Isotretinoin

Pharmacological properties

mechanism of action. isotretinoin is a stereoisomer of transretinoic acid (tretinoin). the exact mechanism of action of isotretinoin has not been fully studied, but it has been established that an improvement in the clinical course of severe forms of acne is associated with inhibition of the activity of the sebaceous glands with a histologically proven decrease in their size. in addition, it is proven that isotretinoin has an anti-inflammatory effect on the skin.

Efficiency. Hyperkeratosis of epithelial cells of the hair bulb and sebaceous gland leads to flaking of corneocytes in the duct of the gland and blockage of the latter with keratin and an excess of sebaceous secretion. After which comedone is formed and in some cases the inflammatory process joins. Acnetin inhibits the proliferation of sebocytes and acts on acne, restoring the normal process of cell differentiation. Sebum is the main substrate for the growth of Propinibacterium acnes, and a decrease in sebum production inhibits bacterial colonization of the duct.

Pharmacokinetics Suction. The absorption of isotretinoin in the gastrointestinal tract is variable and linearly dependent on the dose of the drug in the therapeutic dose range. The absolute bioavailability of isotretinoin has not been determined, since there is no dosage form for intravenous use, but extrapolation of the results of the study on dogs suggests a very low and variable systemic bioavailability. Taking isotretinoin with food doubles bioavailability compared with fasting.

Distribution. Isotretinoin almost completely binds to plasma proteins (99.9%), mainly with albumin. The volume of distribution of isotretinoin in the human body is unknown, since there is no dosage form for iv administration. The concentration of isotretinoin in the epidermis is only half that in plasma. Plasma concentrations of isotretinoin are approximately 1.7 times higher than those in whole blood due to poor penetration of isotretinoin into red blood cells.

Metabolism. After oral administration in plasma, three main metabolites are detected: 4-oxo-isotretinoin, tretinoin (the full name is trans-retinoic acid) and 4-oxo-retinoin. These metabolites have demonstrated biological activity in several in vitro tests. 4-Oxo-isotretinoin, as shown in several clinical studies, has a significant share in the therapeutic activity of isotretinoin (inhibition of sebum excretion, regardless of the level of isotretinoin and tretinoin in blood plasma). The main metabolite is 4-oxo-isotretinoin, the plasma concentration of which in equilibrium is 2.5 times higher than the concentration of the starting drug. Other metabolites, including glucuronide conjugates, are secondary.

Since isotretinoin and tretinoin are reversibly converted into each other, the metabolism of tretinoin is associated with the metabolism of isotretinoin. It was found that 20-30% of the dose of isotretinoin is metabolized by isomerization.

Enterohepatic circulation can play a significant role in the pharmacokinetics of isotretinoin in humans.

In vitro metabolism studies have shown that several CYP enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. Obviously, not one of the isoforms plays a dominant role. Acnetin and its metabolites do not significantly affect the activity of CYP system enzymes.

After ingestion of radiolabeled isotretinoin in urine and feces, approximately the same amount is determined. T_½ the terminal phase for an unchanged drug for oral use in patients with acne is an average of 19 hours. T_½ the terminal phase for 4-oxo-isotretinoin ranges from 7 to 39 hours

Isotretinoin refers to natural (physiological) retinoids.The endogenous concentration of retinoids is restored approximately 2 weeks after the end of the use of Acnetin.

Pharmacokinetics in special clinical cases. Since isotretinoin is contraindicated in case of impaired liver function, data on the pharmacokinetics of the drug in this group of patients are limited.

Renal failure does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.

Indications

Severe forms of acne (in particular nodular and conglobate acne, acne with a tendency to permanent scarring) that do not respond to standard methods of treatment (systemic antibiotic therapy, local treatment).

Application

Acnetin is prescribed for adults and children over the age of 12 years, starting with a dose of 0.4 mg / kg / day. capsules should be taken with food 1-2 times a day. in case of missing the prescribed dose of the drug, it is not recommended to take a double dose! the therapeutic effect of acnetin, as well as undesirable effects, are dose-dependent and have a different degree of severity, which requires an individual dose adjustment during treatment. for most patients, the dose is 0.4-0.8 mg / kg / day.

Often at the beginning of treatment, a short-term aggravation of the disease is noted. The effectiveness of treatment and side effects differ in different patients, therefore, after 4 weeks of therapy, the dose should be individually selected for adults in the range of 0.1–1 mg / kg / day. The maximum daily dose of 1 mg / kg of body weight can be prescribed only for a limited period.

