation of wound.

Paediatric population70% (n = 156) of patients randomised in the pivotal study (see section 5.1) were under the age of 18with a median age of 12 years. 8% (n = 17) of patients were below 4 years of age and 2 patients wereunder 1 year of age. The adverse reactions observed in the overall population were similar to thoseobserved in the paediatric population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdosing with Filsuvez is unlikely. No case of overdose has been reported when a maximumamount of 69 g was used on a daily basis for more than 90 days.

No data have been generated to establish the effect of accidental ingestion of Filsuvez. Furthermanagement should be as clinically indicated.

Pharmacotherapeutic group: Preparations for treatment of wounds and ulcers, other cicatrizants; ATCcode: D03AX13.

Mechanism of action and pharmacodynamic effects

Cell culture assays with human primary keratinocytes and fibroblasts and ex vivo studies with porcineskin show that the extract including the main component betulin modulate inflammatory mediatorsand are associated with activation of intracellular pathways known to be involved in keratinocytedifferentiation and migration, wound healing and closure.

The precise mechanism of action of Filsuvez in wound healing is not known.

The efficacy and safety of Filsuvez in the treatment of partial thickness wounds associated withinherited EB were evaluated in a pivotal global Phase 3, randomised, double blind, controlled study inadults and children (Study BEB-13; EASE). Patients with DEB and JEB were randomised 1:1 toreceive Filsuvez (n = 109) or a blinded control gel (consisting of sunflower oil, refined; beeswax,yellow and carnauba wax) (n = 114) and instructed to apply the investigational product at a thicknessof approximately 1 mm to all their wounds at each dressing change (every 1 to 4 days) for 90 days. Atrandomisation, one wound was selected by the investigator as the target wound for the evaluation ofthe primary efficacy endpoint. The target wound was defined as a partial thickness wound of10-50 cm2 in surface area and present for 21 days to 9 months prior to screening. The primaryendpoint was the proportion of patients with first complete closure of the target wound by day 45 ofthe 90-day double blind phase (DBP) of the study. Following completion of the DBP, patients entereda 24-month open label phase (OLP) of the study during which all wounds were treated with Filsuvez.

Of the 223 patients randomised, the median age was 12 years (range: 6 months to 81 years), 70% wereunder 18 years of age and 8% of patients were below 4 years of age. 60% of patients randomised weremale. Of these 223 patients, 195 had DEB of which 175 patients had recessive DEB (RDEB), 20 haddominant DEB (DDEB); in addition, there were 26 patients with JEB. In the DBP the majority ofpatients applied the study treatment to all wounds either daily or every 2 days (between 70% and78%). Limited data are available for Black and Asian patients.

The results, including the primary endpoint, are presented in Table 2.

Table 2: Efficacy results (study BEB-13; 90-day double-blind phase, full analysis set)

Efficacy parameter Filsuvez Control gel p-valuen = 109 n = 114

Proportion of patients with firstcomplete closure of target wound 41.3% 28.9% 0.013within 45 days

By EB subtype

RDEB (n = 175) 44.0% 26.2% 0.008

DDEB (n = 20) 50.0% 50.0% 0.844

JEB (n = 26) 18.2% 26.7% 0.522

Proportion of patients with firstcomplete closure of target wound 50.5% 43.9% 0.296within 90 days*

* key secondary endpoint

The median daily extent of exposure for all patients in DBP and OLP combined are presented in

Table 3. The median duration of Filsuvez treatment for all patients in the DBP and OLP is 733 dayswith a maximum of 931 days.

Table 3: Median daily and cumulative extent of exposure and number of tubes used monthlyfor DBP and OLP combined - all patients and by age category.

All 0 - < 4 years 4 - < 12 years 12 - < 18 years ≥ 18 yearspatients

Median daily extent 10 15 10 10 9of exposure(grams per day)

Median cumulative 6117 8240 7660 5769 3467extent of exposure(grams)

Median number of 19 24 17 20 19tubes used per month

Systemic exposure to the main component betulin was assessed at baseline and periodically during

BEB-13 using a dried blood spot bioanalytical method. Betulin venous blood concentrations werebelow quantitation limits (10 ng/mL) in the large majority of subjects. In a minority of subjects,measurable venous blood concentrations of betulin were observed, suggesting that there is minimalabsorption of topically administered betulin. These venous blood concentrations, no greater than207 ng/mL, were similar to those observed with ingestion of food sources containing betulin.

The plasma protein binding of betulin is > 99.9%.

The in vitro metabolism of betulin was assessed in a suspension of human hepatocytes, where 99%were completely metabolised in five hours. The most abundant metabolite in vitro was formed throughoxidation, methylation, and sulfation. Three other metabolites were formed by sulfation orglucuronidation. Non-CYP enzymatic pathways are expected to play the predominant role in theoverall hepatic metabolism of betulin (75%), while the CYP mediated pathways (25%) are mainlydriven by CYP3A4/5 isoenzyme.

Betulin showed a direct inhibition of CYP2C8 (test substrate amodiaquine) and CYP3A (testsubstrates testosterone and midazolam) with IC50 values of 0.60 µM (266 ng/mL), 0.17 µM(75 ng/mL) and 0.62 µM (275 ng/mL), respectively in human hepatocytes. In addition, betulin causeda very slight induction of CYP3A4 mRNA (2.7-fold). However given the negligible systemicexposure, no interaction with systemic treatments is expected.

No in vivo elimination studes have been performed.

Non clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, toxicity to reproduction and development, and phototoxicity.

After a 4-week topical treatment with Filsuvez gel, several reactions are observed at the site ofadministration in minipigs, including inflammatory effects, lympho-histiocytic inflammatory cellinfiltration and epithelial hyperplasia. Following a 9-month dermal treatment in minipigs, epidermalhyperplasia, orthokeratotic hyperkeratosis, dermal lymphocytic and/or neutrophilic infiltration, andpustules in the stratum corneum were observed in some animals.

In vitro genotoxicity studies were negative. Further studies on genotoxicity or carcinogenicity have notbeen performed.

Sunflower oil, refined.

Not applicable.

4 years.

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

Store below 30 °C.

White collapsible aluminium tube, interior lacquered with epoxy phenolic coating, and with a sealingcompound in the fold. The tube is closed with a tamper-evident aluminium membrane and fitted with awhite polypropylene screw cap. The tube is packed in a carton.

Pack sizes:1, 10 and 30 tubes of 23.4 g gel.

Not all pack sizes may be marketed.

No special requirements.

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A43122 Parma

Italy

Filsuvez gel, 23.4 g tube

EU/1/22/1652/002

EU/1/22/1652/004

EU/1/22/1652/005

Date of first authorisation: 21 June 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.