Leaflet LEDAGA 160mcg/G gel

Ledaga 160 micrograms/g gel

Each gram of gel contains chlormethine hydrochloride equivalent to 160 micrograms of chlormethine.

Each tube contains 10.5 grams of propylene glycol and 6 micrograms of butylhydroxytoluene.

For the full list of excipients, see section 6.1.

Clear, colourless gel.

Ledaga is indicated for the topical treatment of mycosis fungoides-type cutaneous T-cell lymphoma(MF-type CTCL) in adult patients (see section 5.1).

Treatment with Ledaga should be initiated by an appropriately experienced physician.

A thin film of Ledaga should be applied once daily to affected areas of the skin.

Treatment with Ledaga should be stopped for any grade of skin ulceration or blistering, or moderatelysevere or severe dermatitis (e.g., marked skin redness with oedema). Upon improvement, treatmentwith Ledaga can be restarted at a reduced frequency of once every 3 days. If reintroduction oftreatment is tolerated for at least 1 week, the frequency of application can be increased to every otherday for at least 1 week and then to once-daily application if tolerated.

The dosing recommendation for elderly patients (  65 years old) is the same as for younger adultpatients (see section 4.8).

The safety and efficacy of Ledaga in children aged 0 to 18 years have not been established. No dataare available.

Ledaga is for topical application to the skin.

The following instructions should be followed by patients or caregivers when applying Ledaga:

* Patients must wash hands thoroughly with soap and water immediately after handling orapplying Ledaga. Patients should apply Ledaga to affected areas of the skin. In case of Ledagaexposure to non-affected areas of the skin, patients should wash the exposed area with soap andwater.

* Caregivers must wear disposable nitrile gloves when applying Ledaga to patients. Caregiversshould remove gloves carefully (turning them inside out during the removal to avoid contactwith Ledaga) and wash hands thoroughly with soap and water after removal of gloves. If thereis accidental skin exposure to Ledaga, caregivers must immediately wash exposed areasthoroughly with soap and water for at least 15 minutes. Remove and wash contaminatedclothing.

* The opening of the tube is covered with a foil safety seal. The cap should be used to puncturethe seal. The tube should not be used and the pharmacist should be contacted if the seal ismissing, punctured, or lifted.

* Ledaga should be applied immediately or within 30 minutes after removal from the refrigerator.

The tube should be returned to the refrigerator immediately after each use. With clean hands,the tube should be placed back into the original box and the box should be placed in thesupplied transparent, sealable, plastic bag for storage in the refrigerator.

* Ledaga should be applied to completely dry skin at least 4 hours before or 30 minutes aftershowering or washing. The patient should allow treated areas to dry for 5 to 10 minutes afterapplication before covering with clothing. Occlusive (air- or water-tight) dressings should notbe used on areas of the skin where Ledaga was applied.

* Emollients (moisturisers) or other topical products may be applied to the treated areas 2 hoursbefore or 2 hours after application of Ledaga.

* Fire, flame, and smoking must be avoided until Ledaga has dried.

Hypersensitivity to chlormethine or to any of the excipients listed in section 6.1.

Mucosal or eye exposure

Contact with mucous membranes, especially those of the eyes, must be avoided. Exposure of mucousmembranes such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, and thesemay be severe. Exposure of the eyes to chlormethine causes pain, burns, inflammation, photophobia,and blurred vision. Blindness and severe irreversible anterior eye injury may occur.

Patients should be advised that if any mucous membrane exposure occurs:

* irrigation should be performed immediately for at least 15 minutes with copious amounts ofwater (or sodium chloride 9 mg/ml (0.9%) solution for injection, or a balanced salt ophthalmicirrigating solution may be used if there is eye exposure), and

* medical care should be obtained immediately (including ophthalmological consultation if thereis eye exposure).

Local skin reactions

Patients should be assessed during treatment for skin reactions such as dermatitis (e.g., redness,swelling, inflammation), pruritus, blisters, ulceration, and skin infections. The face, genitalia, anus, andintertriginous skin are at increased risk of skin reactions to topical chlormethine.

For dose modification information in case of skin reactions, see section 4.2.

Hypersensitivity reactions, including isolated cases of anaphylaxis, have been reported in the literatureafter the use of topical formulations of chlormethine (see sections 4.3 and 4.8).

Skin cancer

Skin-directed therapies for MF-type CTCL have been associated with secondary skin cancers,although the specific contribution of chlormethine has not been established. Patients should bemonitored for development of skin cancers during and after discontinuation of treatment withchlormethine.

Secondary exposure to Ledaga

Direct skin contact with Ledaga should be avoided in individuals other than the patient. Risks ofsecondary exposure may include skin reactions, mucosal injury, and skin cancers. Recommendedapplication instructions should be followed to prevent secondary exposure (see section 4.2).