Usually, the course of treatment lasts 16-24 weeks. When evaluating the results of therapy, it must be remembered that the effect of the drug continues after treatment is discontinued. In this regard, a second course should be prescribed no earlier than after 8 weeks.

For most patients, one course of treatment is enough to get rid of acne. If relapse is confirmed, a second course of isotretinoin can be suggested. The dose for re-treatment is prescribed in accordance with the above recommendations.

For patients who do not tolerate the recommended doses, it is possible to continue treatment at a lower dose, which should be accompanied by an increase in the duration of treatment and may, accordingly, lead to an increased risk of relapse. In such patients, it is necessary to continue the course of treatment with the appointment of the most acceptable dose.

Children. The drug is not recommended for children under 12 years of age, since the safety and effectiveness of use in this age group have not been studied.

Contraindications

Women of reproductive age if all the conditions of the “pregnancy prevention program” are not met (see special instructions); hypersensitivity to isotretinoin or any components of the drug; liver failure; severe hyperlipidemia; hypervitaminosis a; concomitant tetracycline therapy. Due to the fact that the drug contains soybean oil, it is contraindicated in patients with allergies to peanuts and soy.

Side effects

Some side effects of isotretinoin are dose dependent. usually adverse reactions are reversible after dose adjustment or drug withdrawal, but some may persist after treatment is discontinued. the symptoms most commonly reported with isotretinoin are dry skin, mucous membranes, including lips (cheilitis), nasal cavity (nosebleeds), eyes (conjunctivitis).

The following categories are used to describe the frequency of adverse reactions: very often (≥1 / 10), often (≥1 / 100, 1/10), rarely (≥1 / 10,000, 1/1000), very rarely (≤1 / 10 000).

Infections: very rarely - gram-positive bacterial infections of the skin and mucous membranes.

Disorders of the blood system and lymphatic system: very often - anemia, accelerated ESR, thrombocytopenia, thrombocytosis; often neutropenia; very rarely - lymphadenopathy.

Immune system disorders: rarely - allergic reactions from the skin, anaphylactic reactions, hypersensitivity reactions.

Metabolic, metabolic disorders: very rarely - diabetes mellitus, hyperuricemia.

Mental disorders: rarely - depression, increased depression, a tendency to aggression, anxiety, mood changes; very rarely - behavioral disorders, psychotic disorders, suicide attempts, suicide.

Disorders of the nervous system: often - headache; very rarely - benign intracranial hypertension, convulsions, drowsiness, dizziness.

Disorders from the organ of vision: very often - blepharitis, conjunctivitis, dry eyes, eye irritation; very rarely - blurred vision, cataracts, impaired color perception, intolerance to contact lenses, clouding of the cornea, decreased visual acuity, keratitis, swelling of the optic nerve (as a manifestation of benign intracranial hypertension), photophobia, visual impairment.

Disorders from the organ of hearing and the maze: very rarely - hearing impairment.

Vascular disorders: very rarely - vasculitis (e.g. Wegeners granulomatosis, allergic vasculitis).

Disorders of the respiratory system, chest and mediastinum: often - nosebleeds, dry nose, nasopharyngitis; very rarely - bronchospasm (especially in patients with AD), dysphonia.

Digestive tract disorders: very rarely - colitis, ileitis, dry throat, gastrointestinal bleeding, hemorrhagic diarrhea, inflammatory bowel disease, nausea, pancreatitis (see SPECIAL INSTRUCTIONS).

Hepatobiliary disorders: very often - an increase in the level of transaminases (see SPECIAL INSTRUCTIONS); very rarely - hepatitis.

Disorders from the skin and subcutaneous tissue: very often - cheilitis, dermatitis, dry skin, localized peeling, itching, erythematous rash, skin invasiveness (risk of damage due to friction); rarely - alopecia; very rarely - fulminant forms of acne, exacerbation of acne (hyperemia of acne), erythema (face), exanthema, disorders of the hair, hirsutism, onychodystrophy, paronychia, photosensitivity, pyogenic granuloma, hyperpigmentation of the skin, increased sweating; the frequency is unknown (the frequency cannot be estimated based on available data) - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Disorders from the bones, muscles and connective tissue: very often - arthralgia, myalgia, back pain (especially in children and adolescents); very rarely - arthritis, calcification (calcification of ligaments and tendons), premature closure of the growth zones of the pineal glands, exostosis, hyperostosis, decreased bone density, tendonitis.

