Instructions for Sotret (Isotretinoin) from acne
Active substance: isotretinoin 10 mg.
Excipients: soybeans, hydrogenated oil - 7.65 mg, hydrogenated vegetable oil - 32.13 mg, white beeswax - 9.18 mg, disodium edetate - 0.08 mg, butylhydroxyanisole - 0.016 mg, soybeans, refined oil - 100.944 mg Gelatin capsule: gelatin - 56.00 mg, glycerol - 29.277 mg, iron dye red oxide - 0.0325 mg, titanium dioxide - 0.190 mg, purified water - q.s., light liquid paraffin * - q.s., isopropanol * - q.s.
Food grade black ink S-1-17823 - 0.75 mg. The composition of black food ink S-1-17823: shellac 45% (20% esterified) in ethanol - 0.333 mg, iron dye black oxide - 0.175 mg, isopropanol * - 0.202 mg, n-butanol * - 0.017 mg, propylene glycol - 0.015 mg , ammonium hydroxide * - 0.008 mg. * The solvent is not present in the final product; it evaporates during the production process.
Isotretinoin is a stereoisomer of polytransretinoic acid (tretinoin). The exact mechanism of action of isotretinoin has not yet been clarified, but it has been established that the improvement in the clinical picture of severe forms of acne is associated with a suppression of the activity of the sebaceous glands and a histologically confirmed decrease in their size.
In addition, the anti-inflammatory effect of isotretinoin on the skin has been proven. Hyperkeratosis of the epithelial cells of the hair bulb and sebaceous gland leads to desquamation of corneocytes in the duct of the gland and to blockage of the latter with keratin and an excess of sebaceous secretion. This is followed by the formation of comedone and, in some cases, the joining of the inflammatory process.
Isotretinoin 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 Propionibacterium acnes, therefore, a decrease in sebum formation inhibits bacterial colonization of the duct.
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 the liver enzymes involved in the metabolism of drugs.
Absorption The absorption of isotretinoin from the gastrointestinal tract is directly proportional to the dose in the therapeutic range. The absolute bioavailability of isotretinoin was not determined, since there is no drug in the dosage form for intravenous administration of isotretinoin.
However, extrapolation of the data obtained in the preclinical study suggests a rather low and variable systemic bioavailability. In patients with acne, the maximum plasma concentration (Cmax) in equilibrium after taking 80 mg of isotretinoin on an empty stomach was 310 ng / ml (range 188-473 ng / ml) and was reached after 2-4 hours.
Plasma isotretinoin concentrations are approximately 1.7 times higher than blood concentrations due to poor penetration of isotretinoin into red blood cells. The intake of isotretinoin with food increases its bioavailability by 2 times compared with fasting. Distribution Isotretinoin is largely associated with plasma proteins, mainly with albumin (99.9%). The volume of distribution of isotretinoin in humans was not determined, since there is no dosage form for intravenous administration. The equilibrium concentration of isotretinoin in the blood (Cmin ss) in patients with severe acne who took 40 mg of isotretinoin 2 times a day ranged from 120 to 200 ng / ml.
There is very little data on the penetration of isotretinoin into tissues in humans. The concentration of isotretinoin in the epidermis is two times lower than in serum. The concentration of isotretinoin in blood plasma is approximately 1.7 times higher than the concentration in the blood as a whole, due to the low level of penetration of isotretinoin into red blood cells. Metabolism After oral administration, three major metabolites are found in blood plasma: 4-oxo-isotretinoin, tretinoin (polytransretinoic acid) and 4-oxo-tretinoin. 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.
Less significant metabolites were also found, including glucuronides, but the structure of not all metabolites was established. Isotretinoin metabolites have biological activity confirmed in several in vitro studies. Thus, the clinical effects of the drug in patients may be the result of the pharmacological activity of isotretinoin and its metabolites.