This medicinal product contains propylene glycol and butylhydroxytoluene.

Propylene glycol may cause skin irritation.

Butylhydroxytoluene may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyesand mucous membranes.

No interaction studies have been performed.

Ledaga is not recommended in women of childbearing potential not using contraception.

There are limited data from the use of chlormethine in pregnant women.

Studies in animals have shown reproductive toxicity after systemic administration (see section 5.3).

Ledaga is not recommended during pregnancy.

It is unknown whether chlormethine is excreted in human milk.

A risk to newborns/infants cannot be excluded due to the potential for topical or systemic exposure ofthe breast-feeding child to chlormethine through contact with the mother’s skin.

A decision must be made whether to discontinue breast-feeding or to discontinue Ledaga therapy,taking into account the benefit of breast-feeding for the child and the benefit of therapy for the breast-feeding mother.

In animals, adverse effects of chlormethine on male fertility after systemic administration have beendocumented (see section 5.3). The relevance to humans receiving topical chlormethine is unknown.

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

In a randomised-controlled trial (n=128 exposed to Ledaga for a median duration of 52 weeks), themost frequent adverse reactions to Ledaga were skin related: dermatitis (54.7%; e.g., skin irritation,erythema, rash, urticaria, skin-burning sensation, pain of the skin), pruritus (20.3%), skin infections(11.7%), skin ulceration and blistering (6.3%), and skin hyperpigmentation (5.5%). Cutaneoushypersensitivity reactions were reported in 2.3% of the treated patients.

Adverse reactions reported with Ledaga in an active-controlled trial in patients with MF-type CTCLare shown below. Frequencies were defined using the following convention: 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); veryrare ( 1/10,000); not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Common Hypersensitivity

Very common Dermatitis, skin infections, pruritus

Common Skin ulceration and blistering, skin hyperpigmentation

In the controlled clinical trial, 31% (79/255) of the study population were aged 65 years or older. Thesafety profile observed in elderly patients was consistent with that in the overall patient population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

No cases of overdose after cutaneous use of Ledaga were reported during the clinical developmentprogramme or post-marketing period. Management of overdose should consist of washing the exposedarea with water.

Pharmacotherapeutic group: Antineoplastic agents, nitrogen mustard analogues, ATC code: L01AA05.

Chlormethine is a bifunctional alkylating agent that inhibits rapidly proliferating cells.

The efficacy and safety of Ledaga were assessed in a randomised, multicentre, observer-blinded,active-controlled, non-inferiority clinical trial (Study 201) of 260 adult patients with Stage IA (141),

IB (115), and IIA (4) MF-type CTCL who had received at least one prior skin-directed therapy.

Qualifying prior therapies included topical corticosteroids, phototherapy, topical bexarotene, andtopical nitrogen mustard. Patients were not required to be refractory to or intolerant of prior therapies.

Patients were stratified based on stage (IA vs IB and IIA) and then randomised to receive either

Ledaga (equivalent to 0.02% chlormethine HCl) or the comparator (a petroleum-based 0.02%chlormethine HCl ointment).

Study medicinal product was to be applied topically once daily for 12 months. Dosing could besuspended or continued at reduced frequency in the case of skin reactions. The median daily usage of

Ledaga was 1.8 g. The maximum individual daily usage in the trial was 10.5 g of gel (i.e., 2.1 mg ofchlormethine HCl).

The primary efficacy endpoint in Study 201 was the Composite Assessment of Index Lesion Severity(CAILS) response rate. Assessment was undertaken by a blinded observer. A response was defined asan at least 50% improvement in the baseline CAILS score, confirmed at a subsequent visit at least4 weeks later. A complete response was defined as a confirmed CAILS score of 0. A partial responsewas defined as an at least 50% reduction in the baseline CAILS score. Non-inferiority was consideredto have been demonstrated if the lower bound of the 95% confidence interval around the ratio ofresponse rates (Ledaga/comparator) was greater than or equal to 0.75. The CAILS score was adjustedby removal of the pigmentation score and simplification of the plaque elevation scale.

As the main secondary endpoint, patients were also evaluated using the Severity Weighted Assessment

Tool (SWAT), which was based on an assessment of all lesions. The response criteria were the sameas for CAILS.

Efficacy was evaluated in the Efficacy Evaluable (EE) population, which included all 185 patientswho were treated for at least 6 months with no major protocol deviations [Table 1], and in the Intent-

To-Treat (ITT) population, which included all 260 randomised patients.

