Description
Release form
Capsules
Packing
30 pcs.
Pharmacological action
Isotretinoin is a stereoisomer of fully transretinoic acid (tretinoin).
The exact mechanism of action of isotretinoin has not yet been identified, 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. Sebum is the main substrate for the growth of Propionibacterium acnes, therefore, a decrease in sebum formation inhibits bacterial colonization of the duct.
Aknekutan suppresses 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
After oral administration, absorption is variable, Aknekutan bioavailability is low and variable – due to the proportion of dissolved isotretinoin in the drug, and may also increase when taken with food. 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. The concentration of isotretinoin in plasma is 1.7 times higher than in the blood, due to poor penetration of isotretinoin into red blood cells. Communication with plasma proteins (mainly with albumin) – 99.9%.
Equilibrium concentrations of isotretinoin in the blood (Css) in patients with severe forms of acne, taking 40 mg of the drug 2 times a day, ranged from 120 to 200 ng / ml. The concentrations of 4-oxo-isotretinoin (the main metabolite) in these patients were 2.5 times higher than those of isotretinoin.
The concentration of isotretinoin in the epidermis is 2 times lower than in serum. It is metabolized with the formation of 3 main biologically active metabolites – 4-oxo-isotretinoin (main), tretinoin (fully transretinoic acid) and 4-oxo-retinoin, as well as less significant metabolites, which also include 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. Enterohepatic circulation can play a significant role in the pharmacokinetics of isotretinoin in humans.
In vitro studies have shown that several CYP enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. Moreover, none of the isoforms, apparently, plays a dominant role. Isotretinoin and its metabolites do not significantly affect the activity of CYP enzymes.
The half-life of the terminal phase for isotretinoin is an average of 19 hours. The half-life of the terminal phase for 4-oxo-isotretinoin is an average of 29 hours.
Isotretinoin is excreted by the kidneys and with bile in approximately equal amounts. Refers to natural (physiological) retinoids. Endogenous retinoid concentrations are restored approximately 2 weeks after the end of the drug.
Pharmacokinetics in special clinical cases
Since 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, conglobate, acne with a risk of scar formation).
Acne not amenable to other types of therapy.
Contraindications
Pregnancy, established and planned (possibly teratogenic and embryotoxic effects), lactation period, liver failure, hypervitaminosis A, severe hyperlipidemia, concomitant tetracycline therapy.
Hypersensitivity to the drug or its components. Aknekutan is not indicated in the treatment of puberty acne and is not recommended for use by children under 12 years of age.
Precautions
Diabetes mellitus, history of depression, obesity, impaired lipid metabolism, alcoholism.
Male Patients:
Existing evidence suggests that in women, exposure to the drug from the seed and seminal fluid of men taking Aknekutan is not sufficient for teratogenic effects of Aknekutan to occur. Men should exclude the possibility of taking the drug by others, especially women.
If, despite the precautions taken, during treatment with Aknekutan or within a month after its termination, pregnancy nevertheless occurred, there is a high risk of very severe fetal malformations. If pregnancy occurs, therapy with Aknekutan is stopped. The advisability of preserving it should be discussed with a doctor specializing in teratology.
Since isotretinoin is highly lipophilic, it is very likely that it passes into breast milk. Due to possible side effects, Aknekutan should not be prescribed to nursing mothers.
Special instructions
It is recommended to monitor liver function and liver enzymes before treatment, 1 month after it is started, and then every 3 months or as indicated. A transient and reversible increase in hepatic transaminases was noted, in most cases within normal values. If the level of hepatic transaminases exceeds the norm, it is necessary to reduce the dose of the drug or cancel it. You should also determine the level of lipids in fasting serum before treatment, 1 month after the start, and then every 3 months or as indicated. Typically, lipid concentrations are normalized after a dose reduction or drug withdrawal, as well as dieting. A clinically significant increase in triglyceride levels must be monitored, since their rise in excess of 800 mg / dl or 9 mmol / l may be accompanied by the development of acute pancreatitis, possibly fatal.
With persistent hypertriglyceridemia or symptoms of pancreatitis, Acnecutan should be discontinued. In rare cases, patients receiving Aknekutan described depression, psychotic symptoms, and very rarely suicidal attempts. Although their causal relationship with the use of the drug has not been established, special care must be taken in patients with a history of depression and all patients should be monitored for depression during treatment with the drug, if necessary referring them to the appropriate specialist. However, the withdrawal of Aknekutan may not lead to the disappearance of symptoms and further monitoring and treatment by a specialist may be required.
