WINLEVI 10mg / g cream medication leaflet

Winlevi 10 mg/g cream

Each gram of cream contains 10 mg of clascoterone.

Each gram of cream contains 25 mg of cetyl alcohol and 250 mg of propylene glycol (E1520).

For the full list of excipients, see section 6.1.

Cream

White to almost white cream.

Winlevi is indicated for the treatment of acne vulgaris.

Adolescents (from 12 to < 18 years of age)

Winlevi is indicated for the treatment of facial acne vulgaris.

Treatment should be initiated and supervised by a physician experienced in the diagnosis andtreatment of acne vulgaris.

A thin uniform layer of cream should be applied to the affected area twice a day, in the morning andthe evening, with at least eight hours between applications.

Two (2) fingertip units of cream (corresponding to approximately 1 g of cream) will cover an area ofabout 28 x 22 cm (approximately 600 cm2 of skin, corresponding to the average surface area of theface).

Total daily dose should not exceed ten (10) fingertip units (corresponding to approximately 5 g of10 mg/g clascoterone cream). The cream can be applied on the face, chest and/or back.

Adolescents (from 12 to < 18 years of age)

Total daily dose should not exceed four (4) fingertip units (corresponding to approximately 2 g of10 mg/g clascoterone cream). The cream must be applied on the face only. No more than 60 g a monthshould be used (corresponding to one 60 g tube or two 30 g tubes).

For adults and adolescents, to achieve the therapeutic effect, it is recommended to treat for threemonths. After three months of treatment, it is recommended that the physician evaluates the continuedimprovement of the patient. Thereafter, regular assessment every three months of the skin and of thestatus of the patient should determine if continued use of the product is needed taking into account thestatus of the disease and the safety profile of the treatment.

In adolescents, the physician may decide to conduct the first evaluation visit earlier than three months,depending on the patient’s adherence to treatment and/or safety considerations (see sections 4.4 and4.8).

No studies have been conducted in patients with renal or hepatic impairment. Given the very lowsystemic absorption, no dose adjustment or special considerations are anticipated for these patients(see section 5.2).

There are no clinical data in patients aged 65 years or older. Winlevi is not recommended for use inpatients aged 65 years or older.

Children from 9 to < 12 years

The safety and efficacy of Winlevi in children aged 9 to < 12 years old has not been established.

Currently available data are described in section 5.1 but no recommendation on a posology can bemade.

Children below 9 years of age

There is no relevant use of Winlevi in children aged less than 9 years for the treatment of acnevulgaris.

Winlevi is for cutaneous use only.

The affected areas should be clean and dry before application. Winlevi should not be applied to cuts,abrasions, eczematous or sunburned skin. The cream must be applied without using occlusive dressingto avoid an increased risk for systemic undesirable effects (see section 4.4).

Other cutaneous medicinal products used to treat other conditions on the same skin areas should beapplied with a minimum of two (2) hours before or after the application of Winlevi. This is alsoapplicable to the use of sunscreen or emollients.

The patient should be instructed to apply a thin, uniform layer of Winlevi to the affected area,massaging gently, avoiding the eyes, eyelids, lips and nostrils, and then wash hands after application.

The cream must be applied to the entire affected area and not to the acne lesions only.

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

Pregnancy (see section 4.6).

Hypothalamic-pituitary-adrenal (HPA) axis suppression

In a dedicated phase 2 clinical study in adults and adolescents from 12 to < 18 years of age, signs of

HPA-axis suppression were limited to a laboratory-based assessment (adrenocorticotropic hormone[ACTH] stimulated cortisol levels, see section 5.1); no other clinical signs, symptoms or relatedendocrine adverse reactions were associated with such laboratory results. This laboratory-basedevidence of HPA-axis suppression self-resolved without sequelae after treatment discontinuation (seesection 4.8).

Conditions which augment systemic absorption (e.g. use over large surfaces, prolonged use, and theuse of occlusive dressings), should be avoided (see section 4.2).

