Aklief (Cream) Instructions for Use

Marketing Authorization Holder

Galderma, SA (Switzerland)

Manufactured By

Laboratoires Galderma (France)

Contact Information

GALDERMA SA (Switzerland)

ATC Code

D10AD06 (Trifarotene)

Active Substance

Trifarotene (Rec.INN registered by WHO)

Dosage Form

Aklief

Cream for external use 50 mcg/1 g: fl. 30 g or 75 g

Dosage Form, Packaging, and Composition

Cream for external use homogeneous, white in color.

Excipients: purified water, propylene glycol, allantoin, medium-chain triglycerides, phenoxyethanol, cyclomethicone, Simulgel 600 PHA (acrylamide/sodium acryloyldimethyltaurate copolymer, isohexadecane, polysorbate 80, sorbitan oleate, water), ethanol 96%.

30 g – polypropylene bottles (1) with a dosing device – cardboard boxes.
75 g – polypropylene bottles (1) with a dosing device – cardboard boxes.

Clinical-Pharmacological Group

Acne treatment drug. Retinoid

Pharmacotherapeutic Group

Drugs for the treatment of acne; drugs for the treatment of acne for topical use; retinoids for the treatment of acne for topical use

Pharmacological Action

Mechanism of action

Aklief cream contains 50 micrograms (mcg/g) (by weight) of trifarotene – a chemically stable derivative of terphenyl carboxylic acid with retinoid activity.

It is a potent RAR_γ (retinoic acid receptor γ-agonist), characterized by high specificity for this receptor compared to RAR_α and RAR_β (50 and 8 times respectively, with no retinoid X receptor (RXR) activity).

Furthermore, in immortalized keratinocyte lines and reconstructed epidermis, Trifarotene modulates the activity of retinoid target genes (differentiation and inflammatory processes).

The exact process by which acne severity is reduced is unknown.

Pharmacodynamic effects

Trifarotene in the hairless mouse model with a rhino mutation provided pronounced comedolytic activity with a reduction in the number of comedones and a noticeable increase in epidermal thickness.

In this model, Trifarotene was not inferior in comedolytic effect to other known retinoids at approximately 10 times lower dose.

Trifarotene also had anti-inflammatory and depigmenting effects.

Clinical efficacy and safety

The use of Aklief cream once a day, in the evening for 12 weeks, was evaluated in two randomized, multicenter, double-blind, placebo-controlled studies in parallel groups with identical design.

A total of 2420 patients aged 9 years and older suffering from acne vulgaris of moderate and severe degree with localization on the skin of the face and trunk participated in them.

Acne severity was assessed using a 5-point Investigator’s Global Assessment (IGA) scale for the face and a Physician’s Global Assessment (PGA) scale for the trunk, with moderate acne considered grade 3 (see Table 1).

Table 1. Investigator’s Global Assessment (IGA) and Physician’s Global Assessment (PGA) Scales

* CI – confidence interval.

Long-term use efficacy

In a long-term – one-year (52 weeks), open-label safety study involving 453 patients aged 9 years and older with moderate to severe acne vulgaris localized on the face and trunk, the use of Aklief cream clinically significantly improved the condition of acne according to the IGA and PGA scales

• From 26.6% at the 12-week visit to 65.1% at the 52-week visit for the face;
• From 38.6% at the 12-week visit to 66.9% at the 52-week visit for the trunk.

The efficacy according to the IGA and PGA scales, achieved in the same participants, increased from 22.0% at week 12 to 57.9% at week 52.

Pharmacokinetics

The pharmacokinetics of trifarotene were evaluated in a study that included 19 adult participants with acne vulgaris, who applied Aklief cream once daily for 29 days (daily dose ranged from 1.5 g/day to 2 g/day) to the face, shoulders, chest, and upper back.

Absorption

The absorption of trifarotene from the Aklief cream formulation was assessed in adults and children (10-17 years) with acne.

Participants were prescribed Aklief cream at 2 grams per day, applied once daily for 30 days to the face, shoulders, chest, and upper back.

Overall systemic exposure levels were low and similar in adults and children.

After 4 weeks of treatment, trifarotene plasma levels were quantifiable in seven out of nineteen (37%) adult patients.

C_max ranged from below the limit of quantification (LOQ< 5 pg/mL) to 10 pg/mL, and AUC_(0-24) ranged from 75 to 104 pg×h/mL.

In three out of seventeen (18%) children, systemic exposure was quantifiable.

C_max ranged from below the limit of quantification (LOQ< 5 pg/mL) to 9 pg/mL, and AUC_(0-24) ranged from 89 to 106 pg×h/mL.

After 2 weeks of topical application, steady-state drug concentration was achieved in both adults and children.

No accumulation is expected with long-term use.