In rare cases, exacerbation of acne is noted at the beginning of therapy, which passes within 7-10 days without dose adjustment.
When prescribing the drug to any patient, the ratio of the possible benefit and risk should be carefully evaluated first.
Patients receiving Aknekutan are advised to use moisturizing ointment or body cream, lip balm to reduce dry skin and mucous membranes at the beginning of therapy.
Against the background of taking Aknekutan, pain in muscles and joints, an increase in serum creatinine phosphokinase, which may be accompanied by a decrease in tolerance to intense physical activity, are possible.
Avoid deep chemical dermabrasion and laser treatment in patients receiving Aknekutan, as well as within 5-6 months after treatment due to the possibility of increased scarring in atypical places and the occurrence of hyper- and hypopigmentation. During treatment with Aknekutan and for 6 months after it, it is impossible to carry out hair removal using wax applications because of the risk of epidermal detachment, the development of scars and dermatitis. 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, recommending that they be careful when driving at night. 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. Sick complaining of vision should be referred to an ophthalmologist and consider the advisability of canceling Aknekutan. In case of intolerance to contact lenses, glasses should be used during therapy. The effects of solar insolation and UV therapy should be limited. If necessary, use a sunscreen with a high protective factor of at least 15 SPF.
Rare cases of the development of benign intracranial hypertension ( ² Ñpseudotumor of the brain ² Ñ), including with combined use with tetracyclines. In such patients, Aknekutan should be withdrawn immediately. With Aknekutan therapy, an inflammatory bowel disease may occur. In patients with severe hemorrhagic diarrhea, Aknekutan should be withdrawn immediately.
Rare cases of anaphylactic reactions, which occurred only after previous external use of retinoids. Severe allergic reactions dictate the need for drug withdrawal and close monitoring of the patient.
High-risk patients (with diabetes, obesity, chronic alcoholism, or impaired fat metabolism) may need more frequent laboratory monitoring of glucose and lipids during treatment with Aknekutan. If you have or suspect diabetes, a more frequent definition of glycemia is recommended.
Patients with diabetes mellitus are advised to monitor their blood glucose more frequently.
During treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities, requiring increased concentration of attention and speed of psychomotor reactions (when taking the first dose).
During the treatment period and within 30 days after its completion, it is necessary to completely exclude blood sampling from potential donors in order to completely exclude the possibility of getting this blood to pregnant patients (high risk of developing teratogenic and embryotoxic effects). Release form Capsules 8 mg and 16 mg. 10 or 14 capsules in a PVC blister coated with aluminum foil.
Blisters-10-N2, N3, N5, N6, N9, N10 blisters-14-N1, N2, N4, N7 in a cardboard box along with instructions for use.
Composition
Composition per 1 capsule
Active ingredients: Isotretinoin 8.0 mg
Excipients: Gelucir® 50/13 (a mixture of stearic acid esters of polyethylene oxide and glycerin), purified soybean oil, Span 80® (sorbitol mixed esters of oleic acid and sorbitol).
Composition of the capsule
body and cap: gelatin, dye iron oxide red (E172), titanium dioxide (E171).
Dosage and administration
Inside, preferably with meals, 1-2 times a day.
The therapeutic efficacy of Aknekutan and its side effects are dose dependent and vary in different patients. This makes it necessary to individually select the dose during treatment.
The initial dose of Aknekutan is 0.4 mg / kg per day, in some cases up to 0.8 mg / kg per day. In severe forms of the disease or with acne of the body, a dose of up to 2 mg / kg per day may be required.
The optimal course cumulative dose is 100-120 mg / kg. Complete remission is usually achieved in 16-24 weeks. With poor tolerance of the recommended dose, treatment can be continued at a lower dose, but longer. In most patients, acne completely disappears after a single course of treatment.
In relapse, a second course of treatment is possible in the same daily and cumulative dose. A second course is prescribed no earlier than 8 weeks after the first, since the improvement may be delayed.
In severe chronic renal failure, the initial dose should be reduced to 8 mg / day.