Typical symptoms of HPA-axis suppression include fatigue, weight loss, decreased appetite, lowblood pressure, hypoglycemia, nausea, diarrhoea, vomiting, or abdominal pain (see section 4.8).

Patients should be instructed to inform their physician if they develop any symptoms of HPA-axissuppression. If adrenal insufficiency is suspected, morning serum cortisol levels could be measuredand the patient may be referred for endocrinological evaluation; treatment should be interrupted if

HPA axis suppression is confirmed.

Adolescents (from 12 to < 18 years of age)

The paediatric population may be at increased risk of HPA axis suppression. In the dedicated phase 2study assessing the potential of clascoterone cream to cause HPA axis suppression, laboratory-basedevidence of HPA axis suppression was more frequently observed in adolescents than in adults (seesection 5.1). In order to reduce the systemic absorption, use in adolescents must be limited to the faceonly (see section 4.2).

Local skin reactions

This medicinal product may induce local irritation (such as erythema, pruritus, scaling/dryness,stinging/burning), mostly of minimal or mild severity (see section 4.8). Caution should be used whenapplying to sensitive areas of the skin, such as the neck: if a local skin reaction in a sensitive areaoccurs, treatment discontinuation should be considered; emollients may also be applied with aminimum of two (2) hours before or after the application of this medicinal product (see section 4.2).

Local irritation could be increased in case of concomitant use of cutaneous anti-acneic medicinalproducts. Concomitant therapy with other anti-acneic cutaneous treatments and other products (i.e.

medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect andproducts with high concentrations of alcohol, astringents, spices or lime) should be used with caution,applied with a minimum of two (2) hours before or after the application of this medicinal product.

Application to abraded, eczematous skin or patients with inflammatory skin conditions that maycoexist with acne, e.g. rosacea or perioral dermatitis, should be avoided.

The concomitant application of astringent cleansing cosmetic products and drying or irritating agents(such as perfumed or alcohol-containing products) should be avoided.

In patients, whose skin has been subjected to procedures such as depilation, chemical peels,dermabrasion or laser resurfacing, the skin should be allowed to recover before application isconsidered.

Concomitant use with photodynamic therapy is not recommended. Treatment with this medicinalproduct should be discontinued prior to initiating photodynamic therapy.

Accidental exposure to mucous membranes

Accidental transfer of cream into eyes, mouth or other mucous membranes should be avoided. Ifcontact with mucous membranes occurs, the area should be rinsed thoroughly with water.

Rebound effect

The rebound effect (i.e., an exacerbation of acne vulgaris) following treatment withdrawal was notassessed during the clinical studies. Rebound effect was reported for compounds structurally related toclascoterone (i.e., topical corticosteroids) and cannot be excluded for this medicinal product. Shouldthere be a reoccurrence of acne vulgaris within days to weeks after successful treatment of thecondition with this medicinal product, a withdrawal reaction should be suspected. Reapplicationshould be done with caution and medical advice is recommended in these cases, or other treatmentoptions should be considered.

Women of childbearing potential have to use an effective contraceptive method during treatment andfor at least 10 days after the last dose (see section 4.6). The pregnancy status should be verified beforeinitiating treatment with this medicinal product in women of childbearing potential (see section 4.6).

Educational materials regarding these precautions are available for healthcare professionals andpatients (or parents/caregivers). A patient card is provided with the package of this medicinal product.

Cetyl alcohol

This medicinal product contains 25 mg cetyl alcohol in each gram. Cetyl alcohol may cause local skinreactions (e.g. contact dermatitis).

This medicinal product also contains 250 mg propylene glycol in each gram. Propylene glycol maycause skin irritation.

No interaction clinical studies have been performed. The use of clascoterone cream at the same time asother cutaneous medicinal products has not been evaluated (see section 4.2).

Since the systemic exposure of clascoterone and its main metabolite cortexolone following cutaneousapplication is negligible, no interaction with systemic treatments is expected; however caution isadvised in concomitant use with glucocorticoid medicinal products.