Disorders of the kidneys and urinary system: very rarely - glomerulonephritis.

General disorders: very rarely - granulation of tissue (increased formation), increased fatigue.

Laboratory indicators: very often - hypertriglyceridemia, decreased HDL; often - hypercholesterolemia, hyperglycemia, hematuria, proteinuria; very rarely - increased CPK in the blood.

special instructions

"Pregnancy prevention program." this medicine is teratogenic. Isotretinoin is contraindicated in women of reproductive age, unless the condition of the woman meets all of the following criteria:

• she is diagnosed with a severe form of acne (nodular and conglobate acne, acne with a tendency to permanent scarring), which does not respond to standard methods of treatment (systemic antibacterial therapy, local treatment);
• she understands the teratogenic risk of the drug;
• she understands the need for a mandatory visit to a doctor every month;
• she is able to adhere to reliable and continuous contraceptives for 1 month before, during and within a month after the end of treatment with Acnetin; it is desirable to use simultaneously 2 different methods of contraception, including the barrier;
• even with amenorrhea, she must adhere to reliable contraceptives;
• she must confirm that she understands the essence of preventive measures;
• she is informed about the danger of pregnancy during treatment with Acnetin and understands the need to immediately consult if pregnancy is suspected;
• she understands the need and agrees to conduct a pregnancy test before, during and 5 weeks after treatment;
• she confirms that she is aware of the dangers of isotretinoin and the need for preventive measures.

The use of contraceptives according to the above recommendations during treatment with isotretinoin should be recommended even for sexually active women, unless the doctor believes that there is every reason indicating that there is no risk of becoming pregnant.

The doctor must be sure that the patient:

• able to understand and fulfill all of the above requirements for the prevention of pregnancy;
• understands these conditions;
• adheres to at least one, and preferably two effective contraceptives, including the barrier method within 1 month before the start, during and within a month after the end of treatment with Acnetin;
• received a negative result of a reliable pregnancy test before, during and 5 weeks after the end of therapy. Dates and results of a pregnancy test must be documented.

Pregnancy Prevention Patients need to familiarize themselves with contraceptive methods. If they do not use effective methods of contraception, the doctor should provide appropriate recommendations.

The minimum requirement is the use in women who have a risk of becoming pregnant, at least 1 effective method of contraception. It is better to use two complementary methods of contraception, including the barrier method. Contraceptive methods should continue to be used for at least another 1 month after stopping treatment with Acnetin, even for patients with amenorrhea.

Pregnancy test. According to existing practice, a pregnancy test with a minimum sensitivity of 25 mIU / ml should be performed in the first 3 days of the menstrual cycle.

Before starting treatment. To exclude a possible pregnancy, the doctor must record the result and date of the first pregnancy test before using contraceptives. In patients with an irregular menstrual cycle, the time for a pregnancy test depends on sexual activity. The test should be performed 3 weeks after unprotected intercourse. The doctor should inform the patient about contraception methods. A pregnancy test should be performed on the day of the appointment of Acnetin or 3 days before the patient’s visit to the doctor. The specialist should register the test results. The drug can be intended only for patients who receive effective contraception for at least 1 month before starting treatment with Acnetin. The test should ensure that the patient is not pregnant at the time of initiation of treatment with isotretinoin.

During treatment. The patient should visit the doctor every 28 days. The need for monthly pregnancy testing is determined according to local practice and taking into account sexual activity and the history of recent menstrual cycles (abnormal periods, lack of periodicity or amenorrhea). If indicated, a pregnancy test should be performed on the day of the visit or 3 days before the doctor’s visit.

Completion of treatment. 5 weeks after the end of treatment, a final pregnancy exclusion test is performed.The pharmacist must make sure that the prescription for Acnetin was prescribed to a woman of reproductive age only for 30 days of treatment, continued treatment requires a new prescription of the drug by a doctor.

Ideally, conducting pregnancy testing, prescribing, and receiving the drug is recommended for one day. The issuance of Acnetin in a pharmacy should be carried out only within 7 days from the date of prescription.

Male patients. Existing data indicate that in women, the exposure of the drug received from the seed and seminal fluid of men taking Acnetin is insufficient for the manifestation of teratogenic effects of the drug. Men should exclude the possibility of using the drug by other persons, especially women.