Distribution

Trifarotene penetrates the skin with exponential distribution from the stratum corneum to the epidermis and dermis.

In vitro studies have shown that Trifarotene is more than 99.9% bound to plasma proteins. No significant binding of trifarotene to erythrocytes was observed.

Metabolism

In vitro studies using human liver microsomes and recombinant CYP450 enzymes noted that Trifarotene is predominantly metabolized by CYP2C9, CYP3A4, CYP2C8 enzymes and to a lesser extent by CYP2B6.

Excretion

Trifarotene is excreted primarily in feces.

Potential for pharmacokinetic drug interactions

In vitro studies have shown that Aklief cream at systemic concentrations achieved after topical application did not inhibit the CYP450 isoenzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4, nor did it induce the CYP1A2, 2B6, 3A4 isoenzymes.

In vitro studies have shown that Aklief cream at systemic concentrations achieved after topical application does not inhibit the uptake transporters MATE, OATP, OAT, OCT, nor the efflux transporters BCRP, Pgp, BSEP, MPR.

Pharmacokinetics in special patient groups

Children. Steady-state C_max ranged from below 5 pg/mL to 9 pg/mL, and AUC_(0-24) ranged from 89 to 106 pg×h/mL in children (10 to 17 years).

After 2 weeks of topical application, a steady-state drug concentration was achieved in patients.

No drug accumulation effect is expected with long-term use.

Indications

For patients over 12 years of age and adults

• External therapy of moderate to severe acne vulgaris in the presence of numerous comedones, papules and pustules on the skin of the face and/or trunk.

ICD codes

Dosage Regimen

Aklief cream should be applied in a thin layer to the entire acne-affected surface of the facial skin (forehead, nose, chin, right and left cheek) and/or trunk once a day, in the evening, on clean and dry skin.

The duration of treatment should be determined by the attending physician based on the patient’s clinical condition. It is recommended to evaluate the therapeutic effect of the patient’s condition after three months of treatment.

Method of application

For external use only.

The cream is applied in a thin layer to previously cleansed and dry affected areas of the face and/or trunk.

One press of the dosing device should be sufficient for application to the entire affected surface of the face (forehead, nose, chin, both cheeks).

Two presses of the dosing device are sufficient for application to the entire upper part of the trunk (e.g., upper back, shoulders, chest).

One additional press may be used for the middle and lower back if necessary.

Special patient groups

The safety and efficacy of Aklief in patients aged 65 years and older have not been established.

No studies of Aklief have been conducted in patients with renal impairment.

No studies of Aklief have been conducted in patients with hepatic impairment.

Children

The safety and efficacy of Aklief in children aged 0 to 12 years have not been established. Data are limited.

Adverse Reactions

Summary of the safety profile

Localized skin reactions at the application site (such as erythema, scaling, dryness, and tingling/burning) were recorded separately from other adverse events as an indicator of local tolerance.

These reactions are widespread and occur on the face with mild, moderate, and severe intensity, in 39%, 29.7%, and 6.2% of patients, respectively.

Mild, moderate, and severe reactions on the trunk developed in 32.9%, 18.9%, 5.2% of patients, respectively.

The most severe manifestations of local reactions were generally observed in week 1 on the face and in weeks 2-4 on the trunk, and decreased with further use of the drug.

The most frequently reported adverse reactions, as described in Table 6 below, were application site irritation, application site pruritus, and sunburn, observed in 1.2-6.5% of patients using Aklief cream in clinical studies.

Tabulated summary of adverse reactions

Adverse reactions noted in the 12-week placebo-controlled Phase 3 studies with Aklief cream in 1220 patients are presented in Table 6.

The following categories are used to determine the frequency of adverse effects: very common (≥1/10), common (from ≥1/100, but <1/10), uncommon (from ≥1/1000, but <1/100), rare (from ≥1/10000, but <1/1000), very rare (<1/10000); and frequency not known (cannot be estimated from the available data).

Table 6. Adverse reactions

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to trifarotene or to any of the excipients included in the drug;
• Pregnancy;
• Planning pregnancy.

Use in Pregnancy and Lactation

Orally administered retinoids are associated with congenital anomalies. However, when used as prescribed by physicians, topical retinoids usually result in minimal systemic exposure due to low absorption through the skin.

Nevertheless, individual reactions may occur (e.g., damage to the skin barrier from excessive application of the drug to the skin) that will lead to increased systemic exposure.

Pregnancy

Aklief is contraindicated during pregnancy or when planning pregnancy.

In animal studies, trifarotene administered orally showed reproductive toxicity at very high systemic exposure.

In reproductive toxicity studies in animals, oral doses of trifarotene were administered to pregnant rats and rabbits during organogenesis, resulting in an 800-fold increase in systemic exposure relative to the maximum recommended human dose for Aklief cream, which, in turn, led to adverse effects on the fetus, including fetal death, as well as external developmental abnormalities, visceral and skeletal abnormalities.

