Acnecutan

Composition for 1 capsule:

Active substances:

Isotretinoin 8.0 mg

Excipients:

 Gelucir® 50/13 (a mixture of polyethylene oxide and glycerin stearic acid esters),

refined soybean oil,

Span 80® (sorbitan oleate - mixed esters of oleic acid and sorbitol).

Capsule composition

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

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

The exact mechanism of action of isotretinoin has not yet been identified, but it has been established that the improvement in the clinical picture of severe forms of acne is associated with 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, therefore, reducing sebum production inhibits bacterial colonization of the duct.

Acnecutan 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

After oral administration, absorption is variable, the bioavailability of Acnecutan is low and variable - due to the proportion of dissolved isotretinoin in the drug, and can also increase when the drug is taken with food. In patients with acne, the maximum plasma concentrations (Cmax) 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 albumin) - 99.9%.

The equilibrium concentrations of isotretinoin in the blood (Css) in patients with severe 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 (completely trans-retinoic acid) and 4-oxo-retinoin, as well as less significant metabolites, which also include glucuronides. Since isotretinoin and tretinoin are reversibly converted into each other in vivo, the metabolism of tretinoin is associated with the metabolism of isotretinoin. 20-30% of the dose of isotretinoin is metabolized by isomerization. Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans.

In vitro studies have shown that several CYP enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. In this case, none of the isoforms, most likely, plays a dominant role. Isotretinoin and its metabolites do not significantly affect the activity of CYP enzymes.

The terminal phase half-life for isotretinoin is on average 19 hours. The terminal phase half-life for 4-oxo-isotretinoin is an average of 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 intake.

Pharmacokinetics in special clinical situations

Since data on the pharmacokinetics of the drug in patients with impaired liver function are limited, isotretinoin is contraindicated in this group of patients. Renal failure of mild to moderate severity does not affect the pharmacokinetics of isotretinoin.

Severe forms of acne (nodular - cystic, conglobate, acne with a risk of scarring). 
Acne that does not respond to other therapies.

Pregnancy is an absolute contraindication for Acnecutan therapy. If pregnancy occurs despite the 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 a period when a woman is taking isotretinoin orally (in any dose and even for a short time), there is a very high risk of having a child with developmental defects.

Acnecutan is contraindicated in women of childbearing age, unless the woman's condition meets all of the following criteria:

• she must have severe acne that is resistant to conventional treatments;
• she must surely understand and follow the instructions of the doctor;
• she should be informed by the doctor about the danger of pregnancy during treatment with Acnecutan, within one month after it, and urgent consultation if pregnancy is suspected;
• she should be warned about the possible ineffectiveness of contraception;
• she must confirm that she understands the essence of the precautions;
• she must understand the need for and continuously use effective methods of contraception for one month before treatment with Acnecutan, during treatment and for a month after its completion (see the section "Interaction with other medicinal products"); it is desirable to use simultaneously 2 different methods of contraception, including barrier;
• She must have obtained a negative valid pregnancy test result within 11 days before starting the drug; a pregnancy test is strongly recommended to be carried out monthly during treatment and 5 weeks after the end of therapy;
• she should start treatment with Acnecutan only on day 2-3 of the next normal menstrual cycle;
• she must understand the need for a mandatory visit to the doctor every month;
• when treating for a relapse of the disease, she should constantly use the same effective methods of contraception for one month before starting treatment with Acnecutan, during treatment and within a month after its completion, as well as undergo the same reliable pregnancy test;
• she must fully understand the need for precautions and confirm her understanding and willingness to use reliable contraceptive methods as explained to her by the doctor.

The use of contraception according to the above directions during treatment with isotretinoin should be recommended even for those women who usually do not use contraception due to infertility (except for patients who have undergone a hysterectomy), amenorrhea, or who report that they are not sexually active.

The doctor must be sure that:

• the patient suffers from severe acne (nodular-cystic, conglobatic acne or acne with risk of scarring); acne that does not respond to other types of therapy;
• a negative result of a reliable pregnancy test was obtained before starting the drug, during therapy and 5 weeks after the end of therapy; the dates and results of the pregnancy test must be documented;
• the patient uses at least 1, preferably 2 effective methods of contraception, including the barrier method, within one month before starting treatment with Acnecutan, during treatment and within a month after its completion; -the patient is able to understand and fulfill all of the above requirements for preventing pregnancy;
• the patient meets all of the above conditions.