Women of childbearing potential have to use an effective method of contraception during treatmentand for at least 10 days after the last dose.

No interaction clinical studies have been performed, therefore, an interaction with hormonalcontraception cannot be excluded. The pregnancy status should be verified before initiating treatmentwith clascoterone in women of childbearing potential.

There are no or a limited amount of data from the use of cutaneous clascoterone in pregnant women.

Animal studies have shown reproductive toxicity following subcutaneous administration (see section5.3). Although systemic absorption of cutaneous clascoterone and its main metabolite cortexolone, isnegligible, there could be individual factors (e.g. use over large surfaces, prolonged use) that maycontribute to an increased systemic exposure. Based on animals studies and its mechanism of action(androgen receptor inhibition), clascoterone can cause fetal harm. This medicinal product iscontraindicated during pregnancy (see section 4.3).

The patient must be informed and understand the risks related to the use of this medicinal productduring pregnancy.

It is unknown whether clascoterone/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded.

Use of this medicinal product is not recommended while breast-feeding or breast-feeding should bediscontinued during treatment with this medicinal product.

There are no data on the effect of clascoterone on human fertility. Results from animal studiesfollowing subcutaneous administration showed no effect on fertility in male or female rats (see section5.3).

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

The most frequently occurring adverse reactions are local skin reactions such as erythema (11.5%),scaling/dryness (10.0%), pruritus (7.4%) and stinging/burning (4.0%). These reactions were usuallyself-limiting and resolved during use of this medicinal product.

Adverse reactions reported with cutaneous clascoterone in both adult and adolescent (from 12 to< 18 years of age) patients, including clinical trials and post-marketing experience, are presented in

Table 1 below, according to the MedDRA system organ classification.

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

Table 1: Adverse reactions in adult and adolescent (from 12 to < 18 years of age) patients

System Organ Class Adverse reaction Frequency

Infections and infestations Application site folliculitis Rare

Immune system disorders Hypersensitivity Rare

Nervous system disorders Headache Rare

Respiratory, thoracic and Oropharyngeal pain Raremediastinal disorders

Skin and subcutaneous tissue Acne Raredisorders Dermatitis contact

General disorders and Application site pain Commonadministration Application site drynesssite conditions Application site erythema

Application sitehypertrichosis

Investigations Adrenocorticotropic Commonhormone (ACTH)stimulation test abnormal*

* assessed in the dedicated phase 2 study at supratherapeutic dosages, see section below.

ACTH stimulation test abnormal

Laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression(i.e., decreased serumcortisol levels at 30 minutes after ACTH stimulation) was observed in the dedicated phase 2 study in1/20 (5%) of adult and in 2/22 (9%) of adolescent patients under maximal usage conditions to theentire face, shoulders, upper chest and upper back of acne patients, corresponding to mean dailyamounts of 11.3 g (adults) and 9.3 g (adolescents). No clinical signs or symptoms of adrenalsuppression were observed. Upon discontinuation of treatment the laboratory test results normalisedwithin 4 weeks (see section 4.4).

If HPA axis suppression occurs, treatment interruption should be considered (see section 4.4).

Among the 444 subjects aged 12 to < 18 years enrolled in phase 2 and phase 3 vehicle-controlledstudies for acne vulgaris and exposed to clascoterone cream, the overall incidence of adverse reactionswas 4/444 (0.9%).

Frequency, type and severity of adverse reactions through week 12 were similar to those in adults aspresented in Table 1, which covers both populations.

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.

There is no specific treatment for an overdose with Winlevi.

In the dedicated phase 2 clinical study, a mean daily amount of 11.3 g and 9.3 g clascoterone cream10 mg/g was administered for 2 weeks to 20 adult and 22 adolescent patients, respectively, resulting inlaboratory-based HPA axis suppression in 5% of adults and 9% of adolescents respectively.

In the event of overdose, Winlevi should be discontinued and the patient monitored for potentialoccurrence of HPA axis suppression signs and symptoms.