Since in vivo isotretinoin and tretinoin (polytransretinoic acid) are reversibly converted into each other, tretinoin metabolism is associated with isotretinoin metabolism. 20-30% of the dose of isotretinoin is metabolized by isomerization. In the pharmacokinetics of isotretinoin in humans, hepatic-intestinal recirculation can play a significant role. In vitro metabolism studies have shown that several cytochrome P450 enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. Apparently, not one of the isoforms plays a dominant role. Isotretinoin and its metabolites do not significantly affect the activity of cytochrome P450 enzymes. Excretion
After ingestion of isotretinoin labeled with radioactive isotopes, approximately equal amounts of it are found in urine and feces. The terminal half-life for the unchanged active component in patients with acne is on average 19 hours. The terminal half-life for 4-oxo-isotretinoin is apparently longer and its average duration is 29 hours. Isotretinoin is a natural (physiological) retinoids. Endogenous retinoid concentrations are reached approximately 2 weeks after the end of isotretinoin intake.
Pharmacokinetics in special cases Since isotretinoin is contraindicated in cases 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 clearance of isotretinoin or 4-oxo-isotretinoin in blood plasma.
Isotretinoin Side effects:
Most of the side effects of isotretinoin are dose dependent. As a rule, when prescribing recommended doses, the ratio of benefit and risk, given the severity of the disease, is acceptable to the patient. Usually, side effects are reversible after dose adjustment or drug withdrawal, but some may persist after treatment is discontinued. The most commonly reported symptoms of adverse events associated with isotretinoin are: dry skin, dry mucous membranes, such as lips (cheilitis), nose (epistaxis), and eyes (conjunctivitis).
The frequency of a side effect is determined as follows: very often (> 1/10 cases), often (> 1/100 and <1/10 cases), infrequently (> 1/1000 and <1/100 cases), rarely ( > 1/10000 and <1/1000 cases), very rarely (<1/10000 cases), the frequency is unknown (the incidence rate cannot be estimated from the available data). From the side of metabolism / Very rarely: diabetes mellitus, hyperuricemia.
Allergic reactions: Rarely: allergy, anaphylactic reaction, hypersensitivity, systemic hypersensitivity reactions. From the central nervous system: Rarely, depression, exacerbation of depression, aggressive behavior, excitability, frequent mood swings; Very rarely: inappropriate behavior, psychotic disorder, suicidal thoughts, suicidal attempts, suicide. From the nervous system: Often: headache; Very rarely: benign intracranial hypertension (“pseudotumor of the brain”: headache, nausea, vomiting, impaired vision, swelling of the optic nerve), cramps, drowsiness, dizziness.
Frequency unknown (including individual reports): excessive fatigue. From the skin: Very often: dermatitis, dry skin and mucous membranes, onychodystrophy, increased proliferation of granulation tissue, rash, itching, erythema of the face, cheilitis, slight trauma to the skin; Rarely: alopecia; Very rarely: increased sweating, pyogenic granuloma, paronychia, persistent thinning of hair, reversible hair loss, nail dystrophy, fulminant forms of acne, hirsutism, hyperpigmentation, photosensitivity, photodermatosis, vasculitis (Wegener's granulomatosis, allergic vasculitis). At the beginning of treatment, exacerbation of acne may occur, lasting several weeks.
Frequency unknown (including some reports): Stevens-Johnson syndrome, toxic epidermal necrolysis, peeling of the skin of the hands and soles. From the urinary system: Often: hematuria, proteinuria; Very rare: glomerulonephritis. From the musculoskeletal system: Very often: myalgia (with an increase in the activity of creatinine phosphokinase (CPK) in the blood serum or without it) *, arthralgia; Very rarely: hyperostosis, arthritis, calcification of ligaments and tendons, other bone changes, tendonitis; Frequency unknown (including individual reports) -, rhabdomyolysis, in some cases fatal.
From the digestive system: Very often: transient and reversible increase in the activity of “liver” transaminases **; Very rarely: nausea, diarrhea, inflammatory bowel disease (colitis, ileitis), gastrointestinal bleeding; pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg / dl), dry throat, hepatitis.