Pregnancy test 
In accordance with current practice, a pregnancy test with a minimum sensitivity of 25 mME / ml should be performed in the first 3 days of the menstrual cycle:

Before starting therapy:

• To rule out possible pregnancy, the result and date of the initial pregnancy test must be recorded by the physician prior to contraception. In patients with irregular periods, the timing of the pregnancy test depends on sexual activity and should be performed 3 weeks after unprotected intercourse. The doctor must inform the patient about the methods of contraception.
• A pregnancy test is carried out on the day Acnecutan is prescribed or 3 days before the patient's visit to the doctor. Test results should be recorded by the technician. The drug can only be prescribed to patients receiving effective contraception for at least 1 month before starting Acnecutan therapy.

During therapy:

• The patient must see a 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, the pregnancy test is carried out on the day of the visit or three days before the visit to the doctor, the test results must be recorded.

End of therapy:

• A pregnancy test is performed 5 weeks after the end of therapy.

A prescription for Acnecutan for a woman capable of childbearing can only be prescribed for 30 days of treatment; continuation of therapy requires a new prescription of the drug by a doctor. It is recommended that the pregnancy test, prescription and drug administration be carried out on the same day.

Acnecutan should be dispensed at the pharmacy only within 7 days from the date of the prescription.

Pregnancy, established and planned (teratogenic and embryotoxic effects are possible), lactation period, hepatic failure, hypervitaminosis A, severe hyperlipidemia, concomitant tetracyclines therapy.

Hypersensitivity to the drug or its components. Acnecutan is not indicated for the treatment of puberty acne and is not recommended for use in children under 12 years of age.

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

Male patients: 
Existing data indicate that in women, exposure to the drug from the semen and seminal fluid of men taking Acnecutan is not sufficient to cause the teratogenic effects of Acnecutan. Men should exclude the possibility of taking the drug by others, especially women.

If, despite the precautions taken, during treatment with Acnecutan or within a month after its termination, pregnancy still occurs, there is a high risk of very severe fetal malformations. If pregnancy occurs, therapy with Acnecutan is discontinued. The feasibility of maintaining it should be discussed with a physician specializing in teratology.

Since isotretinoin is highly lipophilic, it is highly likely that it passes into breast milk. Due to the possible side effects, Acnecutan should not be prescribed to nursing mothers.

Most side effects are dose dependent. Side effects are usually reversible after dose adjustment or drug withdrawal, but some may persist after treatment is discontinued. Symptoms associated with hypervitamnosis A: dry skin, mucous membranes, incl. lips (cheilitis), nasal cavity (bleeding), larynx and pharynx (hoarseness), eyes (conjunctivitis, reversible corneal opacity and contact lens intolerance).

Skin and its appendages: peeling of the skin of the palms and soles, rash, itching, erythema of the face / dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased growth of granulation tissue, persistent thinning of hair, reversible hair loss, fulminant forms of acne, hyperpigsumentation, photosensitivity, easy skin trauma. At the beginning of treatment, acne may worsen and last for several weeks.

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

Central nervous system and mental sphere: excessive fatigue, headache, increased intracranial pressure ("pseudotumor of the brain": headache, nausea, vomiting, visual impairment, swelling of the optic nerve), seizures, rarely - depression, psychosis, suicidal thoughts. Sense organs: xerophthalmia, isolated cases of visual acuity disturbance, photophobia, dark adaptation disturbance (decrease in twilight vision), rarely - color perception disturbance (passing after drug withdrawal), lenticular cataract, keratitis, blepharitis, conjunctivitis, eye irritation, optic neuritis, edema of the optic nerve (as a manifestation of intracranial hypertension); hearing impairment 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 fatal pancreatitis have been reported. Transient and reversible increase in the activity of hepatic transaminases, isolated cases of hepatitis. In many of these cases, the changes did not go beyond the normal range and returned to baseline values ​​during treatment, but in some situations it became necessary to reduce the dose or to cancel Acnecutan.

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

Blood system: anemia, decreased hematocrit, leukopenia, neutropenia, increase or decrease in the number of platelets, accelerated ESR.

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

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 malformations - hydro- and microcephaly, underdevelopment of cranial nerves, microphthalmia, malformations of the CVS, parathyroid glands, skeletal formation disorders - underdevelopment of the digital phalanges, skull, cervical vertebrae, femur, forearms, ankles 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 adhesions, fusion of fingers and toes, developmental disorders of the thymus gland; fetal death during the perinatal period, premature birth, miscarriages), premature closure of the epiphyseal growth zones; in an experiment on animals - pheochromocytoma.

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 weaken the effectiveness of progesterone medications, so you should not use contraceptives containing small doses of progesterone.

Combined use with topical 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.

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

The therapeutic efficacy of Acnecutan 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 Acnecutan 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 period. In most patients, acne completely disappears after a single course of treatment.

