Composition, form of production and packaging
Capsules hard gelatinous, size 3, brown; the content of the capsules is a wax-like paste of yellow-orange color.
1 caps.
isotretinoin 8 mg
Excipients: Gelucir В® 50/13 (mixture of stearic acid esters of polyethylene oxide and glycerol), soybean oil, Span 80 В® (sorbitan oleate - mixed esters of oleic acid and sorbitol).
Composition of the body and capsule capsules: gelatin, iron oxide, red oxide (E172), titanium dioxide (E171).
10 pieces. - blisters (2) - packs of cardboard.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (5) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (9) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (7) - packs of cardboard.
Capsules hard gelatinous, size 1, body white, lid green; the content of the capsules is a wax-like paste of yellow-orange color.
1 caps.
isotretinoin 16 mg
Excipients: Gelucir В® 50/13 (mixture of stearic acid esters of polyethylene oxide and glycerol), soybean oil, Span 80 В® (sorbitan oleate - mixed esters of oleic acid and sorbitol).
The composition of the capsule body: gelatin, titanium dioxide (E171).
Composition of capsule capsule: gelatin, titanium dioxide (E171), iron dye yellow oxide (E172), indigocarmine (E132).
10 pieces. - blisters (2) - packs of cardboard.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (5) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (9) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (7) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
The drug for acne treatment. Isotretinoin is a stereoisomer of fully trans-retinoic acid (tretinoin).
The exact mechanism of action of isotretinoin has not yet been revealed, but it has been established that the improvement in the clinical picture of severe forms of acne is associated with suppression of sebaceous gland activity and histologically confirmed decrease in their size.
Skin fat is the main substrate for the growth of Propionibacterium acnes, so reducing the formation of sebum suppresses the bacterial colonization of the duct.Acnekutan suppresses 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
Suction
Since the kinetics of isotretinoin and its metabolites is linear, its plasma concentrations during therapy can be predicted on the basis of data obtained after a single dose. This property of the drug also suggests that it does not affect the activity of microsomal liver enzymes involved in the metabolism of drugs.
High bioavailability of Acnecutane is due to a high proportion of dissolved isotretinoin in the drug, and may increase with the condition of taking the drug with food.In patients with acne C max in equilibrium after taking isotretinoin in a dose of 80 mg, fasting was 310 ng / ml (range 188-473 ng / ml) and reached after 2-4 hours. The concentration of isotretinoin in plasma was 1.7 times higher than in blood, due to poor penetration of isotretinoin into erythrocytes.
Distribution
Binding to plasma proteins (mainly with albumin) - 99.9%.
C ss isotretinoin in the blood in patients with severe forms of acne, taking the drug at 40 mg 2 times / day, ranged from 120 ng / ml to 200 ng / ml. The concentrations of 4-oxo-isotretinoin (the main metabolite) in these patients were 2.5 times higher than those. The concentration of isotretinoin in the epidermis is 2 times lower than in serum.
Metabolism
Metabolized with the formation of 3 basic biologically active metabolites - 4-oxo-isotretinoin (the main metabolite), tretinoin (fully trans retinoic acid) and 4-oxo-retinoin, as well as less significant metabolites, including glucuronides. Since in vivo isotretinoin and tretinoin are reversibly converted into each other, the metabolism of tretinoin is associated with the metabolism of isotretinoin. 20-30% of the dose of isotretinoin is metabolized by isomerization. In the pharmacokinetics of isotretinoin in humans, an important role may be played by enterohepatic circulation.
In vitro studies have shown that several cytochrome P450 enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. In this case, none of the isoforms, apparently, does not play a dominant role. Isotretinoin and its metabolites have no significant effect on the activity of cytochrome P450 enzymes.
Excretion
T 1/2 of the terminal phase for isotretinoin an average of 19 hours. T 1/2 of the terminal phase for 4-oxo-isotretinoin, on average, 29 h.
Isotretinoin is excreted by the kidneys and with 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 cases
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.
INDICATIONS
- severe forms of acne (nodular-cystic, conglobata, acne with risk of scarring);
- Acne, not amenable to other types of therapy.
DOSING MODE
Inside, preferably with food, 1-2 times / day.
The therapeutic efficacy of acnecutane and its side effects depend on the dose and vary in different patients. This makes it necessary to select the individual dose in the course of treatment.
The initial dose of Acnecutane is 400 Ојg / kg / day, in some cases up to 800 Ојg / kg / day. In severe cases or with acne , a dose of up to 2 mg / kg / day may be required.
The optimal course cumulative dose is 100-120 mg / kg. Complete remission is usually achieved in 16-24 weeks. If the recommended dose is poorly tolerated, treatment can be continued at a lower dose, but longer. In most patients, acne completely disappears after a single course of treatment.
