Aknekutan

General characteristics. Structure:

Active ingredient: 8 mg or 16 mg of an izotretinoin.

Excipients: гелюцир® 50/13 (mix of ethers of stearic acid of poly(ethylene oxide) and glycerin), the purified soy oil, спан 80® (sorbitan oleate – mixed ethers of oleic acid and sorbite).

Structure of the capsule: case: gelatin, titanium dioxide (E171); cover: gelatin, titanium dioxide (E171), dye iron oxide yellow (E172), indigo carmine (E132).

Aknekutan - drug for system treatment of severe and resistant forms of an acne disease (acne).

Pharmacological properties:

Pharmacodynamics. Izotretinoin – stereoisomer of completely transretinoic acid (tretinoin). The exact mechanism of action of an izotretinoin is not revealed yet, however is established that improvement of a clinical picture of severe forms of an acne is connected with suppression of activity of sebaceous glands and histologically the confirmed reduction of their sizes. Skin fat - the main substrate for Propionibacterium acnes growth therefore reduction of formation of skin fat suppresses bacterial colonization of a channel.

Aknekutan suppresses proliferation of sebotsit and acts on an acne, recovering normal process of a differentiation of cells, stimulates regeneration processes. Besides, antiinflammatory action of an izotretinoin on skin is proved.

Pharmacokinetics. As the kinetics of an izotretinoin and its metabolites has linear character, its concentration in plasma during therapy can be predicted on the basis of the data obtained after one-time reception. This property of drug also says that it does not influence activity of the liver enzymes participating in metabolism of medicines.

High bioavailability of Aknekutan is caused by a big share of the dissolved izotretinoin in drug, and can increase on condition of administration of drug with food.

At patients with an acne the maximum concentration in plasma (Cmax) in an equilibrium state after reception of 80 mg of an izotretinoin on an empty stomach made 310 ng/ml (range of 188-473 ng/ml) and were reached in 2-4 hours. Concentration of an izotretinoin in plasma is 1.7 times higher, than in blood, owing to bad penetration of an izotretinoin into erythrocytes. Communication with proteins of plasma (it is preferential with albumine) – 99,9%.

Equilibrium concentration of an izotretinoin in blood (Css) at patients with severe forms of the acne accepting 40 mg of drug 2 times a day fluctuated from 120 to 200 ng/ml. Concentration 4-oxo-izotretinoina (the main metabolite) at these patients by 2,5 times exceeded those an izotretinoin.

Concentration of an izotretinoin in epidermis is twice lower, than in serum. It Ketabolizirutsya with formation of 3 main biologically active metabolites - 4-oxo-izotretinoina (main), a tretinoina (completely transretinoic acid) and 4-oxo-retinoina, and also less significant metabolites including also glucuronides. As in vivo изотретиноин and третиноин reversibly turn each other, metabolism of a tretinoin is connected with metabolism of an izotretinoin. 20-30% of a dose of an izotretinoin are metabolized by an isomerization. In pharmacokinetics of an izotretinoin at the person enterogepatichesky circulation can play an essential role.

The researches in vitro showed that several CYP enzymes participate in transformation of an izotretinoin in 4-oxo-izotretinoin and третиноин. At the same time any of isoforms, most likely, does not play the dominating role. Izotretinoin and his metabolites have no significant effect on activity of CYP enzymes.

Elimination half-life of a terminal phase for an izotretinoin on average 19 hours. An elimination half-life of a terminal phase for 4-oxo-izotretinoina on average 29 hours.

Izotretinoin is brought by kidneys and with bile approximately in equal quantities.
Treats natural (physiological) retinoids. Endogenous concentration of retinoids are recovered approximately in 2 weeks after the end of administration of drug.

Pharmacokinetics in special clinical cases. As data on drug pharmacokinetics at patients with an abnormal liver function are limited, изотретиноин is contraindicated at this group of patients.

The renal failure easy and moderate severity does not influence pharmacokinetics of an izotretinoin.

