home Audience 5 Roaccutane dosage table. The use of systemic retinoids in the "small dose" regimen in patients with moderate to severe forms of acne. Description of the dosage form

Roaccutane dosage table. The use of systemic retinoids in the "small dose" regimen in patients with moderate to severe forms of acne. Description of the dosage form

Roaccutane is an anti-inflammatory and anti-seborrheic drug for the treatment of acne. Refers to retinoids (structural analogues of vitamin A).

Release form and composition

Roaccutane is available in the form of capsules: oval, opaque, with a body and cap in brown-red and white and black inscription on the surface "ROA 10" or "ROA 20"; contents - a homogeneous suspension of yellow or dark yellow color (10 pieces in blisters, in a cardboard bundle 3 or 10 blisters).

1 capsule contains:

Active ingredient: isotretinoin - 10 or 20 mg;
Auxiliary components: yellow beeswax, soybean oil, partially hydrogenated soybean oil, hydrogenated soybean oil;
Capsule body and cap: gelatin, titanium dioxide, 85% glycerol, red iron oxide dye, Karion 83 (mannitol, hydrolyzed potato starch, sorbitol);
Ink composition: black iron oxide dye, shellac (ready-made Opacode Black S-1-27794 ink is allowed).

Indications for use

Roaccutane is used to treat severe forms of acne (acne conglobata, acne with a risk of scarring or nodular cystic acne) and acne that is not amenable to other types of therapy.

Contraindications

Absolute:

Severe hyperlipidemia;
Hypervitaminosis A;
Liver failure;
Simultaneous treatment with tetracyclines;
Pregnancy;
The period of breastfeeding;
Children's age up to 12 years;
Hypersensitivity to the main or auxiliary components of the drug.

Relative (taken with caution, increased risk of side effects):

Diabetes;
Violation of lipid metabolism;
Obesity;
Alcoholism;
History of depression.

Method of application and dosage

Roaccutane is taken orally with meals once or twice a day. The dose is selected individually during treatment and depends on the therapeutic efficacy and side effects of the drug.

The initial dose is 0.5 mg/kg of body weight per day. In most patients, the dose ranges from 0.5-1.0 mg / kg of body weight per day. In severe forms of the disease or in the presence of acne of the trunk, the daily dose of Roaccutane can be up to 2 mg / kg of body weight. It has been established that the prevention of relapses and the frequency of remission are optimal at a course dose of 120-150 mg/kg, so the duration of treatment is different and depends on the daily dose in a particular patient. As a rule, complete remission can be achieved within 16-24 weeks of therapy. If the drug is poorly tolerated, treatment is continued in smaller doses and, accordingly, its duration increases.

In most cases, one course of therapy is sufficient for complete recovery. With obvious relapses, a second course is prescribed in the same daily and course doses. After discontinuation of the drug, improvements are observed for another 8 weeks, so a second course is possible only after the end of this period.

In patients with severe renal insufficiency, Roaccutane is prescribed in smaller doses, starting with 10 mg per day, followed by a gradual increase in dose to 1 mg / kg per day or the maximum tolerated.

Side effects

Side effects of the drug in most cases depend on the dose. When using Roaccutane at the recommended doses, the benefit-risk ratio (taking into account the severity of the disease) is acceptable to the patient. As a rule, side effects are reversible and disappear after discontinuation of the drug or dose adjustment, but some of them may persist even after cessation of therapy.

When using Roaccutane, side effects from the following systems and organs are possible:

During post-marketing surveillance, cases of severe skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme) have been described.

special instructions

Roaccutane should be prescribed by a dermatologist who is aware of the risk of teratogenicity of the drug and has experience in the use of systemic retinoids.

Donor blood should not be taken from patients receiving Roaccutane or using it within the last month.

Before treatment, one month after its initiation and every three months, it is recommended to monitor liver enzymes, fasting serum lipids and liver function.

Exacerbation of acne, observed in rare cases at the beginning of treatment, disappears within 7-10 days and does not require dose adjustment.

In patients receiving Roaccutane, and within 5-6 months after the end of the course, laser treatment, deep chemical dermabrasion and epilation with wax applications should be avoided.

In case of intolerance to contact lenses, glasses should be used during treatment with the drug.

Limit exposure to UV and sun rays and use sunscreen with an SPF of at least 15.

With the development of benign intracranial hypertension, inflammatory bowel disease with severe hemorrhagic diarrhea and severe allergic reactions, Roaccutane should be immediately canceled.

Due to the possible decrease in night vision, patients should be careful when driving at night. Visual acuity should be carefully monitored.

drug interaction

Due to the risk of increased intracranial pressure, the simultaneous use of Roaccutane and tetracyclines is contraindicated.

The drug can weaken the effectiveness of progesterone-containing agents, so it is not recommended to use contraceptives with low doses of progesterone.

Due to the possible increase in local irritation, the simultaneous use of isotretinoin and topical keratolytic or exfoliative drugs for the treatment of acne is contraindicated.

Terms and conditions of storage

Store in a place protected from moisture and light at a temperature not exceeding 25 ° C. Keep away from children.

Shelf life - 3 years.

Dosage form: capsules Ingredients:

COMPOSITION FOR 1 CAPSULE

Capsules 8 mg

Active substances: Isotretinoin - 8.0 mg

Excipients:

Gelucir ® 50/13 (a mixture of polyethylene oxide and glycerin stearic acid esters) - 96.00 mg;

purified soybean oil - 52.00 mg;

Span80 ® (sorbitan oleate - mixed esters of oleic acid and sorbitol) - 8.00 mg.

Capsules 16 mg

Active substances: Isotretinoin - 16.0 mg

Excipients:

Gelucir ® 50/13 (a mixture of polyethylene oxide and glycerin stearic acid esters) - 192.00 mg;

purified soybean oil - 104.00 mg;

Span80 ® (sorbitan oleate - mixed esters of oleic acid and sorbitol) - 16.00 mg

COMPOSITION OF THE CAPSULE

Aknekutan 8mg

body and lid: gelatin, red iron oxide dye (E172), titanium dioxide (E171);

Aknekutan 16mg

body: gelatin, titanium dioxide (E171),

cap: gelatin, titanium dioxide (E171), iron oxide yellow (E172), indigo carmine (E132).

Description:

Capsules 8 mg:

Hard gelatin capsules No. 3 brown. The contents of the capsules are a yellow-orange waxy paste.

Capsules 16 mg:

No. 1 hard gelatin capsules, white body, green cap. The contents of the capsules are a yellow-orange waxy paste.

Pharmacotherapeutic group:Acne treatment remedy ATX:

D.10.B.A.01 Isotretinoin

Pharmacodynamics:

Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin).

The exact mechanism of action of isotretinoin has not yet been identified, however, it has been established that the improvement in the clinical picture of severe forms of acne is associated with the suppression of the activity of the sebaceous glands and a histologically confirmed decrease in their size. Sebum is the main substrate for the growth of Propionibacterium acnes, so reducing sebum production inhibits bacterial colonization of the duct.

Aknekutan ® inhibits the proliferation of sebocytes and acts on acne, restoring the normal process of cell differentiation, stimulates regeneration processes.

In addition, the anti-inflammatory effect of isotretinoin on the skin has been proven.

Pharmacokinetics:

Since the kinetics of isotretinoin and its metabolites is linear, its plasma concentrations during therapy can be predicted based on data obtained after a single dose. This property of the drug also suggests that it does not affect the activity of microsomal liver enzymes involved in drug metabolism.

The high bioavailability of Acnecutane ® is due to the large proportion of dissolved isotretinoin in the preparation, and may increase if the drug is taken with food.

In patients with acne, the maximum plasma concentrations (C max) at steady state after taking 80 mg of isotretinoin on an empty stomach were 310 ng / ml (range 188-473 ng / ml) and were reached after 2-4 hours. The concentration of isotretinoin in plasma is 1.7 times higher than in the blood, due to poor penetration of isotretinoin into red blood cells. Communication with plasma proteins (mainly with albumin) - 99.9%.

Equilibrium concentrations of isotretinoin in the blood (C ss) in patients with severe forms of acne, who took 40 mg of the drug 2 times a day, ranged from 120 to 200 ng / ml. The concentrations of 4-oxo-isotretinoin (the main metabolite) in these patients were 2.5 times higher than those of isotretinoin.

