Excipients: benzyl alcohol, butylhydroxytoluene, carbomer copolymer type B (Pemulen TR-1). carbomer homopolymer type A (Carbopol 981), glycerin, methylparaben, mineral oil, octoxynol 9, purified water, sodium hyaluronate, soluble collagen, triethanolamine.
Dosage form
Lotion.
Main physicochemical properties: opaque pale yellow lotion.
Pharmacotherapeutic group
Acne Treatment Drugs. Retinoids for Topical Acne Treatment.
ATX code D10AD01.
Pharmacological properties
Mechanism of action.
Tretinoin is a derivative of vitamin A. The exact mechanism of action of tretinoin in the treatment of acne is unknown.
Tretinoin binds with high affinity to specific retinoic acid receptors, which are located both in the cytosol and in the nucleus. Tretinoin activates three members of the nuclear retinoic acid receptor (NRR) (NRRKa, NRR(3) and NRRky), which affect the modification of gene expression and subsequent protein synthesis.
Biochemical and pharmacological studies have clearly shown that tretinoin is a potent modulator of the processes of cellular differentiation and keratinization, which are abnormally observed in the pathology associated with acne vulgaris. When applied topically, it alters the growth and differentiation of the epithelium. In patients with acne, it reduces the cohesiveness of follicular epithelial cells with a decrease in the formation of microcomedones. In addition, tretinoin stimulates mitotic activity and increases the rate of renewal of follicular epithelial cells, causing extrusion of comedones.
Clinical efficacy and safety.
The efficacy and safety of Altrenotm Lotion (cutaneous emulsion) were investigated in two large placebo-controlled, randomized, reverse-blind clinical trials of identical design in 1640 patients aged 9 years and older with moderate to severe acne. In both studies, Altrenotm Lotion was superior to placebo in absolute changes from baseline in the number of non-inflammatory and inflammatory lesions after treatment for up to 12 weeks.
In the first study, the absolute change from baseline in non-inflammatory and inflammatory acne lesions was -17.8 and -13.1, respectively, for Altrenotm compared to -10.6 and -10.2, respectively, for vehicle (p<0.001). In addition, 16.5% of participants in the Altrenotm group compared to 6.9% of participants in the placebo group had a reduction of at least 2 points from baseline in the Investigator's Global Assessment of Severity (IGS) and IGS "clear" or "almost clear" at week 12.
Similarly, in the second study, the absolute change from baseline in non-inflammatory and inflammatory acne lesions was -21.9 and -13.9, respectively, for Altreno™ compared to -13.9 and -10.7, respectively, for vehicle (p<0.001). In addition, 19.8% of participants in the Altreno™ group compared to 12.5% of participants in the placebo group had a reduction of at least 2 points from baseline in the Investigator's Global Assessment of Severity (IGS) and IGS "clear" or "almost clear" at week 12.
Children.
The safety and efficacy of Altrenotm for the topical treatment of acne vulgaris in children aged 9 to 17 years were established based on the two multicenter, randomized, double-blind, vehicle-controlled, parallel-group, 12-week studies and an open-label pharmacokinetic study mentioned above. A total of 318 pediatric participants aged 9 to 17 years received Altrenotm in these clinical studies.
The safety and efficacy of the drug in children under 9 years of age have not yet been established. The recurrence rate after acne treatment with topical tretinoin has not been studied.
Pharmacokinetics.
Plasma concentrations of tretinoin and its major metabolites (isotretinoin and 4-oxoisotretinoin) were evaluated in 20 subjects in an open-label, randomized pharmacokinetic study. Subjects 10 to 17 years of age with acne applied approximately 3.5 g of tretinoin to the entire face (excluding the area around the eyes and lips), neck, upper chest, upper back, and shoulders once daily for 14 days. Single-dose pharmacokinetic (PK) characteristics were determined from samples collected on days 1 and 2 of dosing, and steady-state PK was determined from samples collected on days 14 and 15 under full dosing conditions. The mean baseline adjusted Cmax and AUCo-t of tretinoin and its metabolites following daily administration of tretinoin once daily for 14 days are shown below.
Compound
Average value (±SD)
Cmax
(ng/ml)
Average value (±SD)
AUCo-t
(ng*h/ml)
Tretinoin
0.33 (0.33)
6.46(5.15)
Isotretinoin
0.49 (0.66)
9.30 (9.95)
4-oxo-isotretinoin
0.57 (0.82)
14.51 (18.28)
The mean concentrations of tretinoin and its metabolites (isotretinoin and 4-oxo-isotretinoin) remained relatively stable and unchanged over the 24-hour period after both day 1 and day 14 dosing. Systemic concentrations of tretinoin appeared to be at or near steady state by day 14. The mean accumulation ratios of the initial adjusted AUC between day 14 and day 1 were 1.5, 4.5, and 7.3 for tretinoin, isotretinoin, and 4-oxo-isotretinoin, respectively.
