Roakkutan

General characteristics. Structure:

One capsule of 10 mg contains:
Active agent: изотретиноин — 10 mg;

Excipients: soybeans oil — 107.92 mg, yellow beeswax — 7.68 mg, soybeans the oil hydrogenated — 7.68 mg, soybeans the oil which is partially hydrogenated — 30.72 mg;

Capsule cover: глицерол 85% — 31.275 mg, gelatin — 75.64 mg, Karionum 83 (the potato starch hydrolyzed Mannitolum, sorbitol) — 8.065 mg, dye ferrous oxide red (E172) — 0.185 mg, titanium dioxide (E171) — 1.185 mg;
ink for drawing a text on the capsule: shellac, dye ferrous oxide black (E172); use of ready Opacode Black S-1-27794 ink is allowed.

One capsule of 20 mg contains:
Active agent: изотретиноин — 20 mg;

Excipients: soybeans oil — 215.84 mg, yellow beeswax — 15.36 mg, soybeans the oil hydrogenated — 15.36 mg, soybeans the oil which is partially hydrogenated — 61.44 mg;

Capsule cover: глицерол 85% — 49.835 mg, gelatin — 120.66 mg, Karionum 83 (the potato starch hydrolyzed Mannitolum, sorbitol) — 12.86 mg, dye ferrous oxide red (E172) — 0.145 mg, titanium dioxide (E171) — 1.97 mg;
ink for drawing a text on the capsule: shellac, dye ferrous oxide black (E172); use of ready Opacode Black S-1-27794 ink is allowed.

Pharmacological properties:

Retinoid for system therapy of an acne disease
Izotretinoin — stereoisomer of completely transretinoic acid (tretinoin).
The exact mechanism of effect of the drug Roakkutan® is not found out 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. Besides, antiinflammatory action of an izotretinoin on skin is proved.
The hyperkeratosis of cells of an epithelium of a hair bulb and sebaceous gland leads to exfoliating of korneotsit to the canal of gland and to obstruction of the last a keratin and surplus of a grease secret. It is followed by formation of a comedone and, in some cases, accession of inflammatory process. Роаккутан® suppresses proliferation of sebotsit and affects an acne, recovering normal process of a differentiation of cells. Skin fat — the main substrate for Propionibacterium acnes growth therefore reduction of formation of skin fat suppresses bacterial colonization of a channel.

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.

Absorption. Absorption of an izotretinoin from digestive tract fluctuates. Absolute bioavailability of an izotretinoin was not defined as there is no form of production of drug for intravenous use for the person. However extrapolation of the data obtained in an experiment on dogs allows to assume quite low and variable system bioavailability. At patients with an acne the maximum concentration in plasma (Smaks) 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 are about 1.7 times higher than concentration in blood, owing to bad penetration of an izotretinoin into erythrocytes.
Reception of an izotretinoin with food increases bioavailability twice in comparison with reception on an empty stomach.

Distribution. Izotretinoin in strong degree (99.9%) contacts proteins of plasma, mainly albumine so with the broad range of therapeutic concentration contents free (pharmacological active) fractions of drug makes less than 0.1% of its total quantity.
The volume of distribution of an izotretinoin at the person was not defined as the dosage form for intravenous administration does not exist.
Equilibrium concentration of an izotretinoin in blood (Smin ss) at the patients with heavy acnes accepting 40 mg of drug 2 times a day fluctuated from 120 to 200 ng/ml.
Concentration 4-oxo-izotretinoina at these patients by 2.5 times exceeded those an izotretinoin. The person has not enough data on penetration of an izotretinoin into fabrics. Concentration of an izotretinoin in epidermis are twice lower, than in serum.

Metabolism. After intake in plasma three main metabolites are found: 4-oxo-izotretinoin, третиноин (completely transretinoic acid) and 4-oxo-retinoin. The main metabolite is 4-oxo-izotretinoin, plasma concentration of which in an equilibrium state 2.5 times higher, than concentration of initial drug. Also less significant metabolites including also glucuronides are found, however the structure not of all metabolites is established.
Metabolites of an izotretinoin have the biological activity confirmed in several laboratory tests. Thus, clinical effects of drug at patients can be result of pharmacological activity of an izotretinoin and its metabolites.
As in vivo изотретиноин and третиноин (completely transretinoic acid) 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.
Researches of metabolism in vitro showed that several enzymes of system of P450 (CYP) cytochrome participate in transformation of an izotretinoin in 4-oxo-izotretinoin and третиноин. To Povidimy, