Pharmacodynamics. Isotretinoin is a synthetic stereoisomer of transretinoic acid (tretinoin).
The mechanism of action of isotretinoin is not well understood, but it has been established that the improvement in the clinical picture of severe forms of acne is associated with a dose-dependent suppression of the activity of the sebaceous glands and a histologically confirmed decrease in their size. In addition, isotretinoin has a local anti-inflammatory effect. Hypercornification of the epithelium of the excretory duct of the sebaceous gland leads to the prolapse of corneocytes into the duct, blocking it with keratin and excess sebum. This is accompanied by the formation of a comedone and ultimately leads to the development of inflammation. Roaccutane inhibits the proliferation and differentiation of sebocytes. Sebum is the main growth substrate for P. acnes, so a decrease in sebum production prevents bacterial colonization of the sebaceous ducts.
Pharmacokinetics
The dynamics of the concentration of isotretinoin in the blood can be predicted based on the linear type of pharmacokinetics.
Cmax of isotretinoin after taking the preparation at a dose of 80 mg was about 310 ng / ml and was reached after 2–4 hours. Plasma concentrations of isotretinoin were approximately 1.7 times higher than the concentration in blood due to poor penetration of isotretinoin into erythrocytes.
Taking isotretinoin with food increases its bioavailability by 2 times compared to taking it on an empty stomach.
Isotretinoin strongly binds to blood plasma proteins (99.9%), mainly albumin, so that in a wide range of therapeutic concentrations, the content of the free active fraction of the preparation is 0.1% of its total amount. The volume of distribution of isotretinoin in humans is unknown, since there is no dosage form for intravenous administration. The equilibrium plasma concentration of isotretinoin in acne patients ranged from 120 to 200 ng / ml. The concentration of isotretinoin in the epidermis is 2 times lower than in the blood plasma.
After oral administration, 3 main metabolites are detected in blood plasma: 4-oxo-isotretinoin, tretinoin (transretinoic acid), 4-oxo-retinoin. The main metabolite of isotretinoin in the blood is 4-oxo-isotretinoin, the plasma concentrations of which in the equilibrium state are 2.5 times higher than the concentration of the parent preparation.
Isotretinoin metabolites are biologically active, therefore, the clinical effects of the preparation in patients may be the result of the pharmacological activity of isotretinoin and its metabolites.
Since isotretinoin and tretinoin are converted in vivo, the metabolism of tretinoin is related to the metabolism of isotretinoin. 20-30% of the dose of isotretinoin is metabolized by isomerization.
Enterohepatic circulation plays a significant role in the pharmacokinetics of isotretinoin in humans.
In vitro metabolic studies have shown that several CYP enzymes are involved in the conversion of isotretinoin to oxo-isotretinoin and tretinoin. Obviously, none of the lysoforms plays a dominant role. Roaccutane and its metabolites do not significantly affect the activity of enzymes of the CYP system.
After oral administration of radioactively labeled isotritenoin, approximately the same amount was determined in urine and feces. T½ of the terminal phase for the modified preparation in patients with acne is about 19 hours. T½ of the terminal phase for oxo-isotretinoin averages 29 hours.
Isotretinoin belongs to natural (physiological) cretinoids. Endogenous concentrations of cretinoids are restored approximately 2 weeks after the end of the use of the preparation Roaccutane.
Since isotretinoin is contraindicated in patients with impaired liver or kidney function, there are no data on the pharmacokinetics of the preparation in patients of this group.
Severe forms of acne (nodular and conglobatic acne, acne with a tendency to scarring), not amenable to standard treatment methods (systemic antibiotic therapy, local treatment).
Standard dosage regimen
Capsules are taken with meals 1-2 times a day. The therapeutic efficacy of Roaccutane and its side effects are dose dependent and vary from patient to patient. Therefore, you should individually select the dose during treatment.
Adults and children over the age of 12. Treatment begins with a dose of 0.5 mg / kg / day. The therapeutic response to isotretinoin and some adverse reactions are dose dependent and vary from patient to patient. In this regard, an individual dose adjustment is required during treatment. In most patients, the dose is 0.5–1 mg / kg of body weight per day.
Long-term remission and relapse rates are more related to the total dose prescribed than to the duration of treatment or the daily dose. It has been proven that the frequency of remission and prevention of relapse is optimal when using a course dose of 120–150 mg / kg (for a course of treatment), therefore, the duration of therapy may vary depending on the daily dose. Complete remission of acne can often be achieved within 16-24 weeks of treatment.
In most patients, acne disappears completely after a one-time course of treatment. With a pronounced relapse, a second course of treatment with Roaccutane is carried out in the same daily and course dose as the first one. Since an improvement in the condition can occur within 8 weeks after the end of treatment, a second course should be prescribed no earlier than the end of this period.
