Winlevi 10 mg/g cream

Winlevi (clascoterone) is indicated for:

• the topical treatment of acne vulgaris in patients 12 years of age and older.

Paediatrics (<12 years): The safety and efficacy of Winlevi have not been established in paediatric patients under 12 years of age.

Posology

A thin uniform layer (approximately 1 g, corresponding to two fingertip units) of cream should be applied to the affected area twice a day, in the morning and the evening. The affected areas should be clean and dry before application. Do not spot treat for optimal efficacy. Hands should be washed before and after applying Winlevi cream.

If patients forget to take a dose of Winlevi, they should be instructed to apply the next dose at the usual time. Patients should be instructed to not apply a double dose to make up for forgotten doses.

A re-evaluation of patient treatment at 12 weeks should be considered if it is necessary to continue or restart treatment after this period and treatment should be continued after medical review and under regular supervision.

Paediatric population

Use in adolescents (12 – 18 years of age): dose adjustment is not required when Winlevi is administered to adolescents aged 12 – 18 years.

The safety and efficacy of clascoterone in children below 12 years of age have not yet been established.

Renal or hepatic impairment

No studies have been conducted in patients with renal or hepatic impairment. Given the very low systemic levels of clascoterone detected in blood after application of therapeutic or supra-therapeutic doses of Winlevi (see section 5.1), no dose adjustment or special considerations are anticipated for patients with renal or hepatic impairment (see section 5.2).

Elderly

Clinical studies of clascoterone did not include sufficient numbers of subjects aged 65 years of age and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Method of administration

For cutaneous use.

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

Winlevi is for external use only. Not for ophthalmic, oral or vaginal use.

Winlevi should not be applied to cuts, abrasions, eczematous or sunburned skin.

Accidental transfer of cream into eyes, mouth or other mucous membranes should be avoided. If contact with mucous membranes occurs, rinse thoroughly with water.

Local Skin Reactions

Clascoterone may induce local irritation (edema, erythema/redness, pruritus, scaling/ dryness, skin atrophy, stinging/burning, striae rubrae, telangiectasia). Concomitant use with other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect and products with high concentrations of alcohol, astringents, spices or lime) should be limited.

Hypothalamic-pituitary-adrenal (HPA) Axis Suppression

Hypothalamic-pituitary-adrenal (HPA) axis suppression was observed and may occur during or after treatment with clascoterone. All Phase 2 maximum use clinical-trial subjects with HPA-axis suppression returned to normal HPA axis function 4 weeks after stopping treatment (see section 5.1). Conditions, which augment systemic absorption, include use over large surfaces areas, prolonged use and the use of occlusive dressings.

If HPA axis suppression develops, consider withdrawing the medicinal product. HPA axis suppression was observed in 1/20 (5%) of adult subjects and in 2/22 (9%) of adolescent subjects. Paediatric patients may be more susceptible to systemic toxicity (see section 5.1).

Hyperkalemia

Elevated potassium levels were observed in some subjects treated with Winlevi or with the vehicle during the clinical trials (see section 5.1).

Excipients

Cetyl alcohol

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

Propylene glycol

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

No interaction clinical studies, including interaction studies with other topical treatments, have been performed. Since the systemic exposure of the main component clascoterone and its metabolites following cutaneous application is negligible, no interaction with systemic treatments is expected.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Clascoterone inhibited CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 with an IC₅₀ value of >40 µM. Clascoterone up to 50 µM did not induce CYP 1A2, 2B6, or 3A4. These findings suggest that Winlevi has no clinically meaningful effect on the PK of drugs metabolized by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4.

Caution should be exercised in using Winlevi along other drugs known to suppress the HPA axis (e.g., topical or inhaled corticosteroids).

Interactions with food, herbal products and laboratory tests have not been established.

Pregnancy

There are no available data on the use of Winlevi in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of clascoterone to pregnant rats and rabbits during organogenesis at doses 8 or 39 times the MRHD, respectively, increased malformations in rats and post-implantation loss and resorptions in rabbits (see section 5.3).

Breast-feeding

No studies were conducted to determine the presence of clascoterone or its metabolite in human or animal milk, the effects on the breastfed infant or the effects on milk production. It is unknown if the drug is excreted in human milk. Precaution should be exercised because many drugs are excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical benefit from clascoterone and any potential adverse effects on the breastfed child from clascoterone.

Fertility

There are no data on the effect of clascoterone on human fertility. Results from animal studies showed no effect on fertility in male or female rats (see section 5.3).

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

Summary of safety profile

A total of 1,757 subjects have been exposed to at least one application of clascoterone across all of the clinical studies. Exposure to clascoterone twice daily was up to 12 months (including treatment period of the parent studies) for 123 subjects. From clinical studies, the most frequently observed side effects included erythema/redness, scaling/dryness.