Additional caveats. Patients should be informed that they should never give this medicine to others and return the unused capsules to the doctor after treatment. Patients should not be blood donors during treatment and for 1 month after its termination, since there is a potential risk of transfusion transmission to the fetus from the pregnant woman.

Educational materials. To help doctors, pharmacists and patients avoid the risk of Acnetin affecting the fetus, the manufacturer provides training materials aimed at preventing the teratogenic effect of the drug, recommendations for using contraception before starting therapy, and recommendations for the need for pregnancy testing.

Complete information on teratogenic risk and strict adherence to pregnancy prevention is contained in the Pregnancy Prevention Program, which must be provided to all patients, both men and women.

Mental disorders. In patients who received Acnetin, depression, depression with aggravation, anxiety, a tendency to aggressiveness, mood changes, psychotic symptoms, and very rarely suicidal thoughts, suicidal attempts and suicide were identified (see ADVERSE EFFECTS). Caution should be exercised with patients with a history of depression and to observe patients for depression during treatment, if necessary, refer them to appropriate specialists. However, the withdrawal of Acnetin may not lead to the disappearance of symptoms and require further monitoring by specialists.

Violations of the skin and subcutaneous tissue. In rare cases, at the beginning of therapy, exacerbation of acne is noted, which usually goes away after 7-10 days without dose adjustment. Avoid exposure to sunlight or UV rays. If it is necessary to protect from the sun, highly protective factors with a light filter of at least 15 should be used. Deep chemical dermabrasion and laser treatment should not be carried out with Acnetin treatment and for 5-6 months after treatment, since there is a high risk of hypertrophic scars in atypical areas and less often - the appearance of hyper- and hypopigmentation in the treatment areas. During treatment with Acnetin and for 6 months after treatment, waxing with wax applications cannot be performed due to the risk of exfoliation of the epidermis. The simultaneous use of Acnetin with local keratolytic or exfoliative agents for the treatment of acne should be avoided because of the possibility of increasing the severity of local irritation (see INTERACTIONS).

Patients who receive Acnetin are recommended to use moisturizing ointments or body creams, lip balm to reduce dry skin and lips at the beginning of treatment.

In the post-registration period of the use of the drug, cases of severe reactions from the skin have been reported (exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).Since these cases are difficult to differentiate with other skin reactions that may occur (see ADVERSE EFFECTS), patients should be warned about the signs and symptoms of these diseases and carefully monitor severe skin reactions. If skin reactions are suspected, treatment with isotretinoin should be discontinued.

Allergic reactions. Anaphylactic reactions have rarely been reported, in some cases after previous topical retinoids. Allergic skin reactions have been reported infrequently. Serious cases of allergic vasculitis have been reported, often with purpura (blue and red spots), limbs, and non-cutaneous manifestations. Serious allergic reactions require interruption of therapy and careful monitoring.

Disorders of the organ of vision. Dry eyes, clouding of the cornea, worsening night vision and keratitis usually disappear after discontinuation of the drug. With dry mucous membranes of the eye, you can use applications of a moisturizing eye ointment or an artificial tear preparation. If contact lenses are intolerant during treatment, glasses should be used.

In some patients, a decrease in the visual acuity is possible, which sometimes occurs suddenly (see. The ability to influence the reaction rate when driving vehicles or other mechanisms). If there are complaints about the vision of such patients, they should be referred to an ophthalmologist and consider withdrawing the drug.

Musculoskeletal system and connective tissue disorders. Against the background of the use of Acnetin, pain in muscles and joints, an increase in CPK in blood plasma, especially with intense physical exertion, are possible (see ADVERSE EFFECTS).

A few years after the use of Acnetin for the treatment of dyskeratosis in very high doses, bone changes developed, including premature closure of the pineal growth zones, hyperostosis, calcification of ligaments and tendons. The dose level, duration of treatment and the total cumulative dose in these patients were generally higher than those recommended for the treatment of acne.

Benign intracranial hypertension. Cases of benign intracranial hypertension are described, some of them were caused by the simultaneous use with tetracyclines (see CONTRAINDICATIONS, INTERACTIONS). Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual impairment, and swelling of the optic nerve. Patients who develop benign intracranial hypertension should immediately discontinue the drug.