In case of relapse, it is possible to repeat the course of treatment in the same daily and cumulative dose. Repeated course is prescribed not earlier than 8 weeks after the first, tk. the improvement may be deferred.
In chronic renal failure of a severe degree, the initial dose should be reduced to 8 mg / day.
SIDE EFFECT
Most side effects depend on the dose. Usually, side effects are reversible after dose adjustment or drug withdrawal, but some may persist after discontinuation of treatment.
Symptoms associated with hypervitaminosis A: dry skin, mucous membranes, incl. lips (cheilitis), nasal cavity (bleeding), larynx and pharynx (hoarseness), eye (conjunctivitis, reversible corneal opacity and intolerance of contact lenses).
Dermatological reactions: peeling of the skin of the palms and soles, rash, itching, face erythema / dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased granulation tissue proliferation, persistent thinning of hair, reversible hair loss, fulminant forms of acne, hirsutism, hyperpigmentation, photosensitization, slight trauma of the skin. At the beginning of treatment, there may be an exacerbation of acne, which lasts for several weeks.
From the musculoskeletal system: pain in the muscles with increasing serum levels of CK in the serum or without it, joint pain, hyperostosis, arthritis, calcification of ligaments and tendons, tendinitis.
From the side of the central nervous system: excessive fatigue, headache, increased intracranial pressure (pseudotumor brain: headache, nausea, vomiting, impaired vision, edema of the optic nerve), convulsive seizures; rarely - depression, psychosis, suicidal thoughts.
On the part of the sense organs: xerophthalmia, isolated cases of visual acuity, photophobia, disturbance of dark adaptation (reduction of sharpness of twilight vision); rarely - a violation of color perception (which occurs after the drug has been discontinued), lenticular cataract, keratitis, blepharitis, conjunctivitis, eye irritation, optic neuritis, optic nerve swelling (as a manifestation of intracranial hypertension); hearing impairment at certain sound frequencies, difficulties in wearing contact lenses.
On the part of the digestive system: 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 pancreatitis with a lethal outcome are described. There was a transient and reversible increase in hepatic transaminase activity, isolated cases of hepatitis. In many of these cases, the changes did not go beyond the limits of the norm and returned to the baseline in the treatment process, however, in some situations, there was a need to reduce the dose or cancel Acnecutane.
On the part of the respiratory system: rarely - bronchospasm (more often in patients with bronchial asthma in the anamnesis).
On the part of the hematopoiesis system: anemia, a decrease in hematocrit, leukopenia, neutropenia, an increase or decrease in the number of platelets, an acceleration of the ESR.
Laboratory indicators: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, lowering of the level of HDL; rarely - hyperglycemia. During the reception of Acnecutan, cases of newly diagnosed diabetes mellitus were registered. In some patients, especially those engaged in intensive physical activity, individual cases of increased activity of CK in the serum are described.
Infections: 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, hypoplasia of the cranial nerves, microphthalmia, malformations of the cardiovascular system, parathyroid glands, skeletal malformations (underdevelopment of finger phalanges, skull, cervical vertebrae, femur, ankles, bones forearm, facial skull, wolf mouth), low position of the auricles, underdevelopment of the auricles, underdevelopment or complete absence of the external auditory canal, hernia of the brain and spinal cord, bones fusion, fusion of the fingers and toes, developmental disorders of the thymus; fetal death in the perinatal period, premature birth, miscarriages, premature closure of epiphyseal growth zones; in an experiment on animals - pheochromocytoma.
CONTRAINDICATIONS
- Pregnancy, established and planned (possibly teratogenic and embryotoxic action);
- the period of breastfeeding;
- liver failure;
- hypervitaminosis A;
- severe hyperlipidemia;
- concomitant therapy with tetracyclines;
- Hypersensitivity to the drug or its components.
Acnecutane is not recommended for use in children under 12 years of age.
With caution should prescribe the drug in diabetes mellitus, a history of depression, obesity, a violation of lipid metabolism, alcoholism.
PREGNANCY AND LACTATION
Pregnancy is an absolute contraindication for therapy with Acnekutan .
If pregnancy occurs, despite warnings, during treatment or within a month after the end of therapy, there is a very high risk of a child with severe developmental defects.
Isotretinoin is a drug with a strong teratogenic effect. If a pregnancy occurs at a time when a woman is taking orally taking isotretinoin (at any dose and even for a short time), there is a very high risk of a child with developmental defects.