The concentration of isotretinoin in the epidermis is 2 times lower than in serum.

It is metabolized to form 3 main biologically active metabolites - 4-oxo-isotretinoin (main), tretinoin (all-trans-retinoic acid) and 4-oxo-retinoin, as well as less significant metabolites, including also glucuronides. Since in vivo and reversibly transform into each other, the metabolism of tretinoin is associated with the metabolism of isotretinoin. 20-30% of a dose of isotretinoin is metabolized by isomerization. Enterohepatic recirculation may play a significant role in the pharmacokinetics of isotretinoin in humans.

In vitro studies have shown that several cytochrome P 450 isoenzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin, with none of the isoforms apparently playing a dominant role. and its metabolites do not significantly affect the activity of cytochrome P 450 isoenzymes.

The terminal phase half-life for isotretinoin averages 19 hours. The terminal phase half-life for 4-oxo-isotretinoin averages 29 hours.

Isotretinoin is excreted by the kidneys and bile in approximately equal amounts.

Refers to natural (physiological) retinoids. Endogenous concentrations of retinoids are restored approximately 2 weeks after the end of the drug.

Pharmacokinetics in special clinical situations

Since data on the pharmacokinetics of the drug in patients with impaired liver function are limited, it is contraindicated in this group of patients.

Renal failure of mild to moderate severity does not affect the pharmacokinetics of isotretinoin.

Indications:

Severe forms of acne (nodular-cystic, conglobate, acne with a risk of scarring).

Acne unresponsive to other therapies.

Contraindications:

Pregnancy, established and planned (possibly teratogenic and embryotoxic effects), lactation period, liver failure, hypervitaminosis A, severe hyperlipidemia, concomitant tetracycline therapy.

Hypersensitivity to the drug or its components.

Carefully:

Diabetes mellitus, history of depression, obesity, lipid metabolism disorders, alcoholism.

Pregnancy and lactation:

Pregnancy is an absolute contraindication for Acnecutane therapy ® .

If pregnancy occurs, despite warnings, during treatment or within a month after the end of therapy, there is a very high risk of having a child with severe malformations.

Isotretinoin is a drug with a strong teratogenic effect. If pregnancy occurs during the period when a woman takes it orally (at any dose and even for a short time), there is a very high risk of having a child with malformations. Aknekutan ® is contraindicated in women of childbearing age, unless the condition of the woman meets all of the following criteria:

· she must have severe acne resistant to conventional treatments;

· she must accurately understand and follow the instructions of the doctor;

· she must be informed by a doctor about the danger of pregnancy during treatment with Acnecutane ® , within one month after it and an urgent consultation if pregnancy is suspected;

· she should be warned about the possible ineffectiveness of contraceptives;

· she must confirm that she understands the nature of the precautions;

· she must understand the need and continuously use effective methods of contraception for one month before treatment with Aknekutan ® , during treatment and for a month after its completion (see section "Interaction with other drugs"); it is desirable to use 2 different methods of contraception at the same time, including barrier;

· she must have obtained a negative result of a reliable pregnancy test within 11 days before starting the drug; a pregnancy test is strongly recommended monthly during treatment and 5 weeks after the end of therapy;

· she should start treatment with Acnecutane ® only on day 2-3 of her next normal menstrual cycle;

· she must understand the need for mandatory visits to the doctor every month;

· when treated for a relapse of the disease, she must constantly use the same effective methods of contraception for one month before starting treatment with Acnecutane ® , during treatment and for a month after its completion, and also undergo the same reliable pregnancy test;

· she must fully understand the need for precautions and confirm her understanding and willingness to use reliable methods of contraception, as explained to her by the doctor.

The use of contraceptives as indicated above during treatment with isotretinoin should be recommended even for women who do not normally use contraceptive methods due to infertility (with the exception of patients who have had a hysterectomy), amenorrhea, or who report not being sexually active.

The doctor must be sure that:

· the patient suffers from severe acne (nodular cystic, conglobate acne or acne with a risk of scarring); acne, not amenable to other types of therapy;

· a negative result of a reliable pregnancy test was obtained before the start of the drug, during therapy and 5 weeks after the end of therapy; the dates and results of the pregnancy test should be documented;

· the patient uses at least one, preferably two, effective methods of contraception, including a barrier method, within one month before the start of treatment with Acnecutane ® , during treatment and within a month after its completion;

· the patient is able to understand and comply with all of the above requirements for contraception;

· The patient meets all of the above conditions.

Pregnancy test

According to current practice, a pregnancy test with a minimum sensitivity of 25 mIU/ml should be performed on the first 3 days of the menstrual cycle:

Before starting therapy:

· To exclude possible pregnancy, the result and date of the initial pregnancy test must be recorded by the doctor before contraception is started. In women with irregular periods, the timing of the pregnancy test depends on sexual activity and should be performed 3 weeks after unprotected intercourse. The doctor should inform the patient about the methods of contraception.

· A pregnancy test is carried out on the day of the appointment of Acnecutane ® or 3 days before the patient's visit to the doctor. The specialist should record the test results. The drug can be prescribed only to patients receiving effective contraception for at least 1 month before the start of therapy with Aknekutan ® .

During therapy:

· The patient must visit the doctor every 28 days. The need for monthly pregnancy testing is determined in accordance with local practice and taking into account sexual activity, previous menstrual irregularities. If indicated, a pregnancy test is carried out on the day of the visit or 3 days before the visit to the doctor, the test results must be recorded.

End of therapy:

· 5 weeks after the end of therapy, a test is performed to exclude pregnancy.

A prescription for Acnecutane ® for a woman of childbearing potential can only be issued for 30 days of treatment, continuation of therapy requires a new appointment of the drug by a doctor. It is recommended that a pregnancy test, a prescription, and receiving the drug be carried out on the same day.

If, despite the precautions taken, pregnancy still occurs during treatment with Acnecutane ® or within a month after its termination, there is a high risk of very severe fetal malformations.

If pregnancy occurs, Aknekutan ® therapy is discontinued. The feasibility of maintaining the pregnancy should be discussed with a doctor specializing in teratology.

Since it is highly lipophilic, it is highly likely that it passes into breast milk. Due to possible side effects, Aknekutan ® should not be administered to nursing mothers.

For male patients:

Existing data indicate that in women, the exposure of the drug, which came from the semen and seminal fluid of men taking Acnecutane ® , is not sufficient for the appearance of teratogenic effects of Acnecutan ® .

Men should exclude the possibility of taking the drug by other persons, especially women.

Dosage and administration:

Inside, preferably during meals, 1-2 times a day.

The therapeutic efficacy of Acnecutane ® and its side effects depend on the dose and vary in different patients. This makes it necessary to individually select the dose during treatment.

The initial dose of Aknekutan ® is 0.4 mg/kg per day, in some cases up to 0.8 mg/kg per day. In severe forms of the disease or with acne of the trunk, a dose of up to 2 mg / kg per day may be required.

The optimal course cumulative dose is 100-120 mg/kg. Complete remission is usually achieved within 16-24 weeks. If the recommended dose is poorly tolerated, treatment can be continued at a lower dose, but for a longer time.

In most patients, acne disappears completely after a single course of treatment.

In case of relapse, it is possible to repeat the course of treatment in the same daily and cumulative dose. A second course is prescribed no earlier than 8 weeks after the first, as the improvement may be delayed.

In severe chronic renal failure, the initial dose should be reduced to 8 mg/day.

Side effects:

Most side effects are dose dependent. Usually, side effects are reversible after dose adjustment or drug withdrawal, but some may persist after treatment is stopped.

Symptoms associated with hypervitaminosis A: dry skin, mucous membranes, incl. lips (cheilitis), nasal cavity (bleeding), larynx and pharynx (hoarseness), eyes (conjunctivitis, reversible corneal clouding and contact lens intolerance).

Skin and its appendages: peeling of the skin of the palms and soles, rash, itching, facial erythema/dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased growth of granulation tissue, persistent hair thinning, reversible hair loss, fulminant forms of acne, hirsutism, hyperpigmentation, photosensitivity, mild skin injury . At the beginning of treatment, an exacerbation of acne may occur, which persists for several weeks.

Musculoskeletal system: muscle pain with or without elevated serum CPK, joint pain, hyperostosis, arthritis, calcification of ligaments and tendons, tendonitis.