Frequency unknown (including some reports): dry oral mucosa, gum bleeding, gum disease. Rare cases of pancreatitis with a fatal outcome are described. Hematopoietic organs: Very often: anemia, an increase in the erythrocyte sedimentation rate, thrombocytopenia, thrombocytosis; Often, neutropenia; Very rare: lymphadenopathy. Frequency unknown (including individual reports): decreased hematocrit, leukopenia.
From the respiratory system: Often, nasal cavity bleeding, dry nasal mucosa and larynx, nasopharyngitis; Very rarely: bronchospasm (more often in patients with a history of bronchial asthma), hoarseness. From the sensory organs: Very often: blepharitis, conjunctivitis, dry eye syndrome, eye irritation; Very rarely: individual cases of visual acuity, decreased night vision, contact lens intolerance, corneal opacity, color blindness and other color perception abnormalities, cataracts, keratitis, optic nerve disc edema (as a manifestation of benign intracranial hypertension), visual disturbances, hearing impairment . Laboratory indicators: Very often: hypertriglyceridemia, decreased high-density lipoprotein;
Often: hypercholesterolemia, hyperglycemia; Very rare: increased CPK activity in serum. Other: Very rare: local or systemic infections caused by gram-positive pathogens (Staphylococcus aureus). * In some patients, especially those involved in intense physical exertion, individual cases of increased serum CPK activity have been described.
* In many of these cases, the changes did not go beyond the normal range and returned to the initial indicators during the treatment process, however, in some situations, it may be necessary to reduce the dose or cancel the Sotret drug.
The drug Sotret should be prescribed only by doctors, preferably dermatologists, with experience in the use of systemic retinoids and who are aware of the risk of teratogenicity of the drug. Precautions In order to avoid accidental effects of the drug on the body of other people, donor blood should not be taken from patients who take or shortly before (1 month) have taken Sotret. Violations of the liver and biliary tract It is recommended to monitor liver function and hepatic enzymes before treatment, 1 month after its start, and then every 3 months, unless a more frequent analysis is indicated.
An unstable and reversible increase in “liver” transaminases was noted, in most cases within normal values. If the activity of “liver” transaminases exceeds the norm, it is necessary to reduce the dose of the drug or cancel it. Lipid metabolism The level of serum lipids should be checked before starting treatment (on an empty stomach), one month after the start of treatment, and then sequentially at three-month intervals if a more frequent analysis is not indicated. An increased level of serum lipids usually returns to normal with a dose reduction, drug withdrawal, as well as with a diet. Isotretinoin is the cause of an increase in plasma triglycerides.
If hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis are observed, isotretinoin should be discontinued. Triglycerides in excess of 800 mg / dL (9.01 mmol / L) can sometimes be caused by acute pancreatitis, which can be fatal. Mental disorders Depression, depression, excitability, aggressiveness, mood swings, psychotic symptoms, and, very rarely, suicidal thoughts, suicidal attempts and suicide were recorded in patients taking isotretinoin. Particular attention should be given to patients with a history of depression, and all patients should be monitored for signs of depression and, if necessary, receive appropriate treatment.
Moreover, withdrawal of isotretinoin may not be enough to alleviate the symptoms, and therefore, a psychiatric or psychological assessment of the patient's condition may be required in the future. Disorders from the skin and subcutaneous tissues An acute attack of acne is sometimes observed at the initial stage of treatment, but with continued treatment it fades away for 7-10 days, with dose adjustment usually not required.
Exposure to intense sunlight and ultraviolet radiation should be avoided. If necessary, sunscreens with a high protection factor, minimum SPF 15, should be used. Intensive chemical dermabrasion and laser skin treatment are contraindicated in patients taking isotretinoin for 5-6 months after the end of the dose due to the risk of hypertrophic scars in atypical areas, and less often , post-inflammatory hyper- or hypopigmentation in the treated areas.