Preclinical safety data.
Local tolerance testing, dose retesting, and skin sensitivity testing with topical tretinoin revealed only minor signs of irritation at application sites.
A two-year dermal carcinogenicity study in mice was conducted with topical application of 0.005%, 0.025%, and 0.05% tretinoin gel. Although no drug-related tumors were observed in the surviving animals, the irritant effect of the drug precluded daily use, distorting the interpretation of the data and reducing the biological significance of these results. Studies in hairless albino mice using another formulation suggest that simultaneous exposure to tretinoin may enhance the carcinogenic potential of carcinogenic doses of UV-A and UV-B radiation from a solar simulant. This effect was confirmed in a later study in pigmented mice, and dark pigmentation did not prevent the enhancement of photocarcinogenesis with 0.05% tretinoin. Although the relevance of these studies to humans is unclear, patients should minimize exposure to sunlight or artificial sources of ultraviolet radiation. The genotoxic potential of tretinoin was evaluated using an in vitro bacterial reversion induction assay, an in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo micronucleus assay in rats. All tests were negative.
In dermal fertility studies with other formulations of tretinoin in rats, there was a slight (non-statistically significant) decrease in sperm count and motility at 0.5 mg/kg/day (approximately 2 times the MRHD based on the PPT comparison and at 100% absorption), and a slight (non-statistically significant) increase in the number and percentage of non-viable embryos in females receiving 0.25 mg/kg/day and above (approximately the MRHD based on the PPT comparison and at 100% absorption). Tretinoin gel 0.05% was applied topically to pregnant rats during organogenesis at doses of 0.1, 0.3, and 1 g/kg/day (0.05, 0.15, 0.5 mg tretinoin/kg/day). Developmental malformations possibly related to tretinoin (craniofacial anomalies [hydrocephalus], asymmetric thyroid, ossification variations, and enlarged accessory ribs) were observed at doses up to 0.5 mg tretinoin/kg/day (approximately 2 times the MRHD, based on a comparison of the PTT and at 100% absorption). These findings were not observed in control animals. Other maternal and reproductive parameters in animals treated with tretinoin did not differ from controls. For the purpose of comparing effects in animals and humans, the MRHD was determined to be 4 g of Altrenotm administered daily to a 60 kg human.
Indication
Treatment of acne in adults, adolescents and children aged 9 years and older.
Contraindication
Hypersensitivity to the active substance or to any of the excipients included in the medicinal product. The use of the medicinal product should be discontinued if hypersensitivity to any of its components is observed.
Acute form of eczema.
Rosacea and acute inflammatory skin conditions, especially with perioral dermatitis.
Presence of sunburned skin.
Concomitant use with other skin preparations, especially those containing keratolytic agents (see section "Interaction with other medicinal products and other types of interactions"),
During pregnancy (see section "Use during pregnancy or breastfeeding") and for women planning a pregnancy.
Children under 9 years old.
Interaction with other medicinal products and other types of interactions
Concomitant use with other topical or oral retinoid preparations should be avoided. Medicated or abrasive soaps and detergents, products that have a strong drying effect, and products with high concentrations of alcohol, alpha-hydroxy acids, or astringents should be used with caution due to possible interactions with tretinoin.
Caution should be exercised when using topical over-the-counter acne medications containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Altrenotm. It is advisable to wait until the irritation has subsided before applying Altrenotm to areas treated with these medications.
Application features
Applying excessive amounts of lotion (skin emulsion) will not improve efficacy but may increase the likelihood of irritation. Some people's skin may become excessively dry, red, or swollen even with recommended use. Patients should be instructed to temporarily reduce the amount or frequency of application, temporarily discontinue use, or discontinue use altogether if the degree of skin irritation warrants it. Excessive dryness of the skin may also occur; in such cases, it may be advisable to use an appropriate moisturizer throughout the day.
