Isotretinoin INN (capsules, rectal suppositories)
International name: Isotretinoin
Dosage form: capsules, rectal suppositories
The biologically active form of vitamin A can be synthesized in the body. Isotretinoin does not directly bind to nuclear retinoic acid receptors (RAR or RXR), as well as their subclasses (alpha, beta and gamma receptors). It quickly turns into tretinoin (trans-retinoic acid) and other substances-ligands of nuclear retinoic acid receptors and disrupts the expression of a gene that causes changes in protein synthesis (either induction or inhibition, depending on the state of the tissue). Reduces the number and production of sebaceous glands, resulting in a decrease in the content of Propionibacterium acnes (isotretinoin itself does not have an antibacterial effect). It has anti-inflammatory, keratolytic and antiseborrheic effects, inhibits the terminal differentiation of keratinocytes, stimulates regeneration processes.
When taken orally, it is rapidly and fairly completely absorbed; ingestion with food increases absorption. After oral administration at a dose of 80 mg TCmax of isotretinoin – 3 hours, 4-oxo-isotretinoin – 6-20 hours; Cmax of isotretinoin – 256 ng / ml (98-535 ng / ml), 4-oxo-isotretinoin – 87-399 ng / ml. Communication with plasma proteins (mainly with albumin) – 99.9%. After oral administration at a dose of 40 mg 2 times a day, Css of isotretinoin is 160 + 19 ng / ml, 4-oxo-isotretinoin 6 hours after taking the same dose exceeds that of isotretinoin. Isotretinoin is found in many tissues of the body as early as 15 minutes after oral administration, reaches a maximum concentration after 1 hour and decreases to trace concentrations after 24 hours; in trace amounts found in the liver, uterus, ovaries, adrenal glands and lacrimal glands 7 days after application. Metabolized in the liver and intestinal wall with the formation of metabolites – 4-oxoisoretinoin (basic), tretinoin and 4-oxo-tretinoin. T1 / 2 of isotretinoin – 10-20 hours, labeled with radioisotopes of isotretinoin after oral administration at a dose of 80 mg – 90 days, 4-oxoisoretinoin – 25 hours (17-50 hours). It is excreted by the kidneys (65%) and with bile or feces (83%).
Acne vulgaris of severe course (including with the formation of abscesses, hemorrhagic, confluent, prone to scarring and pigmentation disorders), resistant to conventional methods of therapy. Rosacea (severe course); folliculitis caused by gram-negative microorganisms; purulent hidradenitis (auxiliary treatment). Violation of keratinization (including ichthyosis, follicular keratosis, palmar-plantar keratoderma, red hairy pityriasis).
Hypersensitivity, pregnancy established and planned (possibly teratogenic and embryotoxic effects); lactation period; hypervitaminosis A. For rectal use – diseases of the rectum. C with caution. Conditions causing hypertriglyceridemia (including a history of familial hypertriglyceridemia, alcoholism, obesity, diabetes mellitus – isotretinoin increases plasma triglyceride concentrations, lowers HDL and increases the risk of cardiovascular disease), liver and / or kidney failure, chronic pancreatitis, liver and / or kidney failure, CHF, diabetes mellitus and predisposition to its development.
Inside, during meals. With acne vulgaris – at a daily dose of 0.5 mg / kg in one or more doses for 2-4 weeks; then the dose is increased to 1 mg/kg and treatment is continued for another 12-20 weeks; the maximum daily dose is 2 mg/kg. Dose adjustment is carried out depending on the sensitivity to the drug and / or the severity of side effects. A noticeable therapeutic effect is usually observed after 1-2 months of treatment, sometimes it may take 4-5 months to achieve clinical remission. If the number of rashes has decreased by 70% or more in 15-20 weeks, treatment is stopped. The general course dose in most cases does not exceed 100-150 mg/kg. If a persistent or recurrent course of the disease is confirmed, a break of at least 8 weeks should be taken before re-treatment (depending on individual sensitivity, up to 16-20 weeks). In the event of an exacerbation of the disease at the beginning of treatment, you should switch to lower doses of the drug – 0.5 mg / kg (or lower) for 2 weeks. With folliculitis caused by gram-negative microorganisms, rosacea, purulent hydradenitis – at a daily dose of 0.5-1 mg / kg for 4 months. In violation of keratinization – up to 4 mg / kg / day (depending on the disease and severity of the course), the duration of treatment is up to 4 months. After achieving clinical remission, the lowest possible dose should be used. Rectally, 0.5-1 mg / kg 1 time per day, at night. The course of treatment is 8-12 weeks. Intervals between repeated courses – 1-2 months.
On the part of the skin: itching, photosensitivity, peeling of the skin of the palms and soles, thinning of the hair; rarely – cheilitis, skin infections, skin rash. From the senses: xerophthalmia, burning in the eyes, conjunctival hyperemia, difficulty wearing contact lenses; rarely – cataract; with prolonged use in high doses – a violation of the clarity of visual perception, a violation of twilight vision, optic neuritis. From the musculoskeletal system: arthralgia; with prolonged use in high doses – hyperostosis. From the nervous system: headache, excessive fatigue; rarely – depression, psychosis, suicidal thoughts, pseudotumor of the brain (violation of the clarity of visual perception, headache, intractable nausea and vomiting). From the digestive system: dyspepsia, dryness of the oral mucosa, bleeding from the gums, inflammation of the gums; rarely – hepatitis, colitis, regional ileitis. Laboratory indicators: increase in the concentration of TG, cholesterol, decrease in plasma HDL. Local reactions: when the suppository mass flows out – a local irritating effect (keep the “lying” position for 30 minutes after the suppository is inserted). 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 skulls, 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. Other: epistaxis, dryness of the nasal mucosa.
During treatment, liver function, lipid content in blood serum (on an empty stomach) should be monitored. It should not be prescribed for mild to moderate acne vulgaris. Patients with diabetes are advised to conduct more frequent monitoring of blood glucose levels. Patients wearing contact lenses, in case of side effects from the eyes, should use glasses. 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). Women of reproductive age should use reliable contraceptive drugs 4 weeks before, during and for 1 month after the end of treatment. If pregnancy occurs, it should be terminated for medical reasons. It is necessary to avoid increased insolation, incl. UV therapy. In the event of colitis, visual disturbances and symptoms of a pseudotumor of the brain, treatment is stopped. If a brain pseudotumor is suspected, a neurological examination is performed. 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).
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. Tetracyclines (including minocycline) increase the risk of increased intracranial pressure (simultaneous use with isotretinoin is not recommended) .