Pharmacotherapeutic group: Anti-acne preparations, other anti-acne preparations for topical use, ATCcode: D10AX06

Clascoterone is an androgen receptor inhibitor. In vitro studies showed that it potently antagonizes theeffects of androgens in primary human sebocytes to reduce sebum production and accumulation andinflammatory mediators which are known drivers of the acne pathogenesis.

Hypothalamic-pituitary-adrenal (HPA) axis suppression

In the dedicated phase 2 study 171-7151-202 aimed at investigating the potential effects ofclascoterone cream 10 mg/g on the HPA axis and pharmacokinetics in adults and adolescents withacne vulgaris, HPA axis suppression was evaluated in adults (n=20) and adolescents from 12 years ofage (n=22) following application of supratherapeutical doses of clascoterone cream with a mean dailyamount of 11.3 g in adults and 9.3 g in adolescents for 2 weeks (see section 5.2). HPA axissuppression indicated by 30-minute post-stimulation serum cortisol level of ≤ 18 mcg/dL wasobserved in 1/20 (5%) of adult subjects and 2/22 (9%) of adolescent subjects at Day 14. All subjectsreturned to normal HPA axis function at follow-up 4 weeks after the end of treatment.

At approximately 9-times the maximum treatment adult dose (5 g/day of cream), clascoterone does notprolong the QT interval to any clinically relevant extent.

The safety and efficacy of clascoterone cream 10 mg/g applied twice daily for 12 weeks for thetreatment of acne vulgaris were assessed in two identically-designed phase 3, multicentre, randomised,double-blind, vehicle-controlled clinical trials (CB-03-01/25 and CB-03-01/26) enrolling in total1 440 subjects with facial acne vulgaris. The trials enrolled subjects with Investigator’s Global

Assessment (IGA) of moderate or severe facial acne vulgaris (score of 3 or 4), 30 to 75 inflammatorylesions (papules, pustules and nodules), and 30 to 100 non-inflammatory lesions (open and closedcomedones).

Of these 1 440 randomised subjects, 19 (1.3%) were 9 to 11 years of age, 641 (44.5%) were 12 to17 years of age, and 780 (54.2%) were 18 years of age or older. Among adults and adolescents, 62%of the subjects were female and 91% were Caucasian. At baseline, subjects had a mean inflammatorylesion count of 42.4 and a mean non-inflammatory lesion count of 61.4. Approximately 83% ofsubjects had an IGA score of 3.

Efficacy was assessed by three co-primary endpoints: proportion of subjects in each treatment groupachieving “success” at Week 12, with “success” defined as an IGA score of “ clear (score=0)” or“almost clear (score=1)” AND at least a 2-point reduction in IGA compared to baseline, absolutechange from baseline in non-inflammatory lesions count (NILC) in each treatment group at Week 12,and absolute change from baseline in inflammatory lesions count (ILC) in each treatment group at

Week 12.

Adults and adolescents from 12 to < 18 years

The IGA success rate and mean absolute and percent reduction from baseline in acne lesion countsafter 12 weeks of treatment for patients 12 years of age and older are presented in Table 2.

Table 2 Clinical efficacy of clascoterone cream 10 mg/g in adult and adolescent patientswith facial acne vulgaris at week 12

Study CB-03-01/25 Study CB-03-01/26

Clascoterone Vehicle cream Clascoterone Vehicle creamcream cream

N = 342 N = 350 N = 367 N = 362

IGA Successa 18.8% 8.7% 20.9% 6.6%

Difference 10.1% 14.3%from vehicle(95% CI) (4.1%, 16.0%) (8.9%, 19.7%)

Non-inflammatory lesions count (NILC)

Mean absolute 20.4 13.0 19.5 10.8reduction

Difference 7.3 8.7from vehicle(95% CI) (3.5, 11.1) (4.5, 12.4)

Mean percent 32.6% 21.8% 29.6% 15.7%reduction

Difference 10.8% 13.8%from vehicle(95% CI) (3.9%, 17.6%) (7.5%, 20.1%)

Inflammatory lesions count (ILC)

Mean absolute 19.3 15.4 20.1 12.6reduction

Difference 3.9 7.5from vehicle(95% CI) (1.3, 6.5) (5.2, 9.9)

Mean percent 44.6% 36.3% 47.1% 29.7%reduction

Difference 8.3% 17.5%from vehicle(95% CI) (2.2%, 14.4%) (11.8%, 23.1%)aInvestigator Global Assessment (IGA) success was defined as at least a 2-point reduction in IGA compared tobaseline and an IGA score of 0 (clear) or 1 (almost clear).