Central nervous system and mental sphere: excessive fatigue, headache, increased intracranial pressure ("pseudotumor of the brain": headache, nausea, vomiting, blurred vision, swelling of the optic nerve), convulsive seizures, rarely - depression, psychosis, suicidal thoughts.

Sense organs: xerophthalmia, isolated cases of impaired visual acuity, photophobia, impaired dark adaptation (decrease in twilight visual acuity), rarely - impaired color perception (passing after discontinuation of the drug), lenticular cataract, keratitis, blepharitis, conjunctivitis, eye irritation, optic neuritis, optic nerve edema (as a manifestation of intracranial hypertension); hearing loss at certain sound frequencies, difficulty wearing contact lenses.

Gastrointestinal tract: dryness of the oral mucosa, bleeding from the gums, inflammation of the gums, nausea, diarrhea, inflammatory bowel disease (colitis, ileitis), bleeding; pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg / dl). Rare cases of pancreatitis with a fatal outcome have been described. Transient and reversible increase in liver transaminase activity, isolated cases of hepatitis. In many of these cases, the changes did not go beyond the limits of the norm and returned to baseline during treatment, however, in some situations, it became necessary to reduce the dose or stop Aknekutan ® .

Respiratory system: rarely - bronchospasm (more often in patients with a history of bronchial asthma).

Blood system: anemia, decreased hematocrit, leukopenia, neutropenia, increase or decrease in platelet count, accelerated ESR.

Laboratory indicators: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, decreased high-density lipoprotein levels, rarely hyperglycemia. In the course of taking Acnecutane ®, cases of newly diagnosed diabetes mellitus have been reported. In some patients, especially those engaged in intense physical activity, individual cases of increased serum CPK activity are described.

The immune system: local or systemic infections caused by gram-positive pathogens (Staphylococcus aureus).

Other: lymphadenopathy, hematuria, proteinuria, vasculitis (Wegener's granulomatosis, allergic vasculitis), systemic hypersensitivity reactions, glomerulonephritis.

Teratogenic and embryotoxic effects: congenital deformities - hydro- and microcephaly, underdevelopment of the cranial nerves, microphthalmia, malformations of the CCC, parathyroid glands, skeletal disorders - underdevelopment of the digital phalanges, skull, cervical vertebrae, femur, ankles, bones of the forearm, facial skull, cleft palate, low location of the auricles, underdevelopment of the auricles, underdevelopment or complete absence of the external auditory canal, hernia of the brain and spinal cord, bone fusion, fusion of the fingers and toes, impaired development of the thymus gland; fetal death in the perinatal period, premature birth, miscarriage), premature closure of the epiphyseal growth zones; in an animal experiment - pheochromocytoma.

Overdose:

In case of an overdose, signs of hypervitaminosis A may appear.

In the first few hours after an overdose, gastric lavage may be necessary.

Interaction:

Antibiotics of the tetracycline series, GCS reduce the effectiveness.

Simultaneous use with drugs that increase photosensitivity (including sulfonamides, tetracyclines, thiazide diuretics) increases the risk of sunburn.

Simultaneous use with other retinoids (including acitretin, tretinoin, retinol, tazarotene, adapalene) increases the risk of hypervitaminosis A.

Isotretinoin can reduce the effectiveness of progesterone preparations, so you should not use contraceptives containing low doses of progesterone.

Combined use with local keratolytic drugs for the treatment of acne is not recommended due to the possible increase in local irritation.

Since tetracyclines increase the risk of increased intracranial pressure, concomitant use with isotretinoin is contraindicated.

Special instructions:

It is recommended to monitor liver function and liver enzymes before treatment, 1 month after its initiation, and then every 3 months or as indicated. A transient and reversible increase in hepatic transaminases was noted, in most cases within normal limits. If the level of hepatic transaminases exceeds the norm, it is necessary to reduce the dose of the drug or cancel it. Fasting serum lipid levels should also be determined before treatment, 1 month after initiation, and every 3 months thereafter, or as indicated. Usually, lipid concentrations normalize after dose reduction or discontinuation of the drug, as well as with diet. Clinically significant elevations in triglycerides should be monitored, as elevations above 800 mg/dl or 9 mmol/l may be associated with acute pancreatitis, possibly fatal.

With persistent hypertriglyceridemia or symptoms of pancreatitis, Aknekutan ® should be discontinued. In rare cases, patients treated with Aknekutan ® described depression, psychotic symptoms, and very rarely, suicidal attempts. Although their causal relationship with the use of the drug has not been established, special care should be taken in patients with a history of depression and all patients should be monitored for depression during treatment with the drug, if necessary, referring them to the appropriate specialist. However, the abolition of Aknekutan ® may not lead to the disappearance of symptoms and further monitoring and treatment by a specialist may be required.

In rare cases, at the beginning of therapy, an exacerbation of acne is noted, which disappears within 7-10 days without adjusting the dose of the drug.

When prescribing the drug, any patient should first carefully evaluate the ratio of possible benefits and risks.

Against the background of taking Acnecutane ®, pain in muscles and joints, an increase in serum creatinine phosphokinase, which may be accompanied by a decrease in the tolerance of intense physical activity, are possible.

Deep chemical dermabrasion and laser treatment should be avoided in patients receiving Aknekutan ® , as well as within 5-6 months after the end of treatment due to the possibility of increased scarring in atypical areas and the occurrence of hyper- and hypopigmentation. During treatment with Aknekutan ® and for 6 months after it, epilation with wax applications should not be performed due to the risk of epidermal detachment, scarring and dermatitis. Since some patients may experience a decrease in night vision, which sometimes persists after the end of therapy, patients should be informed of the possibility of this condition, advising them to be careful when driving at night. The state of visual acuity must be carefully monitored. Conjunctival dryness, corneal opacities, blurred night vision, and keratitis usually resolve after discontinuation of the drug. With dryness of the mucous membrane of the eyes, applications of a moisturizing eye ointment or an artificial tear preparation can be used. It is necessary to observe patients with dryness of the conjunctiva for the possible development of keratitis. Patients presenting with complaints of vision should be referred to an ophthalmologist and consideration should be given to discontinuing Aknekutan ® . In case of intolerance to contact lenses, glasses should be used during therapy.

Exposure to solar insolation and UV therapy should be limited. If necessary, use a sunscreen with a high protection factor of at least 15 SPF.

Rare cases of the development of benign intracranial hypertension ("pseudotumor of the brain") have been described, incl. when combined with tetracyclines. In such patients, Acnecutane should be discontinued immediately.

Acnecutane ® therapy may cause inflammatory bowel disease. In patients with severe hemorrhagic diarrhea, Aknekutan should be immediately discontinued.

Rare cases of anaphylactic reactions have been described that occurred only after previous topical use of retinoids. Severe allergic reactions dictate the need to discontinue the drug and carefully monitor the patient.

Patients at high risk (with diabetes mellitus, obesity, chronic alcoholism or disorders of fat metabolism) may require more frequent laboratory monitoring of glucose and lipid levels during treatment with Aknekutan ®. In the presence of diabetes or suspicion of it, more frequent determination of glycemia is recommended.

During the period of treatment and within 30 days after its completion, it is necessary to completely exclude blood sampling from potential donors to completely exclude the possibility of this blood getting into pregnant patients (high risk of developing teratogenic and embryotoxic effects).

Influence on the ability to drive transport. cf. and fur.:

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions (when taking the first dose).

Release form / dosage:

Capsules 8 mg and 16 mg.

Package:

10 or 14 capsules in PVC blister, covered with aluminum foil.

Blisters-10-N 2, N 3, N 5, N 6, N 9, N 10; blisters-14-N 1, N 2, N 4, N 7 in a cardboard box along with instructions for use.

Storage conditions:

In a dry, dark place, out of the reach of children, at a temperature not exceeding 25ºС.

Best before date:

2 years. Do not use after the expiration date.

Conditions for dispensing from pharmacies: On prescription Registration number: LSR-004782/09 Date of registration: 16.06.2009 / 19.04.2017 Expiration date: Perpetual Registration Certificate Holder:Jadran Galensky Laboratori a.d. Croatia Manufacturer: Representation: YADRAN Galensky Laboratories a.d. Croatia Information update date: 25.05.2017 Illustrated Instructions

Acne is a chronic relapsing disease of the sebaceous glands and hair follicles (2). The disease is widespread in adolescence. Rarely, acne occurs in infants and adults. The main role in the genesis of acne is played by hereditary predisposition, which determines the number, size and increased sensitivity of sebaceous gland cell receptors to the male sex hormone testosterone and its metabolites (3, 5).