Indications to use:

Severe forms of an acne (узелково – cystous, konglobatny, an acne with risk of formation of hems). The acnes which are not giving in to other types of therapy.

Route of administration and doses:

Inside, it is desirable during food, 1-2 times a day. The therapeutic effectiveness of Aknekutan and his side effects depend on a dose and vary at different patients. It does necessary individual selection of a dose during treatment.

Initial dose of Aknekutan – 0,4 mg/kg a day, in certain cases to 0,8 mg/kg a day. At severe forms of a disease or with an acne of a trunk the dose to 2 mg/kg a day can be required. An optimum course cumulative dose – 100-120 mg/kg. Full remission is reached usually in 16-24 weeks. At bad portability of the recommended dose treatment can be continued in a smaller dose, but is longer.

At the majority of sick acnes completely disappear after a single course of treatment. At a recurrence carrying out a repeated course of treatment in the same daily and cumulative dose is possible. The repeated course is appointed not earlier than 8 weeks after the first as improvement can have the delayed character.

At a heavy chronic renal failure the initial dose has to be reduced to 8 mg/days.

Features of use:

It is recommended to control function of a liver and liver enzymes before treatment, in 1 month after its beginning, and then each 3 months or according to indications. Passing and reversible increase in hepatic transaminases, in most cases within normal values is noted. If the level of hepatic transaminases exceeds norm, it is necessary to reduce a dose of drug or to cancel it. It is necessary to determine also the level of lipids in serum on an empty stomach before treatment, in 1 month after the beginning, and then each 3 months or by indications. Usually concentration of lipids are normalized after reduction of a dose or drug withdrawal, and also at observance of a diet. It is necessary to control clinically significant increase in level of triglycerides as their rise over 800 mg/dl or 9 mmol/l can be followed by development of acute pancreatitis, it is possible with a lethal outcome.

At a resistant gipertriglitseridemiya or symptoms of pancreatitis Aknekutan it is necessary to cancel. In rare instances at the patients receiving Aknekutan the depression, psychotic symptomatology are described and it is very rare - suicide attempts. Though their causal relationship using drug is not established, it is necessary to observe extra care at patients with a depression in the anamnesis and to observe all patients regarding developing of a depression during treatment by drug, if necessary directing them to the corresponding specialist. However Aknekutan's cancellation can not lead to disappearance of symptoms and further observation and treatment at the specialist can be required.

In rare instances at the beginning of therapy the exacerbation of an acne which passes within 7-10 days without drug dose adjustment is noted.

At purpose of drug any patient should estimate previously carefully a ratio of possible advantage and risk.

The patients receiving Aknekutan are recommended to use the moisturizing ointment or body cream, lip balm for reduction of a xeroderma and mucous at the beginning of therapy. Against the background of Aknekutan's reception muscle and joints pains, increase in a kreatininfosfokinaza of blood serum which can be followed by decrease in portability of an intensive exercise stress are possible.

It is necessary to avoid carrying out a deep chemical dermoabraziya and treatment by the laser at the patients receiving Aknekutan and also within 5-6 months after the end of treatment because of a possibility of the strengthened scarring in atypical places and emergence hyper - and hypopigmentation. During treatment by Aknekutan and within 6 months after it it is impossible to carry out an epilation by means of applications of wax because of risk of amotio of epidermis, development of hems and dermatitis. As at some patients decrease in sharpness of a scotopia which sometimes remains also after the end of therapy can be observed, patients should be informed on a possibility of this state, recommending to them to be careful when driving the car at night.

The condition of visual acuity needs to be controlled carefully. Dryness of a conjunctiva of eyes, opacifications of a cornea, deterioration in a scotopia and a keratitis usually pass after drug withdrawal. At dryness of a mucous membrane of eyes it is possible to use applications of the moistening oculentum or drug of an artificial tear. It is necessary to observe patients with dryness of a conjunctiva regarding possible development of a keratitis. The patients showing complaints to sight should be directed to the ophthalmologist and to consider a question of expediency of cancellation of Aknekutan. At intolerance of contact lenses for the period of therapy it is necessary to use points.