Hepatobiliary disorders. It is recommended to monitor the level of liver enzymes before treatment, 1 month after its start, and then every 3 months if there are no clinical indications for more frequent monitoring. A temporary and reversible increase in hepatic transaminases was noted, in most cases within normal limits, which returned to normal during treatment. If the level of transaminases exceeds the norm, it is necessary to reduce the dose of the drug or cancel it.

Renal failure. Impaired renal function or renal failure does not affect the pharmacokinetics of isotretinoin. Therefore, patients with renal failure may take isotretinoin. However, it is recommended to start with a low dose and titrate it to the maximum tolerated dose (see APPLICATION).

Lipid metabolism. It is necessary to determine the level of lipids in fasting plasma (before, 1 month after the start of treatment, then every 3 months, if there is no clinical indication for more frequent monitoring). Usually, elevated plasma lipids are normalized after a dose reduction or drug withdrawal, as well as with a diet. The use of isotretinoin is associated with an increase in TG. You should stop taking isotretinoin in case of uncontrolled hyperlipidemia or with symptoms of pancreatitis.An increase in TG level of 800 mg / dL or 9 mmol / L may be accompanied by the development of acute pancreatitis, possibly fatal.

Gastrointestinal disorders. With treatment with isotretinoin, an inflammatory bowel disease (including regional ileitis) may develop in patients without a history of intestinal disease. Patients with severe (hemorrhagic) diarrhea should immediately discontinue the drug.

High risk groups. Patients with diabetes mellitus, obesity, alcoholism or impaired fat metabolism during treatment with isotretinoin may require more frequent monitoring of blood glucose and / or lipids. An increase in fasting blood glucose and the diagnosis of new cases of diabetes during treatment with isotretinoin have been reported.

Use during pregnancy or lactation. Pregnancy is an absolute contraindication for the use of isotretinoin (see CONTRAINDICATIONS). If pregnancy occurs during the period when a woman takes isotretinoin, despite the precautionary measures, or within a month after the end of therapy, there is a very high risk of having a baby with severe and serious malformations.

Fetal malformations associated with the action of isotretinoin include CNS disorders (hydrocephalus, cerebellar malformations / abnormalities, microcephaly), facial malformations, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory meatus), malformations eye development (microphthalmia), abnormalities of the heart and blood vessels (conotruncal heart defects such as tetralogy of Fallot, transposition of the great vessels, defect of the septum), anomalies of the thymus and parathyroid glands. In addition, the risk of spontaneous miscarriage is increased.

If pregnancy occurs in a woman who is undergoing treatment with isotretinoin, the therapy should be discontinued and consult a doctor who specializes and has experience in the field of teratology to assess the condition and consultation.

Lactation. Due to the high lipophilicity of isotretinoin, there is a high probability that it passes into breast milk. Due to possible side effects in a child associated with the action of the drug through breast milk, the use of isotretinoin is contraindicated during lactation.

The ability to influence the reaction rate when driving vehicles or other mechanisms. During treatment and in rare cases - after it, some patients noted a decrease in the severity of twilight vision (see ADVERSE EFFECTS, SPECIAL INSTRUCTIONS). Since the manifestation of these phenomena was sudden in some individuals, patients should be informed about the possibility of this problem and warn about the need to be careful when driving vehicles or other mechanisms. Very rarely reported cases of drowsiness, dizziness, and visual impairment. Patients should be warned that when these symptoms occur, they should not drive vehicles, operate machinery, or engage in any other activity that could put them or others in danger.

Interactions

Due to the possible increase in the severity of symptoms of hypervitaminosis a, the simultaneous administration of isotretinoin and vitamin a should be avoided.

Cases of benign increase in intracranial pressure (pseudotumor of the brain) have been reported with the simultaneous use of isotretinoin with tetracyclines. Therefore, simultaneous use with tetracyclines should be avoided (see CONTRAINDICATIONS, SPECIAL INSTRUCTIONS).

The combined use with local keratolytic or exfoliative drugs for the treatment of acne is contraindicated because of the possible increase in local irritation (see SPECIAL INSTRUCTIONS).

Overdose

Isotretinoin is a derivative of vitamin A. although the acute toxicity of isotretinoin is low, in the event of an unintentional overdose, signs of vitamin A hypervitaminosis may appear. manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, itching. the symptoms of accidental and intentional overdose are probably the same. these symptoms are reversible and disappear without the need for treatment.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° c.