The initial stage of acne development is the formation of retention hyperkeratosis in the region of the mouth of the hair follicle. Hyperandrogenemia leads to hyperplasia and hypersecretion of the sebaceous glands. Hyperkeratosis and excess sebum production lead to obstruction of the sebaceous gland excretory duct and comedone formation (6, 7).

Under the created anaerobic conditions, Propionibacterium acnes multiplies. Despite the key importance of this microorganism, staphylococci are also involved in the development of the inflammatory process in the sebaceous glands. The growth of bacteria initiates the development of the inflammatory process, forming the inflammatory elements of acne - papules, pustules, nodes or cysts. Recurrent ruptures of cysts with their subsequent re-epithelialization lead to the formation of epithelial passages, which are often accompanied by disfiguring scars.

Severe forms of acne, as well as the tendency of the disease to recur, are usually genetically determined. In this regard, traditional antibiotic therapy, topical agents, as well as various cosmetic effects do not allow to achieve a stable therapeutic result. Often, the use of topical agents (topical retinoids and antibiotics, azelaic acid, combination drugs) is very effective directly in the treatment of patients. However, frequent relapses of the disease against the background of standard therapy not only contribute to the formation of post-acne, but also have an adverse psychological effect on adolescent patients, lead to the formation of dysmorphophobia, depression, and in some cases suicidal thoughts.

Systemic retinoids are effective therapeutic agents for severe forms of acne, the ineffectiveness of antibacterial drugs, and the formation of hypertrophic and keloid scars (4, 8, 9, 15).

In recent years, dermatovenereologists have begun to use drugs of this group more often in the treatment of patients with acne. This is due to the accumulated experience of their use in real clinical practice in Russia, as well as the emerging confidence of specialists in the high safety of systemic retinoids during long-term use in people with severe acne.

Of no small importance in the popularity of isotretinoin is the role of its universal mechanism of action, which allows it to have a beneficial effect on all four components of the pathogenesis of acne. Isotretinoin is able to suppress sebum production by 80%; effectively reduce the phenomena of follicular hyperkeratosis and indirectly inhibit the growth of anaerobic bacteria, reducing inflammation of the sebaceous glands and hair follicles (10, 11).

Moreover, when using standard doses and dosing regimens, isotretinoin induces a long-term remission of the disease or leads to a stable cure in patients (12, 13, 14).

At the same time, in 2010, the expert council of the Russian Society of Dermatovenereologists considered it appropriate to recommend to practitioners a new strategy for managing patients with moderate to severe forms of the disease using the “low dose” isotretinoin regimen (1). First of all, this strategy is aimed at managing patients with recurrent acne of moderate severity, who had a good therapeutic result from the use of topical agents, but the process was resumed again after topical therapy was discontinued.

Table 1.

Dynamics of the main laboratory parameters in patients with acne who used the regimen of "small doses" of Roaccutane (M±m)

Laboratory indicator	Donors	Patients with acne before treatment (n=40)	Patients with acne treated with Roaccutane for 1 month (n=40)	Patients with acne treated with Roaccutane for 2 months (n=40)	Patients with acne treated with Roaccutane for 3 months (n=40)
Cholesterol, µmol/l	3.7±0.1	5.0±0.7	5.1±0.7	5.3±1.2	5.2±2.7	>0,05
Triglycerides, µmol/l	1.7±0.01	1.8±0.02	1.9±0.02	1.8±0.4	1.9±0.8	>0,05
AST, U/l	32±0.5	34±0.9	35±0.9	35±0.7	35±0.8	>0,05
ALT, U/l	24±0.8	25±0.7	25±0.8	25±1.7	25±1.9	>0,05

Note: p - significance of differences between the group of people treated with Roaccutane and donors

In such cases, the initial dose of the drug should be calculated either in the range of 0.1-0.15-0.3 mg / kg / day. in permanent (daily) or intermittent (every other day) regimens, or be prescribed in a standard dose of 10 mg per day, regardless of body weight, followed by a stepwise decrease (after 1 month - up to 5 times a week; after another month - up to 3 times a week a week, in another month - up to 2 times a week; in another month - up to 1 time per week). The duration of treatment with isotretinoin according to the “low dose” regimen should not, on average, exceed 3 to 6 months. From a practical point of view, an important advantage of this method of using isotretinoin is the absence of the need to calculate the total course dose of the drug.

The aim of our study was to study the efficacy and safety of low-dose isotretinoin (Roaccutane) in patients with moderate recurrent acne.

Material and research methods

We observed 40 patients with acne aged 18 to 27 years (women - 25 (62.5%); men - 15 (37.5%). In all study participants, acne manifested at puberty.

The inclusion criteria for the study were: the presence of moderate to severe acne; good therapeutic effect from 2 or more courses of adequate topical therapy of the disease with subsequent acne relapses; signing informed consent to participate in the study.

The exclusion criteria were: a history of indications for therapy with systemic retinoids, antiandrogen drugs; the fact of using systemic antibiotics or topical retinoids within the last 3 months; the presence of clinically significant changes in the hematological and (or) biochemical blood test; the presence of mild or severe acne; the presence of pregnancy; the presence of chronic liver failure or Gilbert's syndrome.

On the skin, inflammatory efflorescences were predominantly recorded in the form of multiple papules and papulo-pustules of a bright pink color, small in size (up to 0.5 cm in diameter) with uneven outlines slightly rising above the skin surface. In 8 (20%) cases, single nodes (cysts) were also visualized.

Against this background, all patients were diagnosed with severe seborrhea, as well as the presence of non-inflammatory forms of acne - open and closed comedones. Despite a long history of acne, the observed individuals did not have scars or other post-acne on the skin.

In 32 (80%) of the acne patients observed, skin lesions were limited to the face. In 8 (20%) cases, multiple papulo-pustular elements were also localized in the upper third of the chest and back.

All patients had previously received various types of therapy. Systemic antibiotics were received by 18 (45%) patients for more than 3 months prior to participation in the study. Topical retinoids were previously used by 26 (65%) of those observed; azelaic acid preparations - respectively 11 (27.5%); topical agents with antibacterial action - 35 (87.5%); combined preparations - 19 (47.5%). It is noteworthy that according to the recommendations of specialists, all 40 patients previously observed used various other topical agents, which, from the point of view of evidence-based medicine, are ineffective for acne.

Facial skin care in 16 (40%) patients with acne was ineffective and consisted of repeated use during the day of various cleansing gels, scrubs, as well as alcohol-containing products, which contributed to additional irritation of the skin. On the contrary, 5 (12.5%) study participants did not carry out any hygienic care for oily or dry skin in seborrheic areas at all.

To assess the severity and prevalence of the disease, the Acne Dermatology Index (ADI) was used, which takes into account the number of comedones, papules, pustules, nodes in the examined subject.

All patients were prescribed isotretinoin (Roaccutane), manufacturer - "F. Hoffman-La-Roche Ltd, Switzerland, at a standard dose of 10 mg/day for three months.

The study of the content of triglycerides, cholesterol, ALT, AST in the blood serum of observed persons with acne was carried out before the start of treatment with isotretinoin (Roaccutane), and was also carried out during therapy with "small doses" of the drug once a month for three months. As a control group, 40 healthy individuals were examined.

After the end of the 3-month course of monotherapy with isotretinoin, patients were followed up prospectively for 6 months.

Results and its discussion. Before treatment, all patients were found to have many miliary and lenticular papules of a conical shape of bright pink color, pustules with a tense cap, cloudy contents, single nodes of purple-bluish color, dense consistency, without signs of fluctuation, associated with an increase in the ADI index to 9, 7±0.5 (Fig. 1) on the back, chest and face.