In case of relapse, it is possible to carry out a second course of treatment at the same daily and cumulative dose. A repeated course is prescribed no earlier than 8 weeks after the first, since the improvement may be delayed.

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

In case of an overdose, signs of hypervitaminosis A may appear. In the first few hours after an overdose, gastric lavage may be necessary.

It is recommended to monitor liver function and liver enzymes before treatment, 1 month after its start, and then every 3 months or if indicated. A transient and reversible increase in hepatic transaminases was noted, in most cases within the normal range. If the level of hepatic transaminases exceeds the norm, it is necessary to reduce the dose of the drug or cancel it. The fasting serum lipid level should also be measured before treatment, 1 month after initiation, and then every 3 months or as indicated. Usually, lipid concentrations return to normal after dose reduction or discontinuation of the drug, as well as following diet. It is necessary to control a clinically significant increase in triglyceride levels, since their rise above 800 mg / dL or 9 mmol / L may be accompanied by the development of acute pancreatitis, possibly with a fatal outcome.

With persistent hypertriglyceridemia or symptoms of pancreatitis, Acnecutan should be canceled. In rare cases, depression, psychotic symptoms and, very rarely, suicidal attempts have been described in patients receiving Acnecutan. 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 drug treatment, referring them to an appropriate specialist if necessary. However, the withdrawal of Acnecutan may not lead to the disappearance of symptoms and further observation and treatment by a specialist may be required.

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

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

Patients receiving Acnecutan are advised to use moisturizing ointment or body cream, lip balm to reduce dry skin and mucous membranes at the beginning of therapy.

While taking Acnecutan, 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.

It is necessary to avoid deep chemical dermoabrasion and laser treatment in patients receiving Acnecutan, as well as within 5-6 months after the end of treatment due to the possibility of increased scarring in atypical places and the occurrence of hyper- and hypopigmentation. During treatment with Acnecutan and for 6 months after it, you cannot carry out epilation using wax applications because of the risk of epidermal detachment, the development of scars and dermatitis. Since some patients may experience a decrease in night vision acuity, which sometimes persists even after the end of therapy, patients should be informed about the possibility of this condition, advising them to be careful when driving at night. The state of visual acuity must be carefully monitored. Dryness of the conjunctiva of the eyes, corneal opacities, deterioration in night vision and keratitis usually resolve after discontinuation of the drug. If the mucous membrane of the eyes is dry, applications of a moisturizing eye ointment or artificial tear preparation can be used. It is necessary to observe patients with dry conjunctiva for possible development of keratitis. Patients presenting with vision complaints should be referred to an ophthalmologist and the advisability of canceling Acnecutan should be considered. If you are intolerant of contact lenses, glasses should be used during therapy. Exposure to sun exposure and UV therapy should be limited. If necessary, use a sunscreen with a high SPF value of at least 15 SPF. It is necessary to observe patients with dry conjunctiva for possible development of keratitis. Patients presenting with vision complaints should be referred to an ophthalmologist and the advisability of canceling Acnecutan should be considered. If you are intolerant of contact lenses, glasses should be used during therapy. Exposure to sun exposure and UV therapy should be limited. If necessary, use a sunscreen with a high SPF value of at least 15 SPF. It is necessary to observe patients with dry conjunctiva for possible development of keratitis. Patients presenting with vision complaints should be referred to an ophthalmologist and the advisability of canceling Acnecutan should be considered. If you are intolerant of contact lenses, glasses should be used during therapy. Exposure to sun exposure and UV therapy should be limited. If necessary, use a sunscreen with a high SPF value of at least 15 SPF.

Rare cases of the development of benign intracranial hypertension ("pseudotumor of the brain"), incl. when combined with tetracyclines. In such patients, Acnecutan should be discontinued immediately. With Acnecutan therapy, inflammatory bowel disease may occur. In patients with severe hemorrhagic diarrhea, Acnecutan should be discontinued immediately.

Described are rare cases of anaphylactic reactions that occurred only after the previous external use of retinoids. Severe allergic reactions dictate the need to discontinue the drug and closely monitor the patient.

Patients from a high-risk group (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 Acnecutan. In the presence or suspicion of diabetes, a more frequent determination of glycemia is recommended.

Patients with diabetes mellitus are advised to carry out more frequent monitoring of blood glucose.

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

During the treatment period 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 to pregnant patients (high risk of teratogenic and embryotoxic effects). Release form Capsules 8 mg and 16 mg. 10 or 14 capsules in a PVC blister covered with aluminum foil.

Blisters-10-N2, N3, N5, N6, N9, N10; blisters-14-N1, N2, N4, N7 in a cardboard box together with instructions for use.