If the drug is used during pregnancy or if the patient becomes pregnant while taking this drug, treatment should be discontinued.

Available data from clinical studies of Aklief cream use in women who became pregnant while using Aklief did not find a risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes associated with drug use.

Clinical cases of major birth defects similar to those observed in the fetus with oral retinoid use have been described in pregnant women using topical retinoids; however, in these clinical cases, a pattern or association with retinoid-associated embryopathy was not established.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

Lactation

It is not known whether Trifarotene or its metabolites are excreted in human breast milk, there are no data on the effects of the drug on the child whose mother is using Trifarotene, and the effects on lactation are also unknown.

Available pharmacodynamic/toxicological data in animals showed excretion of trifarotene/metabolites in milk after oral administration in rats.

Topical application in large doses may lead to systemic absorption of trifarotene and its excretion in milk.

The decision to discontinue breastfeeding or drug use should be made by weighing the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Women during lactation are not recommended to apply Aklief cream to the breast area to avoid direct contact with the child.

Fertility

There are no clinical data on the effect of the drug on human fertility.

No adverse effects of the drug on fertility were found in studies in rats. However, after oral administration to dogs, signs of germ cell degeneration were observed at doses where systemic exposure was 1170 times higher than in humans at the maximum allowable dose for Aklief cream.

Use in Hepatic Impairment

No studies of Aklief have been conducted in patients with hepatic impairment.

Use in Renal Impairment

No studies of Aklief have been conducted in patients with renal impairment.

Pediatric Use

Contraindicated for use in children under 12 years of age (safety and efficacy have not been established).

Geriatric Use

The safety and efficacy of Aklief in patients aged 65 years and older have not been established.

Special Precautions

Redness, scaling, dryness, and burning of the skin may develop with the use of Aklief cream.

To reduce the risk of such reactions, patients are advised to use moisturizing cosmetics from the start of treatment, and if necessary, reduce the frequency of Aklief cream application or temporarily suspend its use.

If, despite the measures taken to reduce the risk, severe adverse reactions persist, treatment may be discontinued.

The drug should not be applied to cuts, abrasions, eczematous skin, or sunburned skin.

The use of wax as a depilation method on areas of skin where Aklief is applied should be avoided, as with other retinoids.

If a hypersensitivity reaction to any component of the drug is suspected, the use of Aklief should be discontinued.

Caution should be exercised when using cosmetics with desquamative (exfoliating), irritating, or drying effects, as when used together with this drug they may have an additional irritating effect.

Avoid getting the medication into the eye area, mouth, nasal passages, and mucous membranes. If the medication gets into the eyes, on the eyelids, lips, or mucous membranes, rinse them immediately with plenty of warm water.

It is recommended to avoid excessive exposure of the skin to sunlight or artificial ultraviolet radiation while using the medication.

If exposure to sunlight is unavoidable, it is necessary to use a waterproof, broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30 and to cover the skin with clothing (e.g., wear a hat and a shirt).

Excipients

The medication contains propylene glycol (E1520), which may cause skin irritation.

Effect on the Ability to Drive Vehicles and Operate Machinery

Aklief has no or negligible influence on the ability to drive vehicles and operate machinery.

Overdose

Symptoms: Overdose is unlikely when the medication is used according to the instructions for use. Excessive application of the medication may lead to severe redness, peeling, and skin discomfort. In such a case, treatment with the medication should be discontinued until the symptoms of irritation completely disappear.

Treatment: In case of accidental ingestion of even a small amount of the medication, gastric lavage should be performed and appropriate symptomatic therapy administered if necessary. Repeated ingestion of the medication may lead to the same side effects as excessive oral intake of vitamin A.

Drug Interactions

Effect of Aklief on Other Medicinal Products

A clinical drug interaction study showed that topical application of trifarotene does not affect the blood concentrations of orally administered hormonal contraceptives (ethinylestradiol and levonorgestrel).

Effect of Other Medicinal Products on Aklief

Studies on the effect of other medicinal products on the systemic concentration of trifarotene have not been conducted.

There are no data on the potential for pharmacodynamic interaction of trifarotene. Caution should be exercised when using cosmetic products with exfoliating, irritating, or drying effects concomitantly due to a possible additional irritant effect.

Studies on Experimental Models

Clinically significant interactions of trifarotene when used in combination with fluconazole (a moderate CYP2C9 and CYP3A inhibitor) are not expected.

Storage Conditions

The medicinal product does not require any special storage conditions.

Shelf Life

The shelf life is 2 years.

After first opening, store for no more than 6 months.

Dispensing Status

The medication is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.