By the 7th day from the start of therapy with isotretinoin (Roaccutane), 25 patients (62.5%) developed a peculiar reaction of exacerbation of dermatosis, manifested by the appearance of fresh nodules and miliary pustules on the face and back. However, already on the 14th day of treatment in all patients treated with isotretinoin (Roaccutane), a clear decrease in the signs of seborrhea was recorded. After 3-4 weeks from the start of taking isotretinoin (Roaccutane), a pronounced positive dynamics was noted on the part of the skin pathological process (papules flattened, faded, pustules shrank into crusts, nodes decreased in size), which was accompanied by a statistically significant decrease in the ADI index to 5, 1±0.1 (p<0,001). Ко 2-му месяцу терапии изотретиноином (Роаккутаном) данный показатель снизился до 3,1±0,1 (р<0,001), клинически отражая исчезновение комедонов, уменьшение количества папулезных узлов и полное исчезновение пустулезных эффлоресценций. Через 3 месяца от начала лечения изотретиноином (Роаккутана) у подавляющего большинства пациентов полностью разрешились комедоны, папулы, пустулы, а величина индекса ADI достигла 0,6±0,01 (р<0,001) (рис. 1).

Rice. Fig. 1. Dynamics of the ADI index in patients with acne who used the regimen of "low doses" of isotretinoin (Roaccutane).

Six months after the start of therapy with isotretinoin (Roaccutane), it was possible to prospectively assess the state of the skin process in 38 patients (two patients dropped out of the observation group for personal reasons). Thus, in 36 individuals observed by us, there were no signs of seborrhea and acne, the value of the ADI index was equal to zero. Only two patients had single lenticular pale pink nodular efflorescences on the back against the background of the complete absence of pustules, comedones, nodules and seborrhea phenomena (ADI index = 2.4 ± 0.1) (Fig. 1).

It was also found that isotretinoin (Roaccutane) was generally well tolerated by patients, and side effects were minimal in severity and spectrum. Thus, all patients (100%) developed cheilitis on the 7th–14th day of treatment. In 18 patients (45%), the presence of retinoid dermatitis of the face was stated, in 22 patients (55%) - dryness of the nasal mucosa. The above side effects did not require the abolition of isotretinoin (Roaccutane), they were easily and quickly stopped by the appointment of moisturizing agents, in particular the drug "Clobase".

When re-examined, laboratory parameters in all patients (in particular, AST, ALT, triglycerides) by the end of a three-month course of therapy with isotretinoin (Roaccutane) were comparable to control values. In 2 patients, an increase in the concentration of cholesterol in the blood was noted, however, there were no significant differences with the control group (p>0.05) (Table 1).

conclusions

1. The use of a mild dosing regimen of isotretinoin (Roaccutane) in patients with moderate to severe forms of acne is very appropriate.

2. The use of small doses of isotretinoin (Roaccutane) makes it possible to achieve a rapid and stable resolution of skin rashes, prevent relapses, minimize the risk of side effects, and does not require any additional therapy for both the underlying disease and those identified during the treatment of side- effects.

A.L. Bakulev, S.S. Kravchenya

Saratov State Medical University named after V.I. Razumovsky

Bakulev Andrey Leonidovich - Doctor of Medical Sciences, Professor of the Department of Skin and Venereal Diseases

2. Samtsov A.V. Acne and acneiform dermatoses. - M., 2009. - S. 32-45.
3. Layton A.M., Knaggs H., Taylor J. et al. Isotretinoin for acne vulgaris - 10 years later: a safe and successful treatment. Br J Dermatol., 1993; 129:292-296.
4. Goodfield M.J., Cox N.H., Bowser A. Advice on the safe introduction and continued use of isotretinoin in acne in the U.K. 2010. Br J Dermatol., 2010 Jun; 162(6): 1172-9.
6. Roodsari M.R., Akbari M.R., Sarrafirad N. et al. The effect of isotretinoin treatment on plasma homocysteine levels in acne vulgaris. ClinExp Dermatol. 2010 Aug; 35(6): 624-6.
7. Li L., Tang L., Baranov E. et al. Selective induction of apoptosis in the hamster flank sebaceous gland organ by a topical liposome 5-alpha-reductase inhibitor: a treatment strategy for acne. J Dermatol., 2010 Feb; 37(2): 156-62.
8. Sardana K., Garg V.K. Efficacy of low-dose isotretinoin in acne vulgaris. Indian J Dermatol Venereol Leprol., 2010 Jan-Feb; 76(1):7-13.
9. Ingram J.R., Grindlay D.J., Williams H.C. Management of acne vulgaris: an evidence-based update. Clin Exp Dermatol., 2010, Jun; 35(4): 351-4.
10. Merritt B., Burkhart C.N., Morrell D.S. Use of isotretinoin for acne vulgaris. Pediatric Ann., 2009, Jun; 38(6): 311-20.
11. Bener A., Lestringant G.G., Ehlayel M.S. et al. Treatment outcome of acne vulgaris with oral isotretinoin. J Coll Physicians Surg Pak., 2009, Jan; 19(1):49-51.
12. Kontaxakis V.P., Skourides D., Ferentinos P. et al. Isotretinoin and psychopathology: a review. Ann Gen Psychiatry., 2009, Jan 20; 8:2.
13. Degitz K., Ochsendorf F. Pharmacotherapy of acne. Expert Opin Pharmacother, 2008, Apr; 9(6): 955-71.
14. O'Reilly K., Bailey S.J., Lane M.A. Retinoid-mediated regulation of mood: possible cellular mechanisms. Exp Biol Med (Maywood), 2008, Mar; 233(3):251-8.
15. Berbis P. Systemic retinoids (acitretin, isotretinoin). Ann Dermatol Venereol., 2007, Dec; 134(12): 935-41.

Roaccutane is a drug from the group of systemic retinoids. intended for the treatment of acne. It is available in capsules with the active substance isotretinoin.

The drug is used to treat severe forms of acne.: nodular-cystic, conglobate, as well as flowing with subsequent scarring. It is also prescribed in cases where other methods of therapy are useless.

For every patient the scheme of application of Roaccutane is selected individually. The drug can be taken only as directed by a doctor after a thorough examination, and self-medication is unacceptable.

Mechanism of action

When choosing an acne treatment it is necessary to consider how Roaccutane acts on the body.

The results of studies have shown that the drug causes an improvement in the clinical picture in severe forms of acne. This is due to the fact that it reduces the activity of the sebaceous glands, and also reduces their size.

With increased production of sebum, a favorable environment is created for the reproduction of Propionibacterium acnes. These are the bacteria that lead to the development of severe acne.

Also scientifically proven that isotretionine reduces inflammation of the skin.

Standard dosing regimen

Before taking the drug you need to be examined by a doctor and take tests for an accurate diagnosis.

After that, the specialist will tell the patient, how to take roaccutane. The dosages given below are indicative and require individual adjustment.

Roaccutane capsules are taken orally 1 or 2 times a day with meals.. The recommended dosage for starters is 0.5-1 mg per 1 kg of body weight. Every month it can be adjusted depending on the result achieved and the severity of side effects.

For the treatment of particularly severe forms of acne or acne on the trunk, it may be necessary to increase the daily dose of the drug to 2 mg / kg.

If the patient does not tolerate the amount of isotretinoin prescribed to him, it is reduced. However, in this case, the treatment is delayed.

First month: (60 mg/day x 30 days) / 70 kg.
Second month: (50 mg/day x 30 days) / 70 kg.
Third month: (40 mg / day x 30 days) / 70 kg.

These are theoretical calculations.. In reality, they should be made only on the basis of the analyzes carried out.

When the cumulative dose reaches 120-150 mg/kg, the likelihood of acne recurrence is greatly reduced. The time when Roaccutane improves is on average 16-24 weeks. During this period, in most cases, it is possible to achieve a stable remission.

Acne usually resolves completely after one treatment. receiving funds. In case of relapse, treatment can be repeated at similar dosages.

However resuming the drug is possible no earlier than after 8 weeks after completing the first course. During this period, as a rule, the therapeutic effect remains.

Contraindications

Contraindications for taking Roaccutane are:

pregnancy and lactation;
kidney failure;
hypersensitivity to the drug or individual components in its composition;
an excess of vitamin A;
severe hyperlipidemia;
simultaneous administration with drugs from the tetracycline group;
age up to 12 years.

With caution, Roaccutane is prescribed for diabetes mellitus, alcoholism, lipid metabolism disorders, obesity and a tendency to depression.

Dosing in special cases

In exceptional cases, the drug is prescribed, even if there are contraindications.

However, the expected benefits of therapy must outweigh the potential health risks.