Acnecutane is contraindicated in women of childbearing age , unless the condition of a woman satisfies all of the following criteria:
- severe form of acne, resistant to conventional methods of treatment;
- the patient must understand and follow the doctor's instructions;
- the patient should be informed by the doctor about the dangers of pregnancy during treatment with Acnecutane, within one month after it and urgent consultation in case of suspected pregnancy;
- the patient should be warned about the possible ineffectiveness of contraceptives;
- the patient must confirm that she understands the nature of the precautionary measures;
- the patient should understand the need and continuously use effective methods of contraception within one month prior to treatment with Acnecutane, during treatment and for a month after its termination; It is desirable to use at the same time 2 different methods of contraception, including barrier;
- the patient should receive a negative result of a valid pregnancy test within 11 days before the start of the drug; a pregnancy test is strongly recommended to be performed monthly during treatment and 5 weeks after the end of therapy;
- the patient should begin treatment with Acnekutan only on the 2-3 day of the next normal menstrual cycle;
- the patient should understand the necessity of compulsory medical visits every month;
- when treating for a relapse of the disease, the patient must constantly use the same effective methods of contraception within one month prior to initiating treatment with Acnecutan, during treatment and for a month after its completion, and also undergo the same reliable pregnancy test;
- the patient should fully understand the need for precautionary measures and confirm her understanding and desire to apply reliable methods of contraception, which the doctor explained to her.
The use of contraceptives in accordance with the above instructions during treatment with isotretinoin should be recommended even to those women who usually do not use contraceptive methods due to infertility (except for patients who underwent hysterectomy), amenorrhea, or who report that they do not have sex.
The doctor should be sure that:
- the patient suffers from severe acne (nodular-cystic, conglobate acne or acne with the risk of scarring); acne, not amenable to other types of therapy;
- a negative result of a valid pregnancy test was obtained prior to taking 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 one, preferably two, effective methods of contraception, including the barrier method, within one month prior to initiation of treatment with Acnecutane, during treatment and for a month after its termination;
- the patient is able to understand and fulfill all of the above requirements for protection from 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 the start of therapy
To exclude a possible pregnancy before the application of contraception, the result and the date of the initial pregnancy test must be recorded by the doctor. In patients with irregular menstruation, the timing of the pregnancy test depends on sexual activity, it should be performed 3 weeks after unprotected intercourse. The doctor should inform the patient about the methods of contraception.
The pregnancy test is performed on the day of appointment of Acnecutane or 3 days before the patient's visit to the doctor. The specialist should register the test results. The drug may be prescribed only to patients receiving effective contraception for at least 1 month prior to initiating therapy with Acnecutant.
During therapy
The patient must visit the doctor every 28 days. The need for monthly pregnancy testing is determined in accordance with local practice and taking into account the sexual activity preceding the menstrual cycle disorders. If there is evidence, the pregnancy test is carried out on the day of the visit or 3 days before the visit to the doctor, the test results must be recorded.
End of therapy
After 5 weeks after the end of therapy, a test is performed to exclude pregnancy.
The recipe for Acnekutan to a woman capable of childbearing can be discharged only for 30 days of treatment, continuation of therapy requires a new prescription of the drug by a doctor. It is recommended that a pregnancy test, a prescription and preparation be conducted on the same day.
If, in spite of the precautionary measures taken, during treatment with Acnecutane or within a month after its termination, pregnancy does occur, there is a high risk of very serious fetal malformations.
If pregnancy occurs, the therapy with Acnecutan is stopped. We should discuss the expediency of maintaining a pregnancy with a doctor specializing in teratology.
Since isotretinoin has a high lipophilicity, it is very likely that it enters the breast milk. Because of possible side effects, Acnecutane should not be given to nursing mothers.
Male Patients
Existing evidence suggests that in women the exposure of the drug from the semen and semen of men taking Acnecutane is not sufficient for the appearance of teratogenic effects of Acnecutane. Men should be excluded from the possibility of taking the drug by other people, especially women.
APPLICATION FOR FUNCTIONS OF THE LIVER
In chronic renal failure of a severe degree, the initial dose should be reduced to 8 mg / day.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
It is recommended to control the function of the liver and liver enzymes prior to treatment, at 1 month after the start and then every 3 months or indications.Observed a transient and reversible increase in liver transaminases, in most cases within the normal range. If the level of liver transaminases above the norm, it is necessary to reduce the dose or cancel it.
APPLICATION FOR CHILDREN
Aknekutan not indicated for the treatment of acne and puberty is not recommended for use in children under 12 years.
SPECIAL INSTRUCTIONS
It is recommended to control the function of the liver and liver enzymes prior to treatment, at 1 month after the start and then every 3 months or indications. Observed a transient and reversible increase in liver transaminases, in most cases within the normal range. If the level of liver transaminases above the norm, it is necessary to reduce the dose or cancel it.