Increased sensitivity to sunlight may occur during treatment with Altrenotm. Excessive exposure to sunlight without the use of sunscreen should be minimized and exposure to UV radiation, including ultraviolet lamps and solariums, should be avoided during the period of use of Altrenotm. Patients with sunburn should be advised not to apply the drug to the affected areas until complete recovery due to increased sensitivity to additional irritation in patients receiving tretinoin treatment. Patients who may be exposed to significant sunlight due to their professional activities and those who have a congenital sensitivity to sunlight should exercise special caution. If such exposure cannot be avoided, sunscreen and protective clothing should be used on the affected areas of the skin. Avoid accumulation of the drug in skin folds or areas of the nose. Altrenotm Lotion should be applied away from the mucous membranes of the eyes, mouth and nose. If the drug gets on these areas, rinse them thoroughly with water.
This medicine contains: 5 mg of benzyl alcohol per 1 g of lotion (cutaneous emulsion). Benzyl alcohol may have a mild local irritant effect and may cause allergic reactions.
Butylated hydroxytoluene (E 321) may cause local skin reactions (e.g. contact dermatitis) or irritation of the eyes and mucous membranes.
Methylparaben (E 218) may cause allergic reactions (possibly delayed).
Use during pregnancy or breastfeeding
Pregnancy.
Although the available studies cannot definitively establish the absence of risk, published data from numerous prospective, controlled observational studies of topical tretinoin use during pregnancy have not found an association between topical tretinoin and major birth defects or miscarriage. The available studies have methodological limitations, including small sample sizes and, in some cases, the lack of a physical examination by a specialist in the treatment of birth defects. There have been published case reports of infants exposed to topical tretinoin during the first trimester that describe major birth defects similar to those seen in infants exposed to oral retinoids; however, no pattern of malformations has been identified and no causal relationship has been established in these cases. The significance of these spontaneous reports with respect to fetal risk is unknown.
Animal studies with topical tretinoin have not revealed any reproductive toxicity (see section 5.3), although literature data suggest that high doses of topical tretinoin may be fetotoxic.
Altrenotm Lotion is contraindicated for use (see Contraindications section) during pregnancy or in women planning a pregnancy.
If the drug is used during pregnancy or if the patient becomes pregnant while using this medication, treatment must be discontinued.
Breastfeeding period.
It is not known whether tretinoin is present in breast milk after topical application. Caution should be exercised when Altrenotm Lotion is administered to nursing women.
The developmental and health benefits of breastfeeding should be taken into account, as well as the mother's clinical need for Altrenotm and any potential adverse effects of Altrenotm on the breastfed child.
Fertility.
See section “Preclinical safety data”.
Ability to influence reaction speed when driving vehicles or other mechanisms
Altrenotm Lotion has no or negligible influence on the ability to drive and use machines.
Method of administration and doses
Dosage: Adults and children 9 years of age and older should apply Altrenotm Lotion to the affected areas of skin once daily.
The results of treatment may be noticeable two weeks after starting, but it may take four or more weeks (up to 12 weeks) before a lasting positive effect is observed.
Children.
The use of the drug in children under 9 years of age is contraindicated.
Overdose
Altrenotm Lotion is for external use only. Excessive application may cause severe redness, peeling, or discomfort. Oral administration of large amounts of the drug may cause the same adverse reactions as excessive oral administration of vitamin A (e.g., dry skin, itching, arthralgia, vomiting, anorexia). If the lotion is accidentally swallowed, and if this has occurred recently, measures should be taken to promote rapid gastric emptying.
Side effects
Adverse reactions are grouped by system organ class. Within each system organ class, frequencies are defined as:
very common (≥ 1/10);
common (≥ 1/100 to < 1/10)
uncommon (≥ 1/1000 to < 1/100)
Rare (1/10,000 to <1/1,000)
very rare (<1/10,000)
frequency unknown (cannot be estimated from the available data).
In clinical studies with Altrenotm Lotion, the majority of adverse reactions were associated with the system organ class Skin and subcutaneous tissue. The majority of these events (such as erythema, burning, stinging, dryness, and desquamation) were mild in intensity, occurred early in treatment, and generally decreased in frequency during the treatment period.
Frequent adverse reactions.
Skin and subcutaneous tissue disorders: erythema, redness, peeling, scaling, exfoliative dermatitis, dryness, itching, hot flushes, burning, rash, tingling sensation or pain.
Temporary hypo- or hyperpigmentation.
The frequency of adverse reactions is unknown.
True contact allergy to topical tretinoin may occur. Increased sensitivity to sunlight or other sources of UV-B rays has been reported.
Expiration date
36 months.
Storage conditions
Store at a temperature of 20 °C to 25 °C. Tolerances from 15 °C to 30 °C. Protect from freezing. Keep out of the reach of children.
Packaging
45 g in a tube, 1 tube in a cardboard box.
Vacation category
According to the recipe.
Producer
Bausch Health Companies Inc.
Location of the manufacturer and its business address.