In maximum-use Phase 2 studies, less common adverse reactions were HPA-axis suppression and hyperkalemia.

Tabulated list of adverse reactions

Adverse reactions reported with clascoterone, including clinical trials and post-marketing experience, are presented in Table 1 below, according to the MedDRA system organ classification (SOC and Preferred Term Level) and frequency. Frequencies have been evaluated according to 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); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 1 Adverse reactions

Description of selected adverse reactions

Local skin reactions

In two identical multicentre, randomized, double-blind, vehicle-controlled trials, 1,421 subjects 12 years and older with facial acne vulgaris applied Winlevi or vehicle twice daily for 12 weeks. Local skin reactions (oedema, erythema/redness, pruritus, scaling/dryness, skin atrophy, stinging/burning, striae rubrae, telangiectasia) were observed during the 12-week treatment and occurred in a similar percentage of subjects treated with vehicle.

Local skin reactions reported by ≥ 1% of subjects treated with clascoterone are shown in Table 2.

Table 2 Incidence of New or Worsening Local Skin Reactions Reported by ≥ 1% of Subjects Treated with Clascoterone After Day 1 in 12-Week Controlled Clinical Trials

^a The denominators for calculating the percentages were the 674 of 709 subjects treated with clascoterone and 656 of 712 subjects treated with vehicle in these trials who had local skin reaction results reported after Day 1.

Clinical Trial Adverse Reactions – Paediatrics

In the pooled Phase 3 studies, in patients aged 12 to <18 years of age, there were no adverse reactions reported in > 1% of patients. The TEAEs reported in ≥ 1% of patients aged 12 to <18 years in the pooled Phase 3 studies, and more often with Winlevi, were headaches (1.3% Winlevi, 0.3% vehicle).

Less Common Clinical Trial Adverse Reactions

The following adverse reactions associated with the use of Winlevi were identified in clinical trials and the long-term safety study. The events are categorized by body system.

Reproductive system and breast disorders: polycystic ovaries

Skin and subcutaneous tissue disorders: hair colour changes

Less Common Clinical Trial Adverse Reactions – Paediatrics

In clinical trials, the types of adverse reactions seen with Winlevi were comparable in adult and paediatric patients.

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings

Clinical laboratory evaluations were not performed in the Phase 3 studies.

In maximum-use Phase 2 studies, the following abnormal laboratory findings were observed:

Endocrine and Metabolism: hypothalamic-pituitary-adrenal (HPA) axis suppression, hyperkalemia (observed in subjects aged 9 to <12 years).

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 Yellow Card Scheme at www.mhra.gov.co.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

No clinical data is available regarding overdose with clascoterone.

Pharmacotherapeutic group: other anti-acne preparations for topical use, ATC code: D10AX06

Mechanism of action

Clascoterone is an androgen receptor inhibitor. When applied topically to the skin, clascoterone acts locally, influencing multiple cellular and molecular acnegenic pathways with minimal systemic exposure. However, the exact mechanism of action of clascoterone for the topical treatment of acne vulgaris is not fully characterised.

Pharmacodynamic effects

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

HPA axis suppression was evaluated in adult (n=20) and adolescent (n=22) subjects with acne vulgaris following twice daily application of clascoterone for 2 weeks in the pharmacokinetic study described in section 5.2. HPA axis suppression indicated by 30-minute post-stimulation serum cortisol level of ≤ 18 µg/dL was observed in 1/20 (5%) of adult subjects and 2/22 (9%) of adolescent subjects at Day 14. All subjects returned to normal HPA axis function at follow-up 4 weeks after the end of treatment. No subject experienced clinical signs and symptoms of adrenal suppression or associated complications.

Potassium

Overall, shifts from normal to elevated potassium levels were observed in 3.6% (17/468) of clascoterone-treated patients and 3.9% (4/103) of vehicle-treated patients (age range: 12 to 64). In a Phase 2 maximum use clinical study with Winlevi administered above the recommended daily dose for up to 2 weeks, an increase in plasma potassium levels (hyperkalemia) was observed in 9/27 (33%) subjects aged 9 to <12.

Cardiac Electrophysiology

At approximately 2-times the systemic exposure observed with the maximum dose, clascoterone does not prolong the QT interval to any clinically relevant extent.

Clinical efficacy and safety

The safety and efficacy of clascoterone applied twice daily for 12 weeks for the treatment of acne vulgaris were assessed in two identically-designed, multicenter, randomised, double-blind, vehicle- controlled clinical trials (CB-03-01/25 and CB-03-01/26) enrolling in total 1,440 subjects with facial acne vulgaris. The trials enrolled subjects 9 years or older with Investigator's Global Assessment (IGA) of moderate or severe facial acne vulgaris (score of 3 or 4), 30 to 75 inflammatory lesions (papules, pustules and nodules), and 30 to 100 non-inflammatory lesions (open and closed comedones). Patients with 2 facial nodules or nodulocystic acne were excluded. Concurrent acne treatment was not allowed.

