Aklief (trifarotene): Uses, Dosage, Side Effects & Warnings

Q: Who makes Aklief?

Aklief is listed by 1 labeler in the FDA NDC directory, including Galderma Laboratories, L.P..

Uses

Cream is a retinoid indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. AKLIEF Cream is a retinoid indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. ( 1 )

Dosage and administration

Apply a thin layer of AKLIEF Cream to the affected areas once daily, in the evening, on clean and dry skin. One pump actuation should be enough to cover the face (i.e., forehead, cheeks, nose, and chin). Two actuations of the pump should be enough to cover the upper trunk (i.e., reachable upper back, shoulders and chest). One additional pump actuation may be used for middle and lower back if acne is present. The use of a moisturizer is recommended as frequently as needed from the initiation of treatment. Avoid contact with the eyes, lips, paranasal creases, mucous membranes. AKLIEF Cream is for topical use only. Not for oral, ophthalmic, or intravaginal use. 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. ( 2 )

Dosage forms and strengths

Cream: 0.005%. Each gram of AKLIEF Cream contains 50 mcg of trifarotene in a white cream. Cream: 0.005% trifarotene. ( 3 )

Contraindications

None None ( 4 )

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. ( 5.1 ) Ultraviolet Light and Environmental Exposure: Minimize exposure to sunlight and sunlamps. Use sunscreen and protective clothing over treated areas when exposure cannot be avoided. ( 5.2 ) 5.1 Skin Irritation Patients using AKLIEF Cream may experience erythema, scaling, dryness, and stinging/burning. Maximum severity of these reactions typically occurred within the first 4 weeks of treatment, and severity decreased with continued use of the medication. Depending upon the severity of these adverse reactions, instruct patients to use a moisturizer, reduce the frequency of application of AKLIEF Cream, or suspend use temporarily. If severe reactions persist the treatment may be discontinued. Avoid application of AKLIEF Cream to cuts, abrasions, or eczematous or sunburned skin. Use of “waxing” as a depilatory method should be avoided on skin treated with AKLIEF Cream. 5.2 Ultraviolet Light and Environmental Exposure Minimize unprotected exposure to ultraviolet rays (including sunlight and sunlamps) during treatment with AKLIEF Cream. Warn patients who normally experience high levels of sun exposure and those with inherent sensitivity to sun to exercise caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided.

Side effects

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 . 6.1 Clinical trials experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice. In the three Phase 3 clinical trials, 1673 subjects with acne vulgaris on the face and trunk, 9 years and older were exposed to AKLIEF Cream. Of these, 1220 subjects were treated once daily for up to 12 weeks and 453 were treated once daily for up to 1 year. Adverse reactions reported in the 2 randomized, double-blind, vehicle-controlled 12-week clinical trials in ≥ 1.0% of subjects treated with AKLIEF Cream (and for which the rate exceeded the rate for vehicle), as well as the corresponding rates reported in subjects treated with the vehicle cream are presented in Table 1. Table 1. Adverse Reactions Occurring in ≥ 1.0% of Subjects with Acne Vulgaris of the Face and Trunk in the Two 12-week Phase 3 Clinical Trials Preferred Term AKLIEF Cream (N=1220) Vehicle Cream (N=1200) Application site irritation 91 (7.5) 4 (0.3) Application site pruritus 29 (2.4) 10 (0.8) Sunburn 32 (2.6) 6 (0.5) Additional adverse reactions that were reported in more than one subject treated with AKLIEF Cream (and at a frequency <1%) included application site pain, application site dryness, application site discoloration, application site rash, application site swelling, application site erosion, acne, dermatitis allergic, and erythema. In the one-year, open-label safety trial that included 453 subjects 9 years and older, with acne vulgaris of the face and trunk, the pattern of adverse reactions for AKLIEF Cream was similar to that experienced in the 12-week controlled trials. A total of 12.6% of subjects had at least one adverse reaction during the trial, and 2.9% of subjects had an adverse reaction leading to treatment discontinuation. The most common adverse reactions (≥1% of subjects) for the entire trial were application site pruritus (4.6%), application site irritation (4.2%), and sunburn (5.5%). The frequency of adverse reactions decreased over time. Skin irritation was evaluated by active assessment of erythema, scaling, dryness, and stinging/burning and collected separately. In the two 12-week Phase 3 clinical trials, these signs/symptoms were assessed at baseline and at least one post-baseline visit, in 1214 subjects (for face) and 1202 subjects (for trunk) treated with AKLIEF Cream. The percentage of subjects who were assessed to have these signs and symptoms at any post baseline visit and at a severity worse than baseline are summarized in Table 2. Table 2. Application Site Tolerability Reactions at Any Post Baseline Visit Face AKLIEF Cream N=1214 Maximum Severity during Treatment Vehicle Cream N=1194 Maximum Severity during Treatment Mild Moderate Severe Mild Moderate Severe Erythema 30.6% 28.4% 6.2% 21% 6.8% 0.8% Scaling 37.5% 27.1% 4.9% 23.7% 5.9% 0.3% Dryness 39% 29.7% 4.8% 29.9% 6.8% 0.8% Stinging/Burning 35.6% 20.6% 5.9% 15.9% 3.8% 0.5% Trunk N=1202 N=1185 Erythema 26.5% 18.9% 5.2% 12.7% 4.4% 0.4% Scaling 29.7% 13.7% 1.7% 13.2% 2.6% 0.1% Dryness 32.9% 16.1% 1.8% 17.8% 3.9% 0.1% Stinging/Burning 26.1% 10.9% 4.3% 9.2% 2.2% 0.5% Local tolerability on the face in subjects treated with AKLIEF Cream worsened for any of the signs/symptoms compared with baseline to a score of moderate for up to 30% of subjects, or severe for up to 6% of subjects. On the trunk, the corresponding percentages were up to 19% (moderate) and up to 5% (severe). The scores reached maximum severity at Week 1 for the face, and at Week 2 to 4 of treatment for the trunk, and decreased thereafter. In the open-label, 1-year Phase 3 trial, the local tolerability profile was comparable to that observed in the two pivotal Phase 3 trials.