Side effects of
Most side effects are dose dependent. Usually, side effects are reversible after dose adjustment or drug withdrawal, but some may persist after treatment is discontinued. Symptoms associated with hypervitampnosis A: dry skin, mucous membranes, including lips (cheilitis), nasal cavity (bleeding), larynx and pharynx (hoarseness of voice), eye (conjunctivitis, reversible clouding of the cornea and intolerance to contact lenses).
Skin and its appendages: peeling of the skin of the palms and soles, rash, itching, erythema of the face / dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased proliferation of granulation tissue, persistent thinning of hair, reversible hair loss, fulminant forms of acne, hyperi , photosensitivity, mild skin trauma. At the beginning of treatment, exacerbation of acne may occur, lasting several weeks.
Musculoskeletal system: muscle pain with increased levels of CPK in the serum or without it, joint pain, hyperostosis, arthritis, calcification of ligaments and tendons, tendonitis.
Central nervous system and mental sphere: excessive fatigue, headache, increased intracranial pressure ( pseudotumor of the brain : headache, nausea, vomiting, blurred vision, swelling of the optic nerve), convulsive seizures, rarely depression, psychosis, suicidal thoughts. Sensory organs: xerophthalmia, individual cases of visual acuity disturbance, photophobia, impaired dark adaptation (diminished twilight visual acuity), rarely – color perception disorder (after drug withdrawal), lenticular cataract, keratitis, blepharitis, conjunctivitis, eye irritation, optic neuritis, swelling of the optic nerve (as a manifestation of intracranial hypertension) hearing impairment at certain sound frequencies, difficulty wearing contact lenses.
Gastrointestinal tract: dry oral mucosa, gum bleeding, gum disease, nausea, diarrhea, inflammatory bowel diseases (colitis, ileitis), bleeding pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg / dl). Rare cases of pancreatitis with a fatal outcome are described. Transient and reversible increase in hepatic transaminase activity, individual cases of hepatitis. 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 was necessary to reduce the dose or cancel Aknekutan.
Respiratory organs: rarely – bronchospasm (more often in patients with a history of bronchial asthma).
Blood system: anemia, decreased hematocrit, leukopenia, neutropenia, increased or decreased platelet count, accelerated ESR.
Laboratory indicators: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, a decrease in the level of high density lipoproteins, rarely hyperglycemia. During the administration of Aknekutan, cases of newly diagnosed diabetes were recorded. In some patients, especially those involved in intense physical activity, individual cases of increased activity of CPK in serum are described.
Immune system: 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, underdevelopment of the cranial nerves, microphthalmia, malformations of the CVS, parathyroid glands, skeletal malformations – underdevelopment of the finger phalanges, skull, cervical vertebrae, femur, ankles, bones of the forearm, facial skull, cleft palate, low location of the auricles, underdevelopment of the auricles, underdevelopment or complete absence of the external auditory meatus, hernia of the brain and spinal cord, bone adhesions, joint of fingers and toes , disorders of the development of the thymus gland, fetal death in the perinatal period, premature birth, miscarriage), premature closure of the pineal gland in the animal experiment – pheochromocytoma.
Drug Interactions
Antibiotics of the tetracycline series, GCS reduce effectiveness. Simultaneous use with drugs that increase photosensitivity (including sulfonamides, tetracyclines, thiazide diuretics) increases the risk of sunburn.
Concomitant use with other retinoids (including acitretin, tretinoin, retinol, tazarotene, adapalene) increases the risk of hypervitaminosis A.
Isotretinoin can weaken the effectiveness of progesterone preparations, therefore, contraceptives containing small doses of progesterone should not be used.
Concomitant use with topical keratolytic drugs for the treatment of acne is not recommended because of the possible increase in local irritation. Since tetracyclines increase the risk of increased intracranial pressure, simultaneous use with isotretinoin is contraindicated.
Overdose
In the event of an overdose, signs of hypervitaminosis A. may occur. In the first few hours after an overdose, gastric lavage may be necessary.
Storage conditions
Keep dry, protected from light, out of reach of children at a temperature not exceeding 25 ° C.
Shelf life
2 years. Do not use after expiration date.
Deystvuyushtee substance
Isotretinoin
Pharmacy terms Pharmacies
prescription
dosage form
capsules
Prescribing
Prescribing
For children prescribed by a doctor, For children over 12 years old, For adults as prescribed by the doctor
Jadran-Galensky Laboratories a.o., Croatia