Patients taking isotretinoin are also contraindicated in waxing due to the risk of exfoliation of the epidermis.
The simultaneous administration of isotretinoin and external keratolytic or exfoliating agents should be avoided, since local irritation may intensify. Patients are advised to use moisturizing ointments or creams and lip balm from the start of isotretinoin, since dry skin and lips can occur at the beginning of isotretionine. Serious skin reactions associated with isotretinoin (polymorphic erythema,
Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported several times. Since these adverse events may be difficult to distinguish from other possible skin reactions, patients should be instructed in the possibility of occurrence and signs of such symptoms and should be carefully monitored to identify serious adverse reactions. If a serious adverse reaction is suspected, isotretinoin should be discontinued. Allergic reactions There are rare reports of anaphylactic reactions, in some cases arising after topical application of retinoids.
In rare cases, the occurrence of skin allergic reactions is reported. Serious cases of allergic limb vasculitis have also been reported, often with purpura and affected areas of the skin. If serious allergic reactions occur, discontinuation of the drug and careful monitoring of the patient are necessary. Disorders of the musculoskeletal system A few years after the use of isotretinoin for the treatment of dyskeratosis with a total course dose and duration of therapy higher than those recommended for acne therapy, changes in the bones developed, including premature closure of the pineal gland growth zones, hyperostosis, calcification of ligaments and tendons . Against the background of taking isotretinoin, myalgia and arthralgia, an increase in serum CPK, which, in particular, can appear with intense physical exertion, are possible.
Visual impairment Since some patients may experience a decrease in visual acuity, which sometimes persists even after the end of therapy, patients should be informed about the possibility of this condition. The state of visual acuity must be carefully monitored. Dry conjunctiva of the eyes, clouding of the cornea, deterioration of night vision and keratitis usually disappear after discontinuation of the drug. When the mucous membrane of the eyes is dry, applications of a moisturizing eye ointment or an artificial tear preparation can be used. It is necessary to observe patients with dry conjunctiva for possible development of keratitis.
Patients complaining of vision should be referred to an ophthalmologist and consider the advisability of withdrawing isotretinoin. In case of intolerance to contact lenses, glasses should be used during therapy. Limit exposure to sunlight and UV rays. Benign intracranial hypertension Rare cases of the development of benign intracranial hypertension (“pseudotumor of the brain”) are described, including when combined with tetracyclines.
Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and swelling of the optic nerve head. In such patients, you should immediately stop taking Sotret. Impaired renal function Impaired renal function and renal failure do not affect the pharmacokinetics of isotretinoin. Therefore, isotretionine can be prescribed to patients with impaired renal function.
However, such patients are advised to start taking isotretinoin with small doses and gradually increase to the maximum tolerated dose. Digestive disorders
Severe forms of acne (nodular-cystic, conglobate acne or acne with a risk of scar formation). Acne not amenable to other types of therapy.
-pregnancy, the period of breastfeeding (see section "Pregnancy and the period of breastfeeding); -the ability to bear children in women who do not observe contraception while taking the drug Sotret;
hypervitaminosis A; -expressed hyperlipidemia; - concomitant therapy with tetracyclines;
- Increased sensitivity to isotretinoin or excipients of the drug Sotret; - an allergy to peanuts and soy (the preparation contains soybeans, hydrogenated oil, vegetable oil, hydrogenated, soybeans, refined oil);
-Children under 12 years old.
With caution: a history of depression, diabetes mellitus, obesity, impaired lipid metabolism, alcoholism. Use during pregnancy and during breastfeeding Pregnancy is an absolute contraindication for therapy with Sotret, the active substance of which is isotretinoin. Isotretinoin has a strong teratogenic effect.