Drug interactions

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

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 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. In animal reproduction studies, oral doses of trifarotene administered to pregnant rats and rabbits during organogenesis that resulted in systemic exposures more than 800 times the systemic exposure at the maximum recommended human dose (MRHD) of AKLIEF Cream resulted in adverse fetal effects, including fetal deaths and external, visceral, and skeletal malformations (see Data) . 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. Data Animal Data Oral administration of trifarotene to pregnant rats during the period of organogenesis at doses that resulted in systemic exposures greater than 1600 times those in humans at the MRHD of AKLIEF Cream resulted in adverse fetal effects, including fetal deaths, reduced mean fetal weight, and external, visceral, and skeletal malformations. Oral administration of trifarotene to pregnant rabbits during the period of organogenesis at doses that resulted in systemic exposures at least 800 times those in humans at the MRHD of AKLIEF Cream resulted in adverse fetal effects, including defects of the tail, limbs, urogenital organs, and vertebral column. Trifarotene administered orally to female rats from gestation Day 6 to lactation Day 20, at doses that resulted in systemic exposures up to 594 times those in humans at the MRHD of AKLIEF Cream, had no effect on maternal function or behavior, including gestation, delivery, pup-rearing, lactation and nursing, or survival or development of pups . There were no effects of maternal treatment on behavior, learning, memory, or reproductive function of pups. 8.2 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. It is possible that topical administration of large amounts of trifarotene could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations) . 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. 8.4 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 [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] . Safety and effectiveness of AKLIEF Cream have not been established in pediatric subjects under the age of 9 years. 8.5 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.

Pregnancy

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 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. In animal reproduction studies, oral doses of trifarotene administered to pregnant rats and rabbits during organogenesis that resulted in systemic exposures more than 800 times the systemic exposure at the maximum recommended human dose (MRHD) of AKLIEF Cream resulted in adverse fetal effects, including fetal deaths and external, visceral, and skeletal malformations (see Data) . 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. Data Animal Data Oral administration of trifarotene to pregnant rats during the period of organogenesis at doses that resulted in systemic exposures greater than 1600 times those in humans at the MRHD of AKLIEF Cream resulted in adverse fetal effects, including fetal deaths, reduced mean fetal weight, and external, visceral, and skeletal malformations. Oral administration of trifarotene to pregnant rabbits during the period of organogenesis at doses that resulted in systemic exposures at least 800 times those in humans at the MRHD of AKLIEF Cream resulted in adverse fetal effects, including defects of the tail, limbs, urogenital organs, and vertebral column. Trifarotene administered orally to female rats from gestation Day 6 to lactation Day 20, at doses that resulted in systemic exposures up to 594 times those in humans at the MRHD of AKLIEF Cream, had no effect on maternal function or behavior, including gestation, delivery, pup-rearing, lactation and nursing, or survival or development of pups . There were no effects of maternal treatment on behavior, learning, memory, or reproductive function of pups. 8.5 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.

Geriatric use

8.4 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 [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] . Safety and effectiveness of AKLIEF Cream have not been established in pediatric subjects under the age of 9 years.

Description

Cream for topical administration contains 0.005% (50 mcg/g) trifarotene. Trifarotene is a terphenyl acid derivative and is a retinoid. The chemical name of trifarotene is 3”-tert-Butyl-4’-(2-hydroxy-ethoxy)-4”-pyrrolidin-1-yl-[1,1’,3’,1”]terphenyl-4- carboxylic acid. Trifarotene has the molecular formula of C 29 H 33 NO 4 , the molecular weight of 459.58, and the following structural formula: Trifarotene is a white to off-white to slightly yellow powder with the melting point of 245°C. It is practically insoluble in water with pKa1 of 5.69 and pKa2 of 4.55. AKLIEF (trifarotene) Cream 0.005% contains the following inactive ingredients: allantoin, copolymer of acrylamide and sodium acryloyldimethyltaurate dispersion 40% in isohexadecane, cyclomethicone, 95% (v/v) ethanol, medium-chain triglycerides, phenoxyethanol, propylene glycol, purified water. trifarotene chemical structure

Mechanism of action

12.1 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.

How supplied

Cream, 0.005% is provided as a white cream supplied in the following packaging configurations with corresponding NDC numbers: 45-gram pump NDC 0299-5935-45 Storage and Handling - Store at 20˚ to 25˚C (68˚ to 77˚F); excursions permitted to 15° to 30°C (59° to 86°F).. - Keep away from heat. - Keep out of reach of children.

Patient 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. Dallas, Texas 75201 USA Made in Canada All trademarks are the property of their respective owners. Patient Information AKLIEF® (trifarotene) cream Important: AKLIEF Cream is for use on the skin only. Do not use AKLIEF Cream in your mouth eyes, or vagina. What is AKLIEF Cream? AKLIEF Cream is a prescription medicine used on the skin (topical) to treat acne vulgaris in people 9 years of age and older. It is not known if AKLIEF Cream is safe and effective in children younger than 9 years old. Before using AKLIEF Cream, tell your healthcare provider about all of your medical conditions, including if you : have skin problems, including eczema, cuts or sunburn are pregnant or planning to become pregnant. It is not known if AKLIEF Cream can harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if AKLIEF Cream passes into your breast milk. Breastfeeding women should use AKLIEF Cream on the smallest area of skin and for the shortest time needed while breastfeeding. Do not apply AKIEF Cream to the nipple and areola to avoid contact with your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-couter medicines, vitamins and herbal supplements. Especially tell your healthcare provider if you use any other medicine for acne. How should I use AKLIEF Cream? Use AKLIEF Cream exactly as your healthcare provider tell you to use it. Apply a thin layer of AKLIEF Cream over the affected areas 1 time each day, in the evening. Applying AKLIEF Cream: Wash the area where the cream will be applied and pat dry. If you receive a sample tube of AKLIEF Cream, follow your healthcare provider’s instructions about how much to apply. AKLIEF Cream comes in a pump. Press down on (depress) the pump 1 time to dispense a small amount of AKLIEF Cream and spread a thin layer over your face (forehead, cheeks, nose, and chin). Avoid contact with your eyes, lips, mouth, and the corners of your nose. Press down on the pump 2 times to dispense enough AKLIEF Cream to apply a thin layer to cover your upper trunk (the area of your upper back that you can reach, shoulders, and chest). One more pump may be used to apply a thin layer of AKLIEF Cream to your middle and lower back, if acne is present. When you begin treatment with AKLIEF Cream, you should begin applying a moisturizer on your skin as often as needed. See “Local skin irritation” below. What should I avoid while using AKLIEF Cream? Minimize exposure to sunlight. You should avoid using sunlamps, tanning beds, and ultraviolet light during treatment with AKLIEF Cream. If you have to be in sunlight or are sensitive to sunlight, use a sunscreen with a SPF (sun protection factor) of 15 or more, and wear protective clothing and a wide-brimmed hat to cover the treated areas. Avoid using AKLIEF Cream on skin areas with cuts, abrasions, eczema, or on sunburned skin. Avoid using skin products that may dry or irritate your skin, such as: medicated or abrasive soaps and cleansers soaps, cleansers, and cosmetics that have strong skin drying effects products that contain high amounts of alcohol Avoid the use of “waxing” as a hair removal method on skin treated with AKLIEF Cream. What are the possible side effects of AKLIEF Cream? AKLIEF Cream may cause serious side effects including: Local skin irritation. Local skin reactions are common with AKLIEF Cream, are most likely to happen during the first 4 weeks of treatment and may decrease with continued use of AKLIEF Cream. Signs and symptoms of local skin reactions include: redness scaling dryness stinging or burning To help reduce your risk of developing these local skin reactions, when you begin treatment with AKLIEF Cream, you should begin applying a moisturizer on your skin as often as needed. Tell your healthcare provider if you develop symptoms of a local skin reaction. Your doctor may tell you to use AKLIEF Cream less often, or temporarily, or permanently stop your treatment with AKLIEF Cream. The most common side effects of AKLIEF Cream include: itching and sunburn. See “What should I avoid while using AKLIEF Cream. These are not all the possible side effects of AKLIEF Cream. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to GALDERMA LABORATORIES, L.P. at 1-866-735-4137. How should I store AKLIEF Cream? Store AKLIEF Cream at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) Keep AKLIEF Cream away from heat.

Active ingredients

Trifarotene in 1 product

Aklief NDC products (1)

NDC	Strength & form	Labeler	Type
0299-5935	Trifarotene 50 ug/g Cream	Galderma Laboratories, L.P.	NDA

Frequently asked questions

What is Aklief used for?

Cream is a retinoid indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. AKLIEF Cream is a retinoid indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. ( 1 )

What are the side effects of Aklief?

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 . 6.1 Clinical trials experience Because clinical trials are conducted under widely varying… See the full label for the complete list.

Who makes Aklief?

Aklief is listed by 1 labeler in the FDA NDC directory, including Galderma Laboratories, L.P..