clascoterone: prescribing information – dosing, contraindications, interactions, side effects

Adults

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 and treatment of acne vulgaris.

Posology

A thin uniform layer of cream should be applied to the affected area twice a day, in the morning and the 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 of about 28 x 22 cm (approximately 600 cm2 of skin, corresponding to the average surface area of the face).

Adults

Total daily dose should not exceed ten (10) fingertip units (corresponding to approximately 5 g of 10 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 of 10 mg/g clascoterone cream). The cream must be applied on the face only. No more than 60 g a month should 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 three months. After three months of treatment, it is recommended that the physician evaluates the continued improvement of the patient. Thereafter, regular assessment every three months of the skin and of the status of the patient should determine if continued use of the product is needed taking into account the status 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 and 4.8).

Renal or hepatic impairment

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

Elderly

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

Paediatric population

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 be made.

Children below 9 years of age

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

Method of administration

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 dressing to 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 be applied with a minimum of two (2) hours before or after the application of Winlevi. This is also applicable 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).

Summary of the safety profile

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 usually self-limiting and resolved during use of this medicinal product.

Tabulated list of adverse reactions

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 and to < 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 mediastinal disorders Oropharyngeal pain Rare Skin and subcutaneous tissue disorders Acne Dermatitis contact Rare General disorders and administration site conditions Application site pain Application site dryness Application site erythema Application site hypertrichosis Common Investigations Adrenocorticotropic hormone (ACTH) stimulation test abnormal* Common * assessed in the dedicated phase 2 study at supratherapeutic dosages, see section below.

Description of selected adverse reactions

ACTH stimulation test abnormal

Laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression(i.e., decreased serum cortisol levels at 30 minutes after ACTH stimulation) was observed in the dedicated phase 2 study in 1/20 (5%) of adult and in 2/22 (9%) of adolescent patients under maximal usage conditions to the entire face, shoulders, upper chest and upper back of acne patients, corresponding to mean daily amounts of 11.3 g (adults) and 9.3 g (adolescents). No clinical signs or symptoms of adrenal suppression were observed. Upon discontinuation of treatment the laboratory test results normalised within 4 weeks (see section 4.4).

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

Paediatric population

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

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

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 national reporting system listed in Appendix V.

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 related endocrine adverse reactions were associated with such laboratory results. This laboratory-based evidence of HPA-axis suppression self-resolved without sequelae after treatment discontinuation (see section 4.8).

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

Typical symptoms of HPA-axis suppression include fatigue, weight loss, decreased appetite, low blood 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-axis suppression. If adrenal insufficiency is suspected, morning serum cortisol levels could be measured and 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 2 study assessing the potential of clascoterone cream to cause HPA axis suppression, laboratory-based evidence of HPA axis suppression was more frequently observed in adolescents than in adults (see section 5.1). In order to reduce the systemic absorption, use in adolescents must be limited to the face only (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 when applying to sensitive areas of the skin, such as the neck: if a local skin reaction in a sensitive area occurs, treatment discontinuation should be considered; emollients may also be applied with a minimum 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 medicinal products. 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 and products 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 may coexist 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 is considered.

Concomitant use with photodynamic therapy is not recommended. Treatment with this medicinal product 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. If contact 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 not assessed during the clinical studies. Rebound effect was reported for compounds structurally related to clascoterone (i.e., topical corticosteroids) and cannot be excluded for this medicinal product. Should there be a reoccurrence of acne vulgaris within days to weeks after successful treatment of the condition with this medicinal product, a withdrawal reaction should be suspected. Reapplication should be done with caution and medical advice is recommended in these cases, or other treatment options should be considered.

Women of childbearing potential

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

Educational materials

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

Excipients with known effect

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 have been performed. The use of clascoterone cream at the same time as other cutaneous medicinal products has not been evaluated (see section 4.2).

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

Women of childbearing potential

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

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

Pregnancy

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 section 5.3). Although systemic absorption of cutaneous clascoterone and its main metabolite cortexolone, is negligible, there could be individual factors (e.g. use over large surfaces, prolonged use) that may contribute 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 is contraindicated during pregnancy (see section 4.3).

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

Breast-feeding

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

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

Fertility

There are no data on the effect of clascoterone on human fertility. Results from animal studies following subcutaneous administration 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.

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 cream 10 mg/g was administered for 2 weeks to 20 adult and 22 adolescent patients, respectively, resulting in laboratory-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 potential occurrence of HPA axis suppression signs and symptoms.

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

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

Pharmacodynamic effects

Hypothalamic-pituitary-adrenal (HPA) axis suppression

In the dedicated phase 2 study 171-7151-202 aimed at investigating the potential effects of clascoterone cream 10 mg/g on the HPA axis and pharmacokinetics in adults and adolescents with acne vulgaris, HPA axis suppression was evaluated in adults (n=20) and adolescents from 12 years of age (n=22) following application of supratherapeutical doses of clascoterone cream with a mean daily amount of 11.3 g in adults and 9.3 g in adolescents for 2 weeks (see section 5.2). HPA axis suppression indicated by 30-minute post-stimulation serum cortisol level of ≤ 18 mcg/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.

Cardiac electrophysiology

At approximately 9-times the maximum treatment adult dose (5 g/day of cream), clascoterone does not prolong the QT interval to any clinically relevant extent.

Clinical efficacy and safety

The safety and efficacy of clascoterone cream 10 mg/g applied twice daily for 12 weeks for the treatment 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 total 1 440 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 inflammatory lesions (papules, pustules and nodules), and 30 to 100 non-inflammatory lesions (open and closed comedones).

Of these 1 440 randomised subjects, 19 (1.3%) were 9 to 11 years of age, 641 (44.5%) were 12 to 17 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 inflammatory lesion count of 42.4 and a mean non-inflammatory lesion count of 61.4. Approximately 83% of subjects had an IGA score of 3.

Efficacy was assessed by three co-primary endpoints: proportion of subjects in each treatment group achieving “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, absolute

change 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

Absorption

After repeated cutaneous administrations of 4 g to 12 g daily of clascoterone cream 10 mg/g in healthy adults and in adult patients with acne vulgaris for up to 6 consecutive weeks, the systemic exposure was 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 g applied 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 ± SD maximum plasma concentrations (Cmax) 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 (Cavg) was 3.1 ± 1.9 ng/mL.

Distribution

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

Biotransformation

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

Elimination

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

Adolescents

In adolescent patients with acne vulgaris aged from 12 to < 18 years (n=22) after 2 weeks of treatment with 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 exposure was similar to that observed in adult patients treated with 6 g twice daily.

Elderly