DRUG INTERACTIONS 

Topical application of AKLIEF Cream is not expected to affect the circulating concentrations of oral hormonal contraceptives containing ethinyl estradiol and levonorgestrel.

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

 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.

 Reduce the risk of such irritation, use a moisturizer from the start of treatment, and, if appropriate, reduce the frequency of application of AKLIEF Cream or suspend use temporarily. 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

 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. The exact process by which trifarotene ameliorates acne is unknown.

2. Pharmacodynamics

At the approved recommended dosage, AKLIEF Cream does not prolong the QT interval to any clinically relevant extent.

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.

 USE IN SPECIFIC POPULATIONS

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 outcomes.

There are case reports of major birth defects similar to those seen in fetuses exposed to oral retinoids in pregnant women exposed to other topical retinoids, but these case reports do not establish a pattern or association with retinoid-related embryopathy.

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.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AKLIEF Cream and any potential adverse effects on the breastfed infant from AKLIEF Cream or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breastmilk, 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.

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.

A total of 897 pediatric subjects aged 9 to 17 years received AKLIEF Cream in the clinical trials 

Safety and effectiveness of AKLIEF Cream have not been established in 3.pediatric subjects under the age of 9 years.

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.