If pregnancy occurs, despite warnings, during treatment with isotretinoin (by mouth, at any dose, or even for a short time) or within a month after the end of therapy, there is a very high risk of having a baby with severe malformations. Pregnancy Prevention Program Sotret is contraindicated in women of childbearing age, unless the woman’s condition meets all of the following criteria: she should have severe acne that is resistant to conventional methods of treatment;
- she must accurately understand the need for careful monthly medical supervision and follow the instructions of the doctor;
- she was informed by the doctor about the danger of pregnancy during treatment with Sotret and within one month after treatment, and about the need for urgent consultation at the risk of pregnancy;
- she should be warned about the possible ineffectiveness of contraception;
- she must confirm that she understands and understands risk factors and the essence of precautionary measures;
- she understands the need for use and must continuously use effective methods of contraception for one month before treatment with Sotret, during treatment and for a month after the end of treatment; it is desirable to use simultaneously 2 different methods of contraception, including the barrier;
- the patient is aware and accepts that the pregnancy test must be carried out monthly during treatment and 5 weeks after the end of therapy;
- she should begin treatment with Sotret only on the 2nd
– 3rd day of the next normal menstrual cycle;
- when treating a relapse of the disease, she must constantly use the same effective methods of contraception for one month before starting treatment with Sotret, during treatment and for a month after its completion, and also undergo the same reliable pregnancy test;
- she fully understands the need for precautionary measures and confirms her understanding and desire to use reliable methods of contraception, which the doctor explained to her; - even in the presence of amenorrhea, the patient should follow all recommendations for effective contraception.
The use of contraceptives according to the above instructions during treatment with isotretinoin should be recommended even to those women who usually do not use contraceptive methods because of infertility (with the exception of patients who underwent hysterectomy), or who report that they do not have sex.
The doctor must be sure that: - the patient suffers from a severe form of acne (nodular-cystic, conglobate acne or acne with a risk of scar formation); acne not amenable to other types of therapy; - a negative result of a reliable pregnancy test was obtained before taking the drug, during therapy and 5 weeks after the end of therapy; dates and results of a pregnancy test must be documented; - the patient uses at least 1, preferably 2 effective methods of contraception, including the barrier method, for at least one month before starting treatment with Sotret, during treatment and within a month after its completion; - the patient is able to understand and fulfill all of the above requirements for the prevention of pregnancy; - the patient meets all of the above conditions; - the patient confirmed the understanding of the above conditions and agreement with them. Contraception Female patients should be provided with comprehensive information on pregnancy prevention and receive contraceptive recommendations if they do not use effective methods of contraception. The minimum requirement for patients with a potential risk of pregnancy is the use of at least one method of contraception. It is better for the patient to use two complementary methods of contraception, including the barrier method.
The use of contraception, even in patients with amenorrhea, should continue for at least 1 month after stopping isotretinoin. Pregnancy test. In accordance with existing practice, a pregnancy test with a minimum sensitivity of 25 tMU / ml should be carried out in the first 3 days of the menstrual cycle:
Before therapy: -To exclude a possible pregnancy before the use of contraception, the result and date of the initial pregnancy test should be registered by a doctor. In patients with irregular menstruation, the time for a pregnancy test depends on sexual activity, it should be done 3 weeks after unprotected intercourse.
The doctor should inform the patient about contraception methods. - A pregnancy test is carried out on the day of the appointment of the drug Sotret or 3 days before the patient’s visit to the doctor. The specialist should record the test results. The drug can only be prescribed to patients, half-effective contraception for at least 1 month before starting therapy with the drug Sotret.
• The patient should 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 there is evidence, a pregnancy test is performed on the day of the visit or three 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.
The prescription for the drug will be erased by a woman capable of childbearing can be prescribed only for 30 days of treatment, continued therapy requires a new prescription of the drug by a doctor. It is recommended that a pregnancy test, prescription and receipt of the drug be carried out in one day.
The issuance of the drug Sotret in a pharmacy should be carried out only within 7 days from the date of prescription.
Complete information on teratogenic risk and strict adherence to pregnancy prevention must be provided to both men and women. Male Patients Existing evidence suggests that in women, exposure to isotretinoin from the seed and seminal fluid of men taking isotretinoin is insufficient for the teratogenic effects of isotretinoin to appear. Male patients should be reminded that they should not share their medicine with anyone, especially women.