A total of 1,421 subjects 12 years and older with facial acne vulgaris were enrolled and randomized. The treatment groups in each study were well-balanced with similar demographic and baseline characteristics in the intent-to-treat (ITT) population, both within and between Trial 1 and Trial 2. Of these subjects, 641 (45%) were 12 to <18 years of age, and 780 (55%) were 18 years of age or older. In addition, 62.1% of the subjects were female and 90.6% were Caucasian. At baseline, subjects had a mean inflammatory lesion count of 42.4 and a mean non-inflammatory lesion count of 61.4.

Additionally, approximately 83% of subjects had an IGA score of 3 (“moderate”), and 16.7% had an IGA score of 4 (“severe”).

Efficacy was assessed at Week 12 by the proportion of subjects in each treatment group with at least a 2-point reduction in IGA compared to baseline and an IGA score of 0 (clear) or 1 (almost clear), absolute change and percent change from baseline in non-inflammatory (NILC) and inflammatory lesions (ILC). Secondary efficacy endpoints included absolute and percent change from baseline in total lesion count (TLC); percent change from baseline in non-inflammatory and inflammatory lesion count.

The IGA success rate and mean absolute and percent reduction from baseline in acne lesion counts after 12 weeks of treatment for subjects 12 years of age and older are presented in Table 3.

Table 3 Clinical efficacy of Clascoterone Cream in subjects with acne vulgaris at week 12

^aInvestigator Global Assessment (IGA) success was defined as at least a 2-point reduction in IGA compared to baseline and an IGA score of 0 (clear) or 1 (almost clear).

The results for the secondary endpoints were similar between the 2 studies. The results were statistically significant compared to vehicle in both studies (Table 4).

Table 4 - Results of Secondary Endpoints for Trial 1 and Trial 2 in Patients with acne vulgaris Aged 12 and older at Week 12 (ITT)

^a LS = Least square; Least square mean and p-value are based on analysis of covariance with treatment and analysis center as fixed effects, and baseline value as a covariate

Absorption

Following topical treatment of clascoterone for 2 weeks with a mean dose of approximately 6 grams applied twice daily 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 ± SD maximum plasma concentrations (C_max) was 4.5 ± 2.9 ng/mL, the mean ± SD area under the plasma concentration-time over the dosing interval (AUCꞇ) was 37.1 ± 22.3 h*ng/mL and the mean ± SD average plasma concentration (C_avg) was 3.1 ± 1.9 ng/mL.

Distribution

Plasma protein binding of clascoterone is 84% to 89% and is independent of concentrations, in vitro.

Biotransformation

Following topical treatment with clascoterone, the plasma concentrations of cortexolone, a possible primary metabolite of clascoterone, were detectable and generally below or near the lower limit of quantitation (0.5 ng/mL) in subjects ≥ 9 years of age with acne vulgaris. The in vitro study indicated that incubation of 10 µmol/L clascoterone with human cryopreserved hepatocytes generated cortexolone as the possible primary metabolite and other unidentified metabolites, including conjugated metabolites.

Elimination

Excretion of clascoterone has not been fully characterised in humans. Paediatric population

In adolescent subjects ≥12 to <18 years of age (n=22) after 2 weeks of twice daily treatment with mean dose of approximately 6 grams of Winlevi (or mean dose of approximately 4 grams in younger, smaller subjects), steady-state concentrations of clascoterone were achieved by Day 5. Clascoterone systemic exposure in adolescents was similar to those observed in adults.

Elderly

No studies were conducted in patients ≥65 years of age

In acute intravenous (IV) and subcutaneous (SC) toxicity studies in mice, a single IV administration produced a median lethal dose (LD₅₀) of > 100 mg/kg and a single SC administration produced an LD₅₀ of > 1000 mg/kg. Three out of seven rats dosed with 100 mg/kg (IV) died shortly after dosing. In estrogen-pretreated immature female rabbits, clascoterone administered subcutaneously at 1 mg/kg showed progestational activity characterized by endometrial stimulation and increased uterine weight.

In a 28-day dermal toxicity study in rabbits, haematological and clinical chemistry changes consistent with glucocorticoid effects were seen in animals treated with 50 mg/kg/day, including decreased lymphocytes, increased plasma phospholipids, increased albumin, and increased enzyme levels (AST, ALT, ALP), along with increased liver weight and decreased adrenal weight. Leukopenia was also observed in rats treated with 25 mg/kg/day in a 13-week subcutaneous toxicity study.