It is necessary to limit influence of solar insolation and UF-therapy. If necessary it is necessary to use sunblock cream with high value of a protective factor not less than 15 SPF.

Exceptional cases of development of benign intracranial hypertensia ("brain pseudoneoplasm") are described, including at the combined use with tetracyclines. At such patients it is necessary to cancel immediately Aknekutan.

At therapy by Aknekutan developing of an inflammatory disease of intestines is possible. At patients with the expressed hemorrhagic diarrhea it is necessary to cancel immediately Aknekutan. Exceptional cases of anaphylactic reactions which arose only after the previous external use of retinoids are described. Heavy allergic reactions dictate need of drug withdrawal and careful observation of the patient.

At treatment by Aknekutan more frequent laboratory control of level of glucose and lipids can be required by patients from group of high risk (with a diabetes mellitus, obesity, an alcoholism or disturbances of a lipometabolism). In the presence of diabetes or suspicion on it more frequent definition of a glycemia is recommended. The sick diabetes mellitus recommends to carry out more frequent control of content of glucose to blood.

During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions (at reception of the first dose).

During treatment and within 30 days after its termination pregnant patients (high risk of development of teratogenic and embriotoksichesky action) need to exclude completely blood sampling at potential donors for a complete elimination of a possibility of hit of this blood.

The doctor has to be sure that:
- the patient suffers from a severe form of an acne (nodular and cystous, konglobatny acnes or an acne with risk of formation of hems); the acnes which are not giving in to other types of therapy;
- the negative take of the authentic test for pregnancy prior to administration of drug is received, during therapy and in 5 weeks after the end of therapy; dates and results of test for pregnancy need to be documented;
- the patient uses not less than 1, preferably 2 effective methods of contraception, including a barrier method, within one month prior to treatment by Aknekutan, during treatment and within a month after its termination;
- the patient is capable to understand and fulfill all above-mentioned requirements for protection from pregnancy;
- the patient corresponds to all above-mentioned conditions.

The test for pregnancy In compliance with the existing practice, the test for pregnancy with the minimum sensitivity of 25 mME/ml it is necessary to carry out in the first 3 days of a menstrual cycle:
Prior to therapy:
• For an exception of possible pregnancy prior to contraception use the result and date of the initial test for pregnancy have to be registered by the doctor. At patients with irregular periods time of test for pregnancy depends on sexual activity, it should be seen off in 3 weeks after the unprotected sexual intercourse. The doctor has to inform the patient on contraception methods.
• The test for pregnancy is carried out in day of appointment of Aknekutan or in 3 days prior to the patient's visit to the doctor. The specialist should register results of testing. Drug can be appointed only to the patients receiving effective contraception not less than 1 month prior to therapy by Aknekutan.

During therapy:
• The patient has to visit the doctor each 28 days. Need of monthly testing for pregnancy decides in compliance on local practice and taking into account sexual activity, the previous disturbances of a menstrual cycle. In the presence of indications the test for pregnancy is carried out in day of a visit or three days before the visit to the doctor, test results have to be registered.

End of therapy:
• In 5 weeks after the end of therapy the test for a pregnancy exception is carried out.

The recipe on Aknekutan to the woman capable to a child-bearing, can be written out only for 30 days of treatment, continuation of therapy demands new purpose of drug the doctor. It is recommended to carry out the test for pregnancy, an extract of the recipe and receiving drug in one day. If, despite the taken precautionary measures, during treatment by Aknekutan or within a month after its termination, pregnancy nevertheless occurred, there is a high risk of very heavy malformations of a fruit.

At pregnancy emergence therapy by Aknekutan is stopped. It is necessary to discuss expediency of preservation of pregnancy with the doctor specializing in a teratology. As изотретиноин has high lipophilicity, it is very probable that it gets to breast milk. Because of possible side effects Aknekutan nursing mothers cannot appoint.