Among the 641 subjects aged 12 to < 18 years enrolled in phase 3 vehicle-controlled studies for facialacne vulgaris, 316 and 325 subjects were randomized to clascoterone cream and to vehicle,respectively.

Clascoterone cream was superior to vehicle in all the three co-primary endpoints: in the IGA successrate at Week 12 (14.9% vs 3.7%, respectively; Adjusted Odds Ratio [95% CI]: 4.3 [2.2; 8.4]; p-value:

< 0.0001), in the absolute change from baseline in NILC at Week 12 (-17.6 vs -11.4, respectively; LSmean difference [95% CI]: -6.2 [-10.6; -1.9]; p-value: 0.0050) and in the absolute change frombaseline in ILC at Week 12 (-17.9 vs -12.5, respectively; LS mean difference [95% CI]: -5.4 [-8.2; -2.7]; p-value: 0.0001).

Children from 9 to < 12 years

Among the 19 subjects aged 9 to 11 years enrolled in phase 3 vehicle-controlled studies for facial acnevulgaris, 13 and 6 subjects were randomized to clascoterone cream and to vehicle, respectively.

No statistically significant differences between clascoterone cream and vehicle were seen in any of thethree co-primary endpoints: in the IGA success rate at Week 12 (15.4% vs 18.0%, respectively;

Adjusted Odds Ratio [95% CI]: 0.8 [0.1; 11.8]; p-value: 0.8903), in the absolute change from baselinein NILC at Week 12 (7.3 vs -23.4, respectively; LS mean difference [95% CI]: 30.8 [-17.9; 79.4]; p-value: 0.2155) and in the absolute change from baseline in ILC at Week 12 (-20.6 vs -26.3; LS meandifference [95% CI]: 5.7 [-2.5; 13.9]; p-value: 0.1719).

After repeated cutaneous administrations of 4 g to 12 g daily of clascoterone cream 10 mg/g in healthyadults and in adult patients with acne vulgaris for up to 6 consecutive weeks, the systemic exposurewas less than 1% of the total administered dose.

No correlation between blood levels and adverse reactions could be established.

Following cutaneous treatment of clascoterone for 2 weeks with a mean dose of approximately 6 gapplied twice daily (12 g/day of cream) to adult subjects with moderate to severe acne vulgaris (n=20),systemic concentrations of clascoterone were at steady state by Day 5. On Day 14, the mean ± SDmaximum plasma concentrations (Cmax) was 4.5 ± 2.9 ng/mL, the mean ± SD area under the plasmaconcentration-time over the dosing interval (AUCꞇ) was 37.1 ± 22.3 h*ng/mL and the mean ± SDaverage plasma concentration (Cavg) was 3.1 ± 1.9 ng/mL.

In in vitro studies, plasma protein binding of clascoterone was 84% to 89% and was independent ofconcentrations.

Following cutaneous treatment with clascoterone, the plasma concentrations of cortexolone, the mainmetabolite of clascoterone, were detectable and generally below or near the lower limit of quantitation(0.5 ng/mL) in subjects with acne vulgaris.

Excretion of clascoterone has not been fully characterised in humans. Because of the relatively lowsystemic bioavailability of clascoterone, the effects of renal or hepatic impairment were not evaluated.