In a 26-week repeat-dose toxicity study in Wistar rats, no test article-related changes that could be considered as adverse occurred following repeated SC injection of clascoterone at any of the dose levels investigated (0.1, 0.5 and 2.5 mg/kg/day). The high dose of 2.5 mg/kg/day was considered the no-observed-adverse-effect-level (NOAEL) in this study.

In a 9-month dermal toxicity study in Göttingen minipigs, mild transient erythema was observed in some animals from both sexes at all dose levels (1%, 2.5% or 5%) of clascoterone, with a few isolated instances of moderate to severe erythema. The mean adrenal gland weight was lower in animals treated with 2.5% and 5% clascoterone cream, which correlated with adrenal cortical atrophy (in the zona reticularis and zona fasciculata); this was not fully reversible in males after the recovery period. Minimal to mild atrophy of the skin of animals treated with all dose levels of clascoterone was observed. The testes of one male in the 5% treatment group had minimal interstitial cell hypertrophy. Hair follicles in the treated skin were also in the resting stage more often compared to vehicle. These findings were not considered to be adverse, therefore the NOAEL was determined to be clascoterone 5% cream, the highest concentration tested.

Clascoterone cream (0.1%, 1% or 5%) was not carcinogenic after daily topical administration in a 2- year carcinogenicity study in rats. An increased incidence of the non-neoplastic finding of atrophy of the skin and subcutis at the application site was reported in male and female rats treated with 1% and 5% clascoterone cream.

Clascoterone was not mutagenic in the Ames reverse mutation assay and was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay. In rats, clascoterone administered via subcutaneous injection did not induce micronuclei in the bone marrow at 500 or 1000 mg/kg but a slight increase in micronuclei occurred in 2 of 5 rats at 2000 mg/kg. The response was considered equivoval. Overall, the weight of evidence indicates that clascoterone does not represent a genotoxic risk.

In an embryofetal development study, clascoterone was administered subcutaneously to pregnant rats at doses of 1, 5, or 25 mg/kg/day during the period of organogenesis. No clascoterone-related maternal toxicity or effects on uterine parameters were noted at doses up to 25 mg/kg/day (336 times the MRHD based on AUC comparison). Clascoterone-related malformations were noted at all dose levels, without a dose relationship. Omphalocele was noted in a single fetus at each dose level. External and visceral malformations (severe dilation of the lateral and third cerebral ventricles; thin skin, small size, and protruding tongue) were noted in two additional fetuses at 1 mg/kg/day (8 times the MRHD based on AUC comparison).

In an embryofetal development study, clascoterone was administered subcutaneously to pregnant rabbits at doses of 0.1, 0.4, or 1.5 mg/kg/day during the period of organogenesis. Post-implantation loss and resorptions were increased at 1.5 mg/kg/day (39 times the MRHD based on AUC comparison). No developmental toxicity was noted at doses up to 0.4 mg/kg/day (12 times the MRHD based on AUC comparison). A similar incidence of external and visceral malformations was seen in the control and clascoterone-treated groups (3, 2, 0, and 4 foetuses were affected at 0, 0.1, 0.4, and 1.5 mg/kg/day, respectively).

In a prenatal and postnatal development study, clascoterone was administered subcutaneously to pregnant rats at doses of 0.5, 2.5, and 12.5 mg/kg/day beginning on gestation day 6 and continuing through lactation day 20. No significant maternal or developmental toxicity was observed at doses up to 12.5 mg/kg/day (163 times the MRHD based on AUC comparison).

In a fertility and early embryonic development study in rats, clascoterone was administered subcutaneously at doses of 0.5, 2.5 or 12.5 mg/kg/day from 2-4 weeks before mating through mating. Clascoterone increased pre-implantation loss at 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). Clascoterone decreased testicular sperm counts and increased caudal epididymis sperm counts in males at 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). Clascoterone had no effects on mating or fertility in rats at doses up to 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). No effects were noted on development at doses up to 2.5 mg/kg/day (33 times the MRHD based on AUC comparison).

Environmental risk assessment studies are not available for clascoterone, but based on its endocrine mechanism of action it may pose a risk to aquatic compartment(s).

Cetyl alcohol

Citric acid monohydrate (E-330) (for pH-adjustment)

Glycerol monostearate 40-55 Type I

Liquid paraffin

Polysorbate 80

Propylene glycol (E-1520)

Purified water

Disodium edetate

all-rac-α-tocopherol (E-307)

Not applicable.

3 years

Discard the unused product 180 days after the date of dispensing or 6 months after first opening, whichever comes first.

Store in a refrigerator (2 °C - 8 °C) prior to dispensing. Once dispensed to patient, do not store above 25 °C. Do not freeze.

Epoxy-lined aluminium blind-end tube with a polypropylene cap closure.

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 local requirements.