Dosing in special cases
Severe renal failure. In patients with severe renal insufficiency, treatment begins with a low dose (for example, 10 mg / day), and then increases to 1 mg / kg / day or to the maximum tolerated dose.
Children. Isotretinoin is contraindicated for the treatment of prepubertal acne and in patients under 12 years of age.
Patients with intolerance to the standard treatment regimen. In patients who cannot tolerate the recommended dose, treatment can be continued at a low dose, but it should be carried out for a longer period. In order to achieve the maximum possible effectiveness, it is necessary to use the maximum tolerated dose.
During pregnancy and breastfeeding; in women of reproductive age if all conditions of the "pregnancy prevention program" are not met; hypersensitivity to isotretinoin or any components of the preparation; liver failure; severe hyperlipidemia; hypervitaminosis a; concomitant therapy with tetracyclines. children under 12 years of age.
Due to the fact that Roaccutane contains peanut oil, soybean oil, partially hydrogenated and hydrogenated soybean oil, the preparation is contraindicated for use in patients with allergies to peanuts and soybeans.
Most of the side effects of Roaccutane are dose dependent. as usual, adverse reactions are reversible after dose adjustment or discontinuation of the preparation, but some may persist after treatment.
Symptoms of vitamin A hypervitaminosis: dry skin, mucous membranes, including lips (cheilitis), nasal cavity (bleeding), hypopharynx (hoarseness), eyes (conjunctivitis, reversible corneal opacity and contact lens intolerance).
From the side of the skin and its appendages: very often - cheilitis, dermatitis, dry skin, localized peeling, itching, erythematous rash, increased skin trauma; rarely - alopecia; very rarely - fulminant forms of acne, facial erythema, exanthema, thinning hair, reversible hair loss, hirsutism, onychodystrophy, paronychia, photosensitivity, pyogenic granuloma, hyperpigmentation, increased sweating, increased growth of granulation tissue, exacerbation of acne.
At the beginning of treatment, acne may worsen and persist for several weeks.
From the musculoskeletal system: very often - arthralgia, back pain, myalgia with or without an increase in the level of CPK in the blood serum (mainly in adolescents); rarely - arthritis, calcification of ligaments and tendons, premature closure of growth zones of the pineal glands, exostosis, hyperostosis, decreased bone mineral density, tendinitis.
From the side of the central nervous system and mental sphere: often - headache; rarely - increased intracranial pressure (pseudotumor of the brain) nausea, vomiting, visual impairment (edema of the optic nerve), convulsions, drowsiness, dizziness, depression, depression with aggravation, tendency to aggressiveness, mood changes, anxiety; very rarely - behavior disorder, psychotic disorders, suicidal thoughts, suicide attempts, suicide.
From the senses: very often - blepharitis, conjunctivitis, dryness of the mucous membrane of the eye, eye irritation; very rarely - impaired visual acuity, cataracts, color vision impairment, contact lens intolerance, corneal opacity, decreased twilight vision, keratitis, optic nerve edema (as manifestation of intracranial hypertension), photophobia, hearing impairment.
From the gastrointestinal tract: rarely - colitis, ileitis, dry throat, hemorrhagic diarrhea, inflammatory bowel disease, nausea, pancreatitis.
Described isolated cases of pancreatitis with a fatal outcome; 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 cases it became necessary to reduce the dose or discontinue the preparation Roaccutane.
On the part of the respiratory system: often - nosebleeds, dryness of the nasal mucosa, nasopharyngitis; very rarely - bronchospasm (more often in patients with asthma in history), dysphonia.
From the side of the blood system: very often - anemia, increased ESR, an increase or decrease in the number of platelets; often neutropenia; rarely, lymphadenopathy.
Laboratory indicators: very often - hypertriglyceridemia, a decrease in HDL levels; often - hypercholesterolemia, hyperglycemia, hematuria, proteinuria; very rarely - an increase in the activity of CPK in the blood plasma.
From the immune system: rarely - allergic reactions, anaphylactic reactions, hypersensitivity reactions.
Infections: very rarely - bacterial infections of the skin and mucous membranes.
Vascular disorders: vasculitis (Wegener's granulomatosis, allergic vasculitis).
From the urinary system: very rarely - glomerulonephritis.
General disorders: very rarely - increased formation of granulation tissue, malaise.
Metabolic disorders, metabolism: very rarely - diabetes mellitus, hyperuricemia.