In adolescent patients with acne vulgaris aged from 12 to < 18 years (n=22) after 2 weeks of treatmentwith a mean dose of approximately 4 g of clascoterone cream 10 mg/g applied twice daily (8 g/day),steady-state concentrations of clascoterone were achieved by Day 14. Clascoterone systemic exposurewas similar to that observed in adult patients treated with 6 g twice daily.

Clinical studies of clascoterone cream did not include sufficient number of subjects 65 years of ageand older to determine whether they respond differently from younger subjects.

CYP enzymes

Clascoterone inhibited CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 with an IC50 value of> 40 µM. Clascoterone up to 30 µM did not induce CYP 1A2, 2B6, or 3A4. These findings suggestthat clascoterone has no clinically meaningful effect on the PK of substances metabolised by CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and repeated dose toxicity studies.

Clascoterone was negative in an in vitro Ames and was aneugenic in an in vitro human lymphocytemicronucleus assay with a threshold of 50 mcg/mL, ˃ 10 000 fold higher than the clinical Cmax reachedwith supratherapeutic doses.

In vivo, in male rats after double subcutaneous administration up to 2000 mg/kg, clascoterone wasclastogenic in the micronucleous test, corresponding to > 100 safety margin calculated on the basis ofanimal versus clinical Cmax and AUC.

Clascoterone was not carcinogenic after daily topical administration of 0.1, 1 or 5 mg/mL cream(1 mg/g, 10 mg/g, or 50 mg/g) in a 2-year carcinogenicity study in rats. A statistically significantincrease in benign sebaceous cell adenoma at the topical application site was observed only in malestreated with the highest concentration of 50 mg/g clascoterone cream. An increased incidence of thenon-neoplastic finding of atrophy of the skin and subcutis at the application site was reported in malesand females treated with 10 mg/g and 50 mg/g clascoterone cream.

In a fertility and early embryonic development study in rats, there was no effect on fertility atsubcutaneous doses up to 12.5 mg/kg/day; increased preimplantation loss and sperm count changeswere noted at this dose level but not at 2.5 mg/kg/day (4.7 to 8.0 times the human exposure based on

AUC comparison).

In an embryofetal development study conducted in rats at subcutaneous doses of 1, 5, or25 mg/kg/day, clascoterone-related malformations were noted at all dose levels, without a doserelationship: omphalocele was noted in a single foetus at each dose level, and external and visceralmalformations (severe dilation of the lateral and third cerebral ventricles; thin skin, small size, andprotruding tongue) were noted in two additional fetuses at 1 mg/kg/day (2.5 times the human exposurebased on AUC comparison).

In rabbits, postimplantation loss and resorptions were increased at a subcutaneous dose of1.5 mg/kg/day whereas no treatment-related effect on embryofetal development was observed at dosesup to 0.4 mg/kg/day (3.7 times the human exposure based on AUC). In a pre- and postnataldevelopment study performed in rats, no significant developmental toxicity was observed atsubcutaneous doses up to 12.5 mg/kg/day.

Based on its endocrine mechanism of action, clascoterone may pose a risk to compartment(s), inparticular the aquatic compartment(s).

Cetyl alcohol

Citric acid monohydrate (E330) (for pH-adjustment)

Glycerol monostearate 40-55 Type I

Liquid paraffin

Polysorbate 80

Propylene glycol (E1520)

Purified water

Disodium edetateall-rac-α-tocopherol (E307)

Not applicable.

3 years

Discard the unused product 1 month after first opening.

Prior to dispensing: store in a refrigerator (2 °C - 8 °C).

Once dispensed to patient: before opening, store in a refrigerator (2 °C - 8 °C). After the first opening,do not store above 25 °C.

Do not freeze.

Epoxy-lined aluminium tube with a polypropylene screw cap.

Pack sizes: tubes of 10 g, 30 g or 60 g.

Not all pack sizes may be marketed.

This medicinal product may pose a risk to the environment (see section 5.3).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Cassiopea S.p.A.

Via C. Colombo, 1

Lainate, 20045

Milan

Italy

EU/1/25/1927/001

EU/1/25/1927/002

EU/1/25/1927/003

Date of first authorisation:

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

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