HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use AKLIEF Cream safely and effectively. See full prescribing information for AKLIEF Cream. AKLIEF® (trifarotene) cream, for topical use

Initial U.S. Approval: 2019

 indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.

 ADVERSE REACTIONS

 Most common adverse reactions (incidence = 1%) in patients treated with AKLIEF Cream were application site irritation, application site pruritus, and sunburn

 CONTRAINDICATIONS

 None 

 WARNINGS AND PRECAUTIONS

 Skin irritation: Erythema, scaling, dryness, and stinging/burning may be experienced with use of AKLIEF Cream. Use a moisturizer from the initiation of treatment, and, if appropriate, reduce the frequency of application of AKLIEF Cream, suspend or discontinue use.

 Ultraviolet Light and Environmental Exposure: Minimize exposure to sunlight and sunlamps. Use sunscreen and protective clothing over treated areas when exposure cannot be avoided.

-------------- ADVERSE REACTIONS ---------------------------- Most common adverse reactions (incidence = 1%) in patients treated with AKLIEF Cream were application site irritation, application site pruritus, and sunburn (6). To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION

 For topical use only. Not for oral, ophthalmic or intravaginal use.

 Apply a thin layer of AKLIEF Cream to the affected areas of the face and/or trunk once a day, in the evening, on clean and dry skin. Avoid contact with the eyes, lips, paranasal creases, and mucous membranes.

 DOSAGE FORMS AND STRENGTHS

- Cream: 0.005% trifarotene. 

PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information).

Advise the patient to: ? Cleanse the area to be treated; pat dry. Apply AKLIEF Cream as a thin layer once daily in the evening to the face, avoiding the eyes, lips, nasolabial folds, and mucous membranes

. A thin layer of AKLIEF Cream may also be applied to the chest, shoulders, and back

. ? Avoid applying AKLIEF Cream to damaged skin (such as cuts, abrasions), eczematous areas, and sunburned skin.

emporarily. AKLIEF Cream may cause irritation such as erythema, scaling, dryness, and stinging or burning.

? Minimize exposure to sunlight, including sunlamps and phototherapy devices. ? Use sunscreen products and protective apparel (e.g., hat) over treated areas when exposure to sunlight cannot be avoided.

? Avoid concomitant use of other potentially irritating topical products (medicated or not).

? Use AKLIEF Cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply AKLIEF Cream directly to the nipple and areola to avoid direct infant exposure.

Marketed by: GALDERMA LABORATORIES, L.P. Fort Worth, Texas 76177 USA Made in Canada GALDERMA is a registered trademark.

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Trifarotene is an agonist of retinoic acid receptors (RAR), with particular activity at the gamma subtype of RAR. Stimulation of RAR results in modulation of target genes which are associated with various processes, including cell differentiation and mediation of inflammation.

3. Pharmacokinetics Pharmacokinetics of trifarotene was evaluated in a study involving 19 adult subjects with acne vulgaris following once daily application of AKLIEF Cream for 29 days (daily dose range 1.5 g/day to 2 g/day) to the face, shoulders, chest and upper back.

Absorption -

Systemic concentrations were at steady state following 2 weeks of treatment and were quantifiable in 7 subjects. Steady state Cmax ranged from below the limit of quantification (less than 5 pg/mL) to 10 pg/mL and AUC0-24h ranged from 75 to 104 pg.h/mL in adults. No drug accumulation is expected with long-term use. Distribution Plasma protein binding is approximately 99.9%.

Elimination The terminal half-life ranged from 2 to 9 hours.

Metabolism Trifarotene is primarily metabolized by CYP2C9, CYP3A4, CYP2C8, and to a lesser extent by CYP2B6 in vitro

Excretion- Trifarotene is primarily excreted by the feces.

Specific Populations-

Pediatric Patients Steady state Cmax ranged from less than 5 pg/mL to 9 pg/mL and AUC0-24h ranged from 89 to 106 pg.h/mL in pediatrics (10 to 17- years-old). Steady state conditions were achieved in patients following 2 weeks of topical administration. No drug accumulation is expected with long-term use.

Drug Interactions Studies-

Clinical Studies and Model-Based Approaches No clinically significant differences in the pharmacokinetics of trifarotene were predicted when used concomitantly with fluconazole (a moderate CYP2C9 and CYP3A inhibitor).

In Vitro Studies Cytochrome P450 (CYP) Enzymes: AKLIEF Cream is not expected to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4, or induce CYP1A2, 2B6, and 3A4. Transporter Systems: AKLIEF Cream is not expected to inhibit MATE, OATP, OAT, OCT, BCRP, P-gp, BSEP, or MRP.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Trifarotene was not carcinogenic when topically applied to mice daily for up to 24 months in the vehicle of the product (AKLIEF Cream) at concentrations of 0.0005% or 0.001% w/w. The systemic exposures at the highest doses evaluated in mice were approximately 82 (males) and 99 (females) times higher than the human exposure at the MRHD of AKLIEF Cream. Trifarotene was not

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary Available data from clinical trials with AKLIEF Cream use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcome

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes

 In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

.2 Lactation Risk Summary

There are no data on the presence of trifarotene in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, trifarotene was present in rat milk with oral administration of the drug. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

3 Pediatric Use -                                                                                                         Safety and effectiveness of AKLIEF Cream for the topical treatment of acne vulgaris have been established in pediatric patients age 9 years to 17 years based on evidence from well-controlled clinical trials, a long-term safety trial, and a pharmacokinetic trial.

4 Geriatric use- Clinical trials of AKLIEF Cream did not include any subjects aged 65 years and over to determine whether they respond differently than younger subjects.