Side effects identified in the post-registration period: exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
The preparation is used with caution in case of a history of depression, diabetes mellitus, obesity, lipid metabolism disorders, alcoholism. during the use of the preparation roaccutane, an increase in blood glucose levels was registered and new cases of diabetes mellitus were diagnosed. high-risk patients (diabetes mellitus, obesity, alcoholism or fat metabolism disorders) may need frequent monitoring of glucose and lipid levels during treatment with Roaccutane. in the presence or suspicion of diabetes, continuous glycemic control is recommended.
Roaccutane is prescribed by a doctor, mainly a dermatologist, with experience in the use of systemic retinoids, given the risk of teratogenicity when using the preparation Roaccutane during pregnancy. Male and female patients are given a copy of the Patient Information Brochure.
It is recommended to monitor liver function and liver enzymes before treatment, 1 month after its start, and then every 3 months or according to indications.
There was a temporary and reversible increase in hepatic transaminases, 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 preparation or cancel it.
You should also determine the level of lipids in blood plasma on an empty stomach (before treatment, 1 month after its start, then every 3 months or according to indications). Lipid concentration usually returns to normal after dose reduction or discontinuation of the preparation, as well as following diet. It is necessary to control the increase in TG levels, since their increase in 800 mg / dL or 9 mmol / L can be accompanied by the development of acute pancreatitis, possibly with a fatal outcome. In case of persistent hypertriglyceridemia or symptoms of pancreatitis, Roaccutane should be discontinued.
In some cases, patients treated with Roaccutane, there was depression, depression with aggravation, anxiety, a tendency to aggressiveness, mood changes, psychotic symptoms, and very rarely - homicidal thoughts, suicidal attempts and suicide. Although a causal relationship with the preparation intake has not been established, care must be taken when prescribing the preparation to patients with a history of depression and to monitor the condition of patients for depression during treatment, if necessary, refer them to an appropriate specialist. However, the withdrawal of the preparation Roaccutane may not affect the disappearance of symptoms, and the patient may need further supervision by a specialist.
In some cases, at the beginning of therapy, an exacerbation of acne is noted, which disappears after 7-10 days without adjusting the dose of the preparation.
Several years after the use of Roaccutane for the treatment of dyskeratosis, with a total course dose and duration of treatment, bone changes developed, including premature closure of the epiphyseal growth zones, hyperostosis, calcification of ligaments and tendons. Therefore, when prescribing a preparation, it is necessary to assess the balance of benefits and risks.
Patients receiving Roaccutane are advised to use moisturizing ointments or body creams, lip balm to reduce dry skin and mucous membranes at the beginning of treatment.
In the post-registration period of using the preparation, there were cases of severe skin reactions (exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis). These events can be serious and lead to death, hospitalization or disability. Patients should be constantly monitored for severe skin reactions and, if necessary, discontinue treatment with Roaccutane.
Against the background of the use of the preparation Roaccutane, pain in muscles and joints, an increase in CPK in the blood plasma, which may be accompanied by a decrease in the tolerance of intense physical activity, are possible.
It is forbidden to carry out deep chemical dermabrasion and laser treatment during treatment with Roaccutane and for 5-6 months after treatment, since there is a high risk of hypertrophic scars in atypical zones and the appearance of hyper- and hypopigmentation. During treatment with Roaccutane and for 6 months after treatment, epilation should not be performed using wax applications due to the risk of epidermal exfoliation, the development of scars and dermatitis.
Since it is possible to reduce the acuity of night vision, which sometimes persists after treatment, patients should be informed about this condition and it is recommended to exercise caution when driving at night. The state of visual acuity should be carefully monitored. Dryness of the conjunctiva of the eye, corneal opacity, deterioration in night vision and keratitis usually resolve after discontinuation of the preparation. In case of dryness of the mucous membrane of the eye, it is recommended to use applications of a moisturizing ointment for the eyes or an artificial tear preparation. Observation of such patients is necessary to prevent the development of keratitis. If there are complaints of visual impairment, such patients are referred to an ophthalmologist and the question of discontinuing the preparation is considered. If you are intolerant of contact lenses, it is recommended to use glasses during treatment. It is necessary to limit the influence of solar and UV radiation. If necessary, use a sunscreen with a high level of protective factor of at least 15 SPF.
To prevent the accidental effect of the preparation on the body of other people in patients who are taking or shortly before (1 month) used Roaccutane, it is forbidden to take donor blood.
Described are individual cases of the development of benign intracranial hypertension, including with simultaneous use with tetracyclines. Such patients should immediately discontinue the preparation.
During treatment with Roaccutane, the development of inflammatory bowel diseases is possible. Patients with severe hemorrhagic diarrhea should immediately discontinue the preparation.