When prescribing a treatment regimen, the doctor takes into account the results of the patient's examination. During the entire course of taking the funds the patient should be constantly monitored by his doctor.

kidney failure

Patients with severe kidney failure initially prescribed Roaccutane in small doses.

Usually it is 10 mg/day.

If the patient tolerates the treatment well, it is possible to increase the daily dosage, but up to a maximum of 1 mg / kg.

Pregnancy

Pregnancy is an absolute contraindication for taking Roaccutane. If it occurs during treatment or within a month after completion of therapy, there is a high risk of miscarriage or the detection of severe malformations in the born child:

hydrocephalus;
microcephaly;
malformations of the cerebellum;
anomalies of the outer ear;
microphthalmia;
cardiovascular pathologies;
wolf's mouth;
malformations of the thymus and parathyroid glands.

The appointment of Roaccutane to women of childbearing age is possible only with all of the following conditions are met simultaneously:

Even those women who are diagnosed with infertility, amenorrhea, as well as those who inform the doctor about the complete absence of sexual life, should use contraceptives during the period of treatment with Roaccutane. An exception is made for patients who have undergone a hysterectomy.

If during the period of treatment a woman is pregnant, taking Roaccutane is immediately stopped. The patient should consult with a specialist in the field of teratology about the advisability of preserving it.

During lactation, taking Roaccutane is also not recommended.. Isotretinoin is highly lipophilic, so there is a high risk that it will pass into breast milk. This is fraught with side effects for the baby.

special instructions

The drug is intended for the treatment of only severe forms of acne.. With acne vulgaris of mild or moderate course, the use of Roaccutane is not recommended.

During the period of taking the drug, it is necessary to carefully monitor the patient's condition. Also The patient should adhere to the following guidelines:

donate blood to study lipid levels to monitor liver function;
patients who wear contact lenses - use glasses when side effects from the eyes appear;
patients with diabetes - more often to monitor the concentration of glucose in the blood;
donors - refuse to donate blood for the entire period of treatment and for 1 month after its completion (to exclude the transfusion of this blood to pregnant women);
when taking the first dose - be extra careful while driving and when performing work associated with risk or requiring increased concentration of attention, quick response;
avoid exposure to ultraviolet radiation (including UV therapy, prolonged exposure to direct sunlight, visits to solariums).

Interaction with other drugs

During treatment with the drug, caution should be exercised when taking other medicines. So, in combination with tetracycline antibiotics, the effectiveness of Roaccutane is reduced.

Simultaneous reception with sulfonamides, thiazide diuretics, tetracyclines increases the risk of sunburn. Tetracyclines are forbidden to be combined with Roaccutane also because of the likelihood of an increase in intracranial pressure.

Side effects

During treatment with Roaccutane, side effects often occur. Dose adjustment sometimes helps to get rid of them, but some persist even after discontinuation of the drug.

On the part of the skin and mucous membranes are possible:

The most likely musculoskeletal side effects are:

muscle and joint pain;
arthritis;
bone changes (including calcification of tendons and ligaments).

From the side of the central nervous system, some patients experience:

Separate cases of side effects from the sense organs are also described.:

photophobia;
impaired visual acuity and adaptation to the dark;
swelling of the optic nerve;
hearing loss at certain frequencies;
eye irritation;
reversible disturbances in color perception.

From the gastrointestinal tract, the following adverse reactions occur:

nausea;
diarrhea;
colitis;
bleeding.

Described isolated cases of hepatitis in patients receiving Roaccutane. Extremely rarely, the drug provokes the occurrence of pancreatitis with a fatal outcome.

In addition, spasms in the bronchi are possible in patients with bronchial asthma, anemia and malfunctions in the functioning of the immune system. Cases of primary diabetes mellitus have also been reported.

For citation: Lvov A.N., Kirilyuk A.V. Roaccutane® in the treatment of acne: standard regimens and a new low-dose regimen // BC. 2008. No. 23. S. 1541

About 25 years ago, the first reports appeared in the world scientific literature about the possibility of oral use of isotretinoin (13-cis-retinoic acid - Roaccutane®, F. Hoffmann-La Roche Ltd., Switzerland) for the treatment of severe forms of acne. The therapeutic triumph of this technique in complex inflammatory and sclerosing forms of acne, other dermatoses (for example, rosacea) was confirmed by numerous, constantly increasing number of solid publications from year to year, which, from the standpoint of evidence-based medicine, made it possible not only to reliably assess the clinical effectiveness of the drug, but also to objectify it. tolerability, as well as to draw up a clear range of indications and contraindications.