To male patients. The existing data demonstrate that women have an exposure of the drug which arrived from a seed and semen of the men accepting Aknekutan is not sufficient for emergence of teratogenic effects of Aknekutan. Men should exclude a possibility of administration of drug by other persons, especially women

Side effects:

The majority of side effects depend on a dose. Usually side effects have reversible character after dose adjustment or drug withdrawal, but some can remain after the treatment termination.

The symptoms connected with a hypervitaminosis And: xeroderma, mucous membranes, including lips (cheilitis), nasal cavity (bleeding), throat and throat (hoarseness of a voice), eyes (conjunctivitis, reversible opacification of a cornea and intolerance of contact lenses).

Skin and its appendages: a peeling of skin of palms and soles, rash, an itch, an erythema face/dermatitis, perspiration, a piogenic granuloma, paronychias, onikhodistrofiya, the strengthened growth of granulyatsionny fabric, permanent thinning of hair, a reversible hair loss, fulminantny forms of an acne, a hirsutism, a hyperpegmentation, a photosensitization, an easy travmiruyemost of skin. In an initiation of treatment there can be an exacerbation of an acne remaining several weeks.

Musculoskeletal system: muscle pains with increase in the KFK level in serum or without it, joint pains, a hyperostosis, arthritis, calcification of sheaves and sinews, tendinites.

Central nervous system and mental sphere: excessive fatigue, headache, increase in intracranial pressure ("brain pseudoneoplasm": a headache, nausea, vomiting, a vision disorder, hypostasis of an optic nerve), convulsive attacks, it is rare - a depression, psychosis, suicide thoughts.

Sense bodys: a xerophthalmia, separate cases of disturbance of visual acuity, a photophobia, disturbance of dark adaptation (decrease in sharpness of twilight sight), it is rare – the disturbance of color perception (which is taking place after drug withdrawal), a lentikulyarny cataract, a keratitis, a blepharitis, conjunctivitis, irritation of eyes, an optic neuritis, hypostasis of an optic nerve (as display of intracranial hypertensia); a hearing disorder at certain acoustical frequencys, difficulties when carrying contact lenses.

Digestive tract: dryness of a mucous membrane of an oral cavity, odontorrhagia, inflammation of gums, nausea, diarrhea, inflammatory diseases of intestines (colitis, ileitis), bleedings; pancreatitis (especially at the accompanying gipertriglitseridemiya it is higher than 800 mg/dl). Exceptional cases of pancreatitis with a lethal outcome are described. Tranzitorny and reversible increase in activity of hepatic transaminases, separate cases of hepatitis. In many these cases of change did not overstep the bounds of norm and were returned to initial indicators in the course of treatment, however in some situations there was a need to reduce a dose or to cancel Aknekutan.

Respiratory organs: seldom - a bronchospasm (is more often at patients with bronchial asthma in the anamnesis).

System of blood: anemia, decrease in a hematocrit, leukopenia, neutropenia, increase or reduction of number of thrombocytes, acceleration of SOE.

Laboratory indicators: a gipertriglitseridemiya, a hypercholesterolemia, a hyperuricemia, decrease in level of lipoproteins of high density, it is rare – a hyperglycemia. During Aknekutan's reception cases for the first time of the revealed diabetes mellitus were registered. At some patients who are especially engaged in an intensive exercise stress separate cases of increase in activity of KFK in serum are described.

Immune system: the local or system infections caused by gram-positive activators (Staphylococcus aureus).

Other: lymphadenopathy, hamaturia, proteinuria, vasculitis (Wegener's granulomatosis, allergic vasculitis), system reactions of hypersensitivity, glomerulonephritis.

Teratogenic and embriotoksichesky effects: inborn uglinesses – gidro-and a nanocephalia, an underdevelopment of cranial nerves, a microphthalmia, malformations of CCC, epithelial bodies, disturbance of formation of a skeleton - an underdevelopment of manual phalanxes, skulls, cervical vertebrae, a femur, anklebones, bones of a forearm, a facial skull, a wolf mouth, a low arrangement of auricles, an underdevelopment of auricles, an underdevelopment or total absence of outside acoustical pass, hernia of a head and spinal cord, bone unions, an union of fingers of hands and legs, disturbances of development of a thymus; death of a fruit during the perinatal period, premature births, abortions), premature closing of epiphyseal regions of growth; in an experiment on animals - a pheochromocytoma.