In the event of pregnancy If, during treatment with Sotret or within a month after its termination, despite the precautions described in the pregnancy prevention program, the patient nevertheless has become pregnant, there is a high risk of very severe fetal malformations (in particular, side of the central nervous system, heart and large blood vessels). In addition, the risk of spontaneous miscarriages increases.
If pregnancy occurs, therapy with Sotret is discontinued. The advisability of preserving it should be discussed with a doctor specializing in teratology. Severe congenital malformations of the fetus in humans associated with the administration of isotretinoin, including hydrocephalus, microcephaly, cerebellar malformations, external ear abnormalities (microtia, narrowing or absence of the external auditory canal, absence of the external ear), microphthalmia, cardiovascular abnormalities (tetrad) have been documented.
Fallot, transposition of the great vessels, defects of the septa), malformations of the face (cleft palate), thymus gland, parathyroid pathology. Since isotretinoin is highly lipophilic, it is very likely that it passes into breast milk. Due to possible side effects, isotretinoin should not be given to nursing mothers.
Due to the possible intensification of the symptoms of hypervitaminosis A, co-administration of isotretinoin with vitamin A and other retinoids (including acitretin, tretinoin, retinol, tazarotene, adapalene) should be avoided. Since tetracyclines can also cause an increase in intracranial pressure, their use in combination with isotretinoin is contraindicated.
Isotretinoin can weaken the effectiveness of progesterone preparations, so you should not use contraceptives containing small doses of progesterone.
The combined use of isotretinoin with local keratolytic or exfoliative drugs for the treatment of acne is contraindicated because of the possible increase in local irritation.
Standard dosage regimen Inside, with food, twice a day. The therapeutic efficacy of Sotret and its side effects are dose-dependent and vary in different categories of patients.
This dictates the need for individual selection of doses during treatment. Adults, including adolescents, and elderly patients: Treatment with Sotret should be started with a dose of 0.5 mg / kg per day. In most patients, the dose ranges from 0.5 to 1.0 mg / kg body weight per day.
Patients with very severe forms of the disease or with acne of the trunk may require higher daily doses of up to 2.0 mg / kg. Expect significant additional benefits with a total dose of over 120-150 mg / kg should not be. The duration of treatment depends on the individual daily dose.
To achieve remission, a course of treatment lasting 16-24 weeks is usually sufficient. In patients who tolerate the recommended dose very poorly, treatment can be continued in a lower dose, but spend it longer. In most patients, acne completely disappears after a single course of treatment. With a pronounced relapse, a second course of treatment with Sotret is shown in the same daily and course dose as the first.
Since improvement can continue up to 8 weeks after discontinuation of the drug, a second course should be prescribed no earlier than the end of this period. Dosing in special cases In patients with severe renal failure, treatment should be started with a lower dose (for example, 10 mg / day) and then increased to 1 mg / kg / day or the maximum tolerated dose.
Patients with intolerance to the recommended dose. Patients who show intolerance to the recommended dose can continue to take the drug at a lower dose, taking into account the consequences of longer therapy and a higher risk of relapse.
In order to achieve the greatest possible effectiveness, such patients should continue treatment, taking the maximum tolerated dose of the drug.
Isotretinoin is a derivative of vitamin A. Despite the fact that the acute toxicity of vitamin A is low, in case of accidental overdose there may appear signs of hypervitaminosis (dry skin and mucous membranes, cheilitis, nasal bleeding, hoarseness, conjunctivitis, reversible corneal opacity, intolerance to contact lenses) .
The manifestation of acute toxicity of vitamin A is expressed in severe headache, nausea or vomiting, drowsiness, irritability, and skin itching.
Signs and symptoms of accidental or intentional overdose of isotretinoin should be similar. These symptoms should probably be reversible and disappearing without any treatment.