4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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

System organ class

Frequency

Adverse Drug Reaction

Metabolism and nutrition disorders

Common

hyperkalemia

Skin and subcutaneous tissue disorders

Very common

erythema/redness, scaling/dryness

Common

pruritus, stinging/burning, oedema, striae rubrae, skin atrophy, telangiectasia

Reproductive system and breast disorders

Rare

polycystic ovaries, amenorrhea

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

Clascoterone (N=674a)

Vehicle (N=656a)

Oedema

24 (3.6%)

23 (3.5%)

Erythema/redness

82 (12.2%)

101 (15.4%)

Pruritus

52 (7.7%)

54 (8.2%)

Scaling/dryness

71 (10.5%)

68 (10.4%)

Skin atrophy

11 (1.6%)

17 (2.6%)

Stinging/burning

28 (4.2%)

28 (4.3%)

Striae rubrae

17 (2.5%)

10 (1.5%)

Telangiectasia

8 (1.2%)

12 (1.8%)

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.

4.9. Overdose

No clinical data is available regarding overdose with clascoterone.