What are the currently well-established principles of systemic acne therapy with Roaccutane and what are the possible ways to modify well-known schemes? Before answering this question, let us turn to the unique cytoregulatory and pharmacokinetic properties of the drug, which, in accordance with modern indications and the individual situation, in most cases immediately consider it as a first-line drug for the initial treatment of acne.
By the beginning of the 70s of the XX century, information began to appear in the specialized literature about the presence of pronounced regulatory properties in relation to the sebaceous glands of animals and humans in one of the cis-derivatives of retinoic acid. A few years later, this drug was introduced into clinical practice under the international name isotretinoin (13-cis isomer of retinoic acid), patented as Roaccutane® (F. Hoffmann-La Roche Ltd, Switzerland). A significant number of works all over the world have been devoted to the study of the unique properties of the drug. It has been established that Roaccutane®, interacting with nuclear receptors, affects the processes of differentiation of sebaceous gland cells, which leads to a pronounced decrease in the size of the sebaceous glands, suppression of activity and a sharp decrease in sebum excretion. Depending on the dose and duration of the drug, the sebostatic effect reaches 90% of the initial level. Additionally, Roaccutane® has a moderate immunomodulatory effect and has a mild anti-inflammatory effect. In this regard, Roaccutane® quickly became the world's number one treatment for severe (conglobate, phlegmonous and cystic) forms of acne. Currently, the drug is also prescribed for milder forms of acne (accompanied, in particular, by severe psycho-emotional disorders, social maladjustment, as well as a tendency to scarring, etc.), which is due to a significant improvement in the quality of life of patients against the backdrop of effective treatment. The latter is an indirect confirmation of the fact that often the benefits obtained from the use of Roaccutane® in any groups of patients significantly outweigh the possible risk.
It can be stated that due to the study of the mechanisms of action of Roaccutane®, the pathogenesis of acne has largely become clear. As you know, the starting point for acne is genetically determined hyperandrogenism or increased sensitivity of sebocytes to testosterone derivatives. Ultimately, this background determines the leading importance of four factors: follicular hyperkeratosis, hypertrophy of the sebaceous glands with their hypersecretion, microbial hypercolonization and inflammatory response. The pathogenetic validity and effectiveness of the use of Roaccutane® is determined by the fact that this drug affects, to one degree or another, all links in the pathogenesis of acne.
Standard therapy regimens
Treatment usually begins with a dose of 0.5 mg/kg per day. As our more than a decade of experience with Roaccutane® shows, more than 200 patients with moderate (acne severity II-III) and predominantly severe (acne severity IV) forms of acne (n = 213; 133 men, 80 women), optimal the initial dose is 0.75 mg/kg. It provides a faster therapeutic effect with minimal side effects. In young patients, treatment can be started with a dose of 1.0 mg / kg per day, which makes it possible to quickly reach the total course dose. Dose adjustment is usually made 3-5 weeks after the start of therapy, depending on the effect and tolerability of the drug. In most patients, by the end of the 1st - the beginning of the 2nd week of treatment, an exacerbation of the skin process is noted, consisting primarily in an increase in the number of rashes. The latter is not a reason to reduce the daily dose, since this exacerbation soon subsides. After achieving a stable positive therapeutic effect, the daily dose can be adapted to maintenance (0.1-0.3 mg/kg). The duration of treatment with isotretinoin is usually at least 4 months, and usually 6-8 months (with a total course dose of 120-150 mg / kg). The stability of the treatment result and the absence of relapses largely depend on the achievement of the indicated course dose. So, according to our experience, the overall clinical efficacy of treatment of patients with conglobate form of acne (with localization of rashes on the skin of the face and trunk) after 8 months of therapy reached 92%, while in terms of long-term prognosis, a recurrence of the disease was subsequently observed only in 5.6% patients in this subgroup.
It is not uncommon to encounter a situation where dermatologists avoid prescribing Roaccutane® for fear of its allegedly expressed undesirable effects. In our opinion, these fears are exaggerated. The benefits of using Roaccutane far outweigh the risks. You should clearly understand the possible side effects of systemic isotretinoin and be informed about ways to correct them. Our observations show that the inevitable side effects are facial dermatitis and cheilitis. Less commonly observed dryness in the nose, "dry" blepharoconjunctivitis, mild episodic myalgia during exercise. Deviations in laboratory parameters (primarily in the form of an increase in ALT and AST) are not always noted, they are usually unstable and normalize even without reducing the daily dose of the drug.
Isotretinoin has a strong teratogenic effect. Every woman of childbearing age receiving the drug must use effective contraceptives one month before treatment, during the entire period of treatment, and also within a month after its completion. We do not share the opinion about the unreasonable, in our opinion, prohibition of pregnancy within 2 years after the end of Roaccutane®. The latter, apparently, can be associated with an unjustified, purely mechanical transfer of the indicated period (2 years) from the instructions for the use of other retinoids - etretinate and the currently used acitretin. The fact is that the calculation of the period of mandatory contraception recommended after the end of treatment is based on data on the half-life of the retinoid: to remove 99% of the drug from the body, a time equal to 7 half-lives is required. The half-life of etretinate is about 100 days, which leads to mandatory contraception for 2 years. The half-life of acitretin is on average only 2 days, however, it must be taken into account that in the human body acitretin can be esterified with the formation of etretinate. In this regard, a period of time after the end of treatment with acitretin was established, during which pregnancy should be avoided, also for a period of 2 years. The half-life of isotretinoin (Roaccutane®) averages 19 hours, the half-life of its main metabolite 4-oxo-isotretinoin averages 29 hours. Long-term circulating teratogenic substances in the body are not formed, endogenous concentrations of retinoids are restored approximately 2 weeks after the end of Roaccutane®. In this case, a period of obligate contraception lasting 4 weeks after the end of treatment seems reasonably sufficient. Nevertheless, we recommend prolonging the pregnancy ban up to 2 months after the end of therapy, which coincides with the opinion of reputable German dermatologists.
In women, therapy with Roaccutane® should begin on the 2nd-3rd day of the next normal menstrual cycle. Before starting treatment, patients should be informed about the appropriate precautions and possible consequences in writing. If pregnancy occurs while taking isotretinoin or within a month after its withdrawal, there is a significant risk of developing severe malformations of the organs and systems of the fetus (primarily the central nervous system and the cardiovascular system). Isotretinoin should not be administered to women during lactation.
Other side effects of Roaccutane®, as already noted, are usually mild and dose-dependent, completely regressing at the end of treatment. Nevertheless, in the course of therapy, for the prevention of retinoid cheilitis, retinoid facial dermatitis, retinoid "dry" conjunctivitis, it is advisable for patients to recommend the application of various moisturizing and emollient drugs (hygienic lipstick, emollient creams, moisturizing eye drops like "artificial tears", etc. .).
Low-dose regimens
Recently, in connection with the expansion of indications for the use of Roaccutane® in the foreign scientific and practical literature, the issue of the so-called method of "low-dose" and "ultra-low-dose" use of the drug has been actively discussed. It should be noted that with the standard dosing regimen, low doses of the drug (0.1-0.3 mg / kg or 10 mg per day) were used at the final stages of treatment, while the pharmacokinetic properties of the drug (the half-life of the main metabolite - an average of 30 hours) allowed to use it both daily and intermittently, i.e. in one day. As both foreign and our own experience shows, the use of Roaccutane® immediately from low doses is possible in a number of conditions, including severe seborrhea associated with mild acne, diseases from the group of decalvaning folliculitis, excoriated acne, and acne of varying severity under the condition psychological mood of patients for treatment with systemic retinoids.
It should be noted that empirically many dermatologists and cosmetologists around the world use low doses of Roaccutane® in practice, however, there have been practically no reliable clinical studies based on the principles of evidence-based medicine. Fundamentally, in the appointment of low doses in the so-called "problem skin" abroad, the following four approaches are distinguished: 1) the appointment of Roaccutane® at a dose of 10 mg per day, regardless of body weight, for approximately 4 weeks; then 10 mg every 5 days a week; then 10 mg every 3 days per week; then 10 mg every 2 days per week; then 10 mg once a week, while the stepwise dose adjustment is carried out monthly; 2) 5 mg per day, regardless of body weight for a long time; 3) 2.5 mg per day, regardless of body weight for a long time; 4) 2.5 mg per day twice a week for a long time. Of all the proposed schemes, the first method of using low-dose Roaccutane®, developed and tested in practice from 1991 to 2004 by G. Plewig and co-workers, seems to us the most reasonable. According to them, one study included 28 patients with grade III and IV acne who received isotretinoin at a standard dose of 0.5 mg/kg daily for 6 months. In the second study, patients received ultra-low doses of isotretinoin from 10 to 5 mg per day, as well as 2.5 mg 2 times a week for 6 months. In the first group, the effectiveness of the therapy was confirmed: the number of rash elements decreased, as an indicator of therapeutic effectiveness, the number of follicular elements was reduced, the level of P. acne colonization decreased, and sebum excretion decreased. In the second study, the effectiveness was also noted in the main clinical parameters, the level of seborrhea and the amount of P. acne decreased. Thus, the data obtained demonstrate the effectiveness of low doses of isotretinoin for the treatment of seborrhea, persistent acne1, as well as maintenance therapy for patients with severe forms of acne treated with higher doses, as well as for the treatment of patients with various sebaceous hyperplasia. In our experience, we also stated a good effect from its use in patients with moderate acne (photos 1, 2). At the same time, the course dose when using low-dose Roaccutane® regimens can be 15, 7.5 and even 1 mg/kg of body weight, which completely reduces the current idea of the need to calculate it as a significant benchmark for the clinical effectiveness of Roaccutane® therapy. We fully share the postulate put forward by this authoritative author about the optionality of calculating the course dose in clinical practice.
Combination therapy with low doses of isotretinoin in combination with other systemic or topical acne treatments also seems to be a very tempting target for dermatologists. A group of researchers evaluated the effectiveness of treating patients with acne with low doses of isotretinoin in combination with cyproterone acetate. 27 patients were treated for 12 weeks at 0.05 mg/kg/day. isotretinoin (10 patients) or 50 mg/day. cyproterone acetate (8 patients), or two drugs at the same time in the same doses (9 patients). The study showed that the clinical efficacy in all groups was approximately the same, however, the increase in triglyceride levels caused by isotretinoin was significantly less common during concomitant therapy with an antiandrogen drug.
A promising direction is the use of low doses of Roaccutane® in patients with late persistent acne (acne adultorum). In a study conducted by R. Marks, the effectiveness of treating patients with advanced acne aged 30-60 years with low doses of isotretinoin at a dose of 0.25 mg/kg per day for 6 months was confirmed. Against the background of the therapy, patients noted regression of acne manifestations, stable remission for 36 months after the end of treatment, and very good tolerability of the therapy. In the course of the work, the effectiveness of using low doses of isotretinoin in a group of patients with torpid acne was also noted in comparison with the use of external forms of retinoids and benzyl peroxide. The use of isotretinoin in the standard regimen caused a significantly greater number of side effects (dry skin, cheilitis, changes in biochemical parameters), which was one of the reasons for interrupting isotretinoin therapy in some patients from this group.
One of the key questions when using low doses of Roaccutane® is how long can such therapy be carried out in a safe mode? It is no secret that long-term use of systemic retinoids in standard or high doses can lead to changes in biochemical markers of bone tissue and toxic effects on bone tissue (early closure of growth zones). With regard to the low-dose regimen, this view has been refuted. Trifiro G. and Norbiato G. studied the ratio of markers of various types of collagen, as well as excretory indicators of bone resorption in 10 young people aged 17-19 years who received treatment with low and medium doses of Roaccutane®. Against the background of a good clinical effect, the effect of isotretinoin on skin type I collagen was noted, while no changes were found in biochemical parameters reflecting the state of the bones. Given this fact, it can be hypothesized that the treatment of patients with acne with low doses of isotretinoin over a long period of time can contribute not only to the reduction of inflammatory elements of acne, but also to a significant correction of cicatricial changes (post-acne).
Of undoubted interest is the use of low doses of Roaccutane® in psychosomatized forms of acne, the skin process in which does not always correlate with the severity of mental disorders. So, in a study by Ng C.H., Schweitzer I. (2003), with a confirmed association of depressive spectrum disorders and acne of varying severity, dynamics was noted during treatment with low doses of Roaccutane® not only from the skin process, but also from psychopathological symptoms.
In this context, we can also refer to priority own data on the inclusion of low doses of systemic isotretinoin in the therapeutic complex for excoriated acne. In all patients with excoriated acne that developed within the framework of the psychopathological symptom complex of overvalued hypochondria of beauty (n=28, 25 women, 3 men, mean age 25.1±2.3 years), self-destruction phenomena prevailed over manifestations of acne vulgaris in the skin status. At the first stage, we prescribed treatment with the use of psychotropic drugs - atypical antipsychotics (risperidone 2-4 mg / day, olanzapine 2.5-10 mg / day, etc., for 6-8 weeks) and antidepressants (SSRIs - fluoxetine 40 mg/day, sertraline up to 100 mg/day, etc., 6-8 weeks). Subsequently, Roaccutane® was prescribed at an initial dose sufficient to stop the minimal manifestations of acne, at the rate of 0.3 mg/kg, subsequently the dose was reduced to 0.15-0.1 mg/kg per day. After achieving a stable clinical improvement, they switched to an intermittent intake of 10 mg of Roaccutane® every other day. The duration of treatment was 4-6 months. In the process of combined treatment, positive dynamics was noted in the form of regression of comedones, papules, pustules, and seborrhea phenomena. Due to the absence of the appearance of new acne elements, as well as the reduction of psychopathological symptoms, the number of self-extractions also decreased (Fig. 1, photo 3.4). The overall clinical efficacy was 78.2%.
Tolerability of low doses of Roaccutane® was good. The phenomena of retinoid dermatitis were significantly less pronounced in comparison with the treatment according to the standard schemes for the use of Roaccutane®. All patients developed symptoms of retinoid dermatitis on the 2nd-3rd day of therapy (the phenomena of cheilitis, dryness and flaking of the skin of the face were especially disturbing), approximately half of the patients experienced moderate dryness of the skin of the hands during 1-2 months of therapy. Thus, isotretinoin, when used systemically in low doses, is sufficient to stop background skin changes in excoriated acne and, in combination with neuroleptic therapy, significantly improves the quality of disease therapy.
Another model for the use of a low-dose regimen can serve as a dermatosis belonging to the group of inverse acne: decalvaning folliculitis of the scalp, considered by some authors as an erased version of abscessing and undermining folliculitis and Hoffmann's perifolliculitis (photo 5). The disease has a pathogenesis similar to acne, is characterized by an extremely torpid course, is resistant to systemic antibiotic therapy and external retinoids, at the same time, the process is often erased, subclinical, and therefore the appointment of standard doses of Roaccutane® is unjustified. There is only a single experience of treating this condition according to the considered innovative scheme.
In conclusion, it should be especially noted that despite the decrease in side effects with low-dose isotretinoin, its teratogenicity and, as a result, obligatory contraception for the entire period of treatment and a month after it remains an unchanged fact. It should be taken into account that the prolongation of the period of taking the drug, even at low doses, leads to an increased risk of pregnancy, even in conditions of adequate contraception.
Thus, based on literature data and numerous of our own observations, we believe that Roaccutane® is still the most pathogenetically justified agent for the treatment of moderate and especially severe forms of acne, which gives a stable high therapeutic effect with minimal and well controllable side effects. The use of low and very low doses of isotretinoin for the treatment of patients with various forms of acne is a new and promising method. This approach allows not only minimizing the possible effects of standard therapy and expanding therapeutic options, but also significantly optimizes pharmacoeconomic indicators in the direction of reducing the cost of treatment with Roaccutane®.