It should also determine the level of fasting serum lipids before the treatment 1 month after the start and then every 3 months or indications. Typically, a lipid concentration normalized after decreasing the dose or discontinuation of the drug, but also with diet.
It is necessary to control a clinically significant increase in triglycerides, as they rise above 800 mg / dl or 9 mmol / l can be accompanied by development of acute pancreatitis, possibly with fatal consequences. When resistant hypertriglyceridemia or symptoms of pancreatitis Aknekutan should be abolished.
In rare cases, patients treated with Aknekutan described depression, psychotic symptoms, and very rarely - suicide attempts. Although their causal relationship to the use of the drug has not been established, you must take special care in patients with a history of depression and observe all patients for the occurrence of depression in the course of drug treatment, referring them to a specialist if necessary. However Aknekutana cancellation can not lead to the disappearance of symptoms and may need further observation and treatment by a specialist.
In rare cases, therapy is celebrated at the beginning of the exacerbation of acne, which takes place within 7-10 days without a correction dose.
In appointing the drug to any patient should first carefully weigh the potential benefits and risks.
Patients receiving Aknekutan, it is recommended to use a moisturizing cream or body lotion, lip balm to reduce the dryness of the skin and mucous membranes at the beginning of therapy.
While taking Aknekutana may be pain in muscles and joints, increased CPK serum, which may be accompanied by a reduction in tolerability intense exercise.
Avoid carrying out a deep chemical dermoabrazii and laser treatment in patients receiving Aknekutan and within 5-6 months after treatment because of the potential power of scarring in atypical areas and the occurrence of hyper- and hypopigmentation. During treatment Aknekutanom and for 6 months after hair removal can not be performed with the help of applications of wax due to the risk of detachment of the epidermis, the development of scarring and dermatitis.
Because some patients may experience a decrease in the severity of night vision, which sometimes persists after the end of therapy, patients should be informed about the possibility of this state, encouraging them to use caution when driving at night. Status of visual acuity should be carefully monitored. Dryness of the conjunctiva of the eye, corneal opacity, Decreased night vision and keratitis usually disappear after discontinuation of the drug. When the mucous membrane of dry eye can be used application moisturizing eye ointment or preparation of artificial tears. Should be monitored in patients with dryness of the conjunctiva for the possible development of keratitis. Patients complained of vision, should be sent to the ophthalmologist and to consider whether to cancel Aknekutana.Intolerance to contact lenses at the time of therapy should be used glasses.
Should limit the impact of the solar insolation and UV treatment. If necessary, use a sunscreen with a high shielding factor of not less than 15 SPF.
Described rare cases of benign intracranial hypertension (pseudotumor brain) including the combined use with tetracyclines. These patients should be lifted immediately Aknekutan.
In therapy Aknekutanom may cause inflammatory bowel disease. In patients with severe hemorrhagic diarrhea should immediately cancel Aknekutan.
Described rare cases of anaphylactic reactions that occurred only after prior external application of retinoids. Severe allergic reactions necessitate discontinuation of therapy and careful monitoring of the patient.
Patients at high risk (diabetes, obesity, alcoholism or disorders of lipid metabolism) Aknekutanom the treatment may require more frequent laboratory control of glucose and lipid. In the presence of diabetes or suspected, it is recommended more frequent blood glucose determination. Patients with diabetes are recommended more frequent monitoring of blood glucose.
During the period of treatment and for 30 days after it is necessary to completely eliminate the blood samples from potential donors in order to avoid any possibility of getting this blood pregnant patients (high risk of teratogenic and embryotoxic action).
Impact on the ability to drive vehicles and manage mechanisms
During the period of treatment must be careful when driving vehicles and occupation of other potentially hazardous activities that require high concentration and psychomotor speed reactions (when receiving the first dose).
OVERDOSE
In the case of overdose can be signs of hypervitaminosis A.
In the first few hours after the overdose may need gastric lavage.
DRUG INTERACTION
Tetracycline antibiotics, corticosteroids reduce the effectiveness Aknekutana.
The simultaneous use of drugs that enhance the photosensitivity (including sulfonamides, tetracyclines, thiazide diuretics) increases the risk of sunburn.
The simultaneous use of other retinoids (incl acitretin, tretinoin, retinol, tazarotenom, adapalene) increases the risk of hypervitaminosis A.
Isotretinoin may weaken the effectiveness of progesterone preparations, however not necessary to use contraceptives containing small doses of progesterone.
Combined use with local keratolytic treatments for acne is not recommended due to the possible increase of local irritation.
Because tetracyclines increase the risk of increased intracranial pressure with simultaneous application of isotretinoin is contraindicated.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in a dry, protected from light, out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 2 years. Do not use after expiry date.