Interaction with other medicines:

Antibiotics of a tetracycline row, GKS reduce efficiency.

Simultaneous use with the drugs increasing photosensitivity (including sulfonamides, tetracyclines, thiazide diuretics) increases risk of emergence of sunblisters.

Simultaneous use with other retinoids (including atsitretiny, tretinoiny, Retinolum, tazaroteny, adapaleny) increases risk of emergence of a hypervitaminosis A. Izotretinoin can weaken efficiency of drugs of progesterone therefore it is not necessary to use the contraceptive means containing small doses of progesterone.

The combined use with local keratolytic drugs for treatment of an acne is not recommended because of possible strengthening of local irritation.

As tetracyclines increase risk of increase in intracranial pressure, simultaneous use with izotretinoiny is contraindicated.

Contraindications:

The pregnancy established and planned (perhaps teratogenic and embriotoksichesky action), the feeding period a breast, a liver failure, A hypervitaminosis, the expressed lipidemia, the accompanying therapy by tetracyclines. Hypersensitivity to drug or its components. Aknekutan is not recommended to use to children up to 12 years.

With care. A diabetes mellitus, a depression in the anamnesis, obesity, disturbance of lipidic exchange, alcoholism.

Pregnancy – an absolute contraindication for therapy by Aknekutan. If pregnancy arises, despite cautions, during treatment or within a month after the end of therapy, there is very big danger of the birth of the child with heavy malformations.

Izotretinoin - drug with strong teratogenic action. If pregnancy arises during this period when the woman orally accepts изотретиноин (in any dose and even short time), there is very big danger of the birth of the child with malformations. Aknekutan is contraindicated to women of childbearing age if only the condition of the woman does not meet all following criteria:

- she has to suffer from a severe form of an acne steady against usual methods of treatment;
- she has to understand and follow instructions of the doctor for certain;
- she has to be informed by the doctor on danger of approach of pregnancy during treatment by Aknekutan, within one month after it and urgent consultation at suspicion on pregnancy approach;
- she has to be warned about possible inefficiency of contraceptives; - she has to confirm that she understands an essence of precautionary measures;
- she has to understand need and continuously use effective methods of contraception within one month before treatment by Aknekutan, during treatment and within a month after its termination (see the section "Interaction with Other Medicines"); it is desirable to use at the same time 2 various ways of contraception, including barrier;
- at it the negative take of the authentic test for pregnancy within 11 days prior to administration of drug has to be received; the test for pregnancy is strongly recommended to be carried out monthly to time of treatment and in 5 weeks after the end of therapy;
- it has to begin treatment by Aknekutan only for 2-3 day of the following normal menstrual cycle;
- she has to understand need of obligatory visit of the doctor every month;
- at treatment concerning a disease recurrence it has to use constantly the same effective methods of contraception within one month prior to treatment by Aknekutan, during treatment and within a month after its end, and also take the same authentic test for pregnancy;
- she has to understand completely need of precautionary measures and confirm the understanding and desire to apply reliable methods of contraception which to her were explained by the doctor.

Use of contraceptives according to the above-stated instructions during treatment izotretinoiny should be recommended even to those women who usually do not apply contraception methods because of infertility (except for the patients who transferred a hysterectomy), amenorrheas or who report that they have no sex.

Overdose:

In case of overdose signs of a hypervitaminosis of A. V after overdose can appear the first several hours the gastric lavage can be necessary.

Storage conditions:

In dry, protected from light, the place, unavailable to children, at a temperature not over 25 ºС. Period of validity 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Capsules of 8 mg and 16 mg. On 10 or 14 capsules in PVC the blister covered with aluminum foil.

Blisters-10-N2, N3, N5, N6, N9, N10; blisters-14-N1, N2, N4, N7 in a cardboard pack together with the application instruction.