Table 1 CAILS and SWAT-confirmed response rates by 12 months in Study 201 (efficacyevaluable population)

Response rates (%)

Ledaga Comparator

N=90 N=95 Ratio 95% CI

CAILS Overall Response (CR+PR) 76.7% 58.9% 1.301 1.065-1.609

Complete Response (CR) 18.9% 14.7%

Partial Response (PR) 57.8% 44.2%

SWAT Overall Response (CR+PR) 63.3% 55.8% 1.135 0.893-1.448

Complete Response (CR) 8.9% 4.2%

Partial Response (PR) 54.4% 51.6%

CAILS = Composite Assessment of Index Lesion Severity; CI = confidence interval; CR = Complete Response; PR = Partial

Response; SWAT = Severity Weighted Assessment Tool.

The ratio of response and the 95% confidence interval in the ITT population were 1.226 (0.974-1.552)for CAILS and 1.017 (0.783-1.321) for SWAT and therefore consistent with those in the EEpopulation for both the overall CAILS and SWAT responses.

Reductions in mean CAILS scores were observed as early as at 4 weeks, with further reductionsobserved with continuing therapy.

In the EE population, the percentage of patients who achieved a confirmed response by CAILS wassimilar between disease stages IA (79.6 %) and IB-IIA (73.2%).

Results in other secondary endpoints (response in percentage of body surface area affected, time tofirst confirmed CAILS response, duration of first confirmed CAILS response and time to diseaseprogression) were consistent with those for CAILS and SWAT.

A small number of subjects (6.3%, 8/128) treated with Ledaga utilised topical corticosteroids. Thus,the safety of the concomitant use of Ledaga with topical corticosteroids has not yet been established.

The European Medicines Agency has waived the obligation to submit the results of studies with

Ledaga in all subsets of the paediatric population in cutaneous T-cell lymphoma (see section 4.2 forinformation on paediatric use).

Patients who received Ledaga in Study 201 had no measurable concentrations of chlormethine inblood collected 1, 3 and 6 hours post-application on Day 1, and at the first month visit.

Similarly, patients who received chlormethine gel 0.04% in a follow-up study (Study 202) had nomeasurable concentrations of chlormethine or its degradation product (half-mustard) in blood collected1 hour post-application on Day 1 or after 2, 4, or 6 months of treatment.

Chlormethine was shown to be genotoxic in bacterial, plant, and mammalian cells. Chlormethine wascarcinogenic in rat and mouse carcinogenicity studies after subcutaneous and intravenousadministration.

Dermal application of chlormethine to mice at a dose of 15 mg/kg for up to 33 weeks resulted in skintumours (squamous cell carcinomas and skin papilloma). There were no reports of systemic tumoursafter topical administration of chlormethine.

Intravenously administered chlormethine impaired male fertility in rats at a dose of  0.25 mg/kg onceevery 2 weeks for 24 weeks. No dedicated animal studies on the effects of chlormethine on femalefertility have been reported in the literature.

Chlormethine caused foetal malformations in mice and rats when given as single injections of 1-2.5 mg/kg. Other findings in animals included embryo-lethality and growth retardation whenadministered as a single injection.

Diethylene glycol monoethyl ether

Propylene glycol (E 1520)

Isopropyl alcohol

Glycerol (E 422)

Lactic acid (E 270)

Hydroxypropylcellulose (E 463)

Sodium chloride

Menthol racemic

Disodium edetate

Butylhydroxytoluene (E 321)

Not applicable.

Frozen tube5 years in the freezer (-15 °C to -25 °C).

After defrosting60 days in the refrigerator (+2 °C to +8 °C).

Ledaga should be removed from the refrigerator just prior to application and returned to therefrigerator immediately after each use in its box inside the child-resistant, transparent, sealable,plastic bag.

Unopened tube

Store and transport frozen (−15 °C to −25 °C) or refrigerated (+2 °C to +8 °C).

After defrosting

Store and transport refrigerated (+2 °C to +8 °C).

Ledaga is provided in a white aluminium tube with an inner lacquer and an aluminium seal and awhite polypropylene screw cap. Each tube contains 60 g of gel.

Ledaga is a cytotoxic medicinal product.

Caregivers must wear nitrile gloves when handling Ledaga. Patients and caregivers must wash handsafter handling Ledaga.

Ledaga is an alcohol-based product and is flammable. The recommended application instructionsshould be followed (see section 4.2).

Unused refrigerated Ledaga should be discarded after 60 days, together with the plastic bag.

Any unused medicinal product or waste material, including the plastic bag and the nitrile gloves usedfor application, must be disposed of in accordance with local requirements.

Helsinn Birex Pharmaceuticals Ltd.

Damastown

Mulhuddart

Dublin 15

Ireland

EU/1/16/1171/001

Date of first authorisation: 3 March 2017

Date of latest renewal: 7 January 2022

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

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