1 Plewig also considers the treatment of severe, conglobate-
forms of acne with low doses of isotretinoin: the first
Oral corticosteroids 1 mg/kg body weight are used for 7-14 days
body, then within 7-10 days - antibiotics from the macrolide group,
subsequently, after a decrease in the acute inflammatory process
treatment with isotretinoin at a dose of 0.2 to 0.4 mg / kg of body weight is prescribed
body. This scheme allows to achieve faster clinical
effect than isotretinoin monotherapy.

Literature
1. Samgin M.A., Gromova S.A., Kolesnikov Yu.Yu. // Vestn dermatol venerol, 1989; 56-60
2. Samgin M.A., Lvov A.N., Potekaev N.S. and others // Ross Journal of Skin Veins Bol 2002, 3, 60-65
3. Lvov A.N., Samgin M.A. Excoriated acne: the first experience of treatment with low-dose roaccutane // Abstracts of the X Russian National Congress "Man and Medicine". - Moscow, 7-11 April 2003 52
4. Skripkin Yu.K., Kubanova A.A., Samsonov V.A. and others // Vestn dermatol venerol, 1994; 2:3-6
5. Miner I.Ya., Pokryshkin V.I., Pisarenko M.F. // Vestn dermatol 1984; 3:26-31
6 Chu A; Cunliffe WJ // J Eur Acad Dermatol Venereol, 1999 May, 12:3, 263
7 Geiger JM; Saurat JH // Dermatol Clin, 1993 Jan, 11:1, 117-29
8. Kindmark A, et al // Acta Derm Venereol, 1998, Jul 7: 24-9
9. Leyden JJ // J Am Acad Dermatol 1998 Aug, 39:2 Pt 3, S45-9
10. Orfanos CE // Dermatology, 1998, 196:1, 140-7
11. Plewig G., Jansen T. Isotretinoin. // In: Fortschritte der praktischen Dermatologie und Venerologie - Springer - Berlin, 1994; pp. 280-284
12. Wessels F. // S Afr Med J, 1999 Jul, 89:7 Pt 2, 780-4
13. Wiegand UW. // J Am Acad Dermatol, 1998 Aug, 39:2 Pt 3, 8-12
14. Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the treatment of acne vulgaris. //J Am Acad Dermatol. 2006 Apr;54(4):644-6.
15. Benifla JL, Ville Y, Imbert MC, Frydman R, Thomas A, Pons JC. Fetal tissue dosages of retinoids. Experimental study concerning a case of isotretinoin (Roaccutan) administration and pregnancy. // Fetal Diagn. Ther. 1995 May-Jun;10(3):189-91
16. Dreno B, Daniel F, Allaert FA, Aube I. Acne: evolution of the clinical practice and therapeutic management of acne between 1996 and 2000. // Eur J Dermatol. 2003 Mar-Apr;13(2):166-70.
17. Lvov A.N., Samgin M.A. Low doses of systemic isotretinoin for acne excoriee: the first experience of treatment // JEADV, Abstr. of the 12th Congress of the EADV, 15-15 Oct. 2003 Barcelona. Spain - p.168
18. Marks R. Acne and its management beyond the age of 35 years. //Am J Clin Dermatol. 2004;5(6):459-62.
19. Marsden JR, Laker MF, Ford GP, Shuster S. Effect of low dose cyproterone acetate on the response of acne to isotretinoin. // Br J Dermatol. 1984 Jun;110(6):697-702
20. Ng CH, Schweitzer I The association between depression and isotretinoin use in acne. //Aust N Z J Psychiatry. 2003 Feb;37(1):78-84.
21. Plewig G, Hennes R, Maas B, Mack-Hennes A. Remission behavior following low-dose 13-cis-retinoic acid in papulopustular acne // Z Hautkr. 1986 Sep 1;61(17):1205-10.
22. Plewig G. Isotretinoin Therapie: Wann, was, wie? // In: Fortschritte der praktischen Dermatologie und venerologie 2004 (Hrsg. G. Plewig, P. Kaudewitz, C.A. Sander) - Springer Berlin Heidelberg - 2005, p. 245-258
23. Trifiro G, Norbiato G. Type I collagen N-telopeptide variation in adolescents receiving oral isotretinoin for severe acne. // J Pediatr Endocrinol Metab. 2002 Jan;15(1):35-9.
24. Zouboulis CC. Exploration of retinoid activity and the role of inflammation in acne: issues affecting future directions for acne therapy. // J Eur Acad Dermatol Venereol. 2001;15 Suppl 3:63-7.