Described are individual cases of anaphylactic reactions that occurred only after the previous external use of cretinoids. Allergic reactions from the skin were rare. Serious cases of allergic vasculitis have been reported, often with purpura on the extremities and extracutaneous lesions. Severe allergic reactions require discontinuation of the preparation and constant monitoring of patients.
Roaccutane contains sorbitol. Patients with fructose intolerance are not advised to take Roaccutane.
Use during pregnancy and lactation. Roaccutane is a preparation with a strong teratogenic effect. Pregnancy is an absolute contraindication for the use of Roaccutane. If pregnancy occurs during the period when a woman is taking Roaccutane (in any dose and even for a short time) or within a month after the end of therapy, there is a very high risk of having a child with developmental abnormalities.
"Pregnancy Prevention Program"
Roaccutane is contraindicated in women of reproductive age, unless the woman's condition meets all of the following criteria:
If pregnancy occurs, therapy with Roaccutane must be discontinued.
The use of contraception according to the above recommendations during treatment with isotretinoin should be recommended even for sexually passive women.
The doctor must be sure that:
Pregnancy prevention
Patients should be familiar with contraceptive methods. If they are not using effective contraceptive methods, the doctor should provide appropriate advice.
Two reliable methods of contraception should be used, including the barrier method. Contraceptive methods should be used for at least 1 month after stopping treatment with Roaccutane, even in patients with amenorrhea.
Pregnancy test
According to current practice, a pregnancy test with a minimum sensitivity of 25 IU / ml should be performed in the first 3 days of the menstrual cycle.
Before starting treatment:
to exclude a possible pregnancy, the doctor must register the result and the date of the first pregnancy test before starting contraceptive use. In patients with irregular menstrual periods, the timing of a pregnancy test depends on sexual activity. The test should be performed 3 weeks after unprotected intercourse. The doctor should inform the patient about contraceptive methods;
a pregnancy test is performed on the day after the appointment of the preparation Roaccutane or 3 days before the patient's visit to the doctor. Test results should be recorded by the specialist. The preparation can be intended only for patients who receive effective contraception for at least 1 month before starting treatment with Roaccutane.
During treatment:
the patient must see a doctor every 28 days. The need for monthly pregnancy testing is determined by 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 are recorded.
Completion of treatment:
5 weeks after the end of treatment, a pregnancy test is performed.
The pharmacist must ensure that:
To help doctors, pharmacists and patients avoid the risk of fetal exposure to Roaccutane, the manufacturing company has created a Pregnancy Prevention Program aimed at preventing the preparations teratogenic effects and emphasizing the absolute need to use reliable contraceptive methods for women of reproductive age. The program contains the following materials:
For doctors:
For patients:
For pharmacists:
The existing data indicate that in women, the exposure of the preparation, which came from the seminal fluid of men using Roaccutane, is insufficient for the appearance of teratogenic effects of the preparation Roaccutane.
Men should exclude the possibility of using the preparation by others, especially women.
In humans, severe congenital malformations of the fetus associated with the use of Roaccutane have been documented, including hydrocephalus, microcephaly, impaired cerebellar development, anomalies of the external ear (microtia, narrowing or absence of the external auditory canal), microphthalmia, cardiovascular anomalies (tetralogy of Fallot , transposition of great vessels, septal defects), anomalies in the development of the face (cleft palate), thymus, pathology of the parathyroid glands.
Lactation
Due to the lipophilicity of isotretinoin, there is a possibility that it passes into breast milk, in this regard, the preparation is contraindicated in women during breastfeeding.
Children. The use of the preparation Roaccutane in children under the age of 12 has not been studied, therefore, the preparation should not be prescribed to children of this age category.
The ability to influence the reaction rate when driving and working with other mechanisms. During and after treatment, a decrease in the acuity of twilight vision is possible, therefore, patients should be informed about the possibility of this problem and the need to be careful when driving or working with other mechanisms at night.
In view of the possible increase in the severity of the symptoms of hypervitaminosis a, the simultaneous use of the preparation roaccutane and vitamin a should be avoided. Since tetracyclines can also cause an increase in intracranial pressure, their use in combination with Roaccutane is contraindicated.
Isotretinoin can reduce the effectiveness of progesterone medications, so you should not use contraceptives that contain low doses of progesterone.
Combined use with topical keratolytic or exfoliative preparations for the treatment of acne is contraindicated due to the possible increase in local irritation.
Isotretinoin is a vitamin A derivative. although the toxicity of isotretinoin is low, in case of an overdose, signs of hypervitaminosis a (headache, nausea, vomiting, drowsiness, irritability, itching) may appear. in the first few hours after an overdose, gastric lavage may be necessary. the symptoms of accidental or deliberate overdose are the same. these symptoms are reversible and disappear without treatment.
At temperatures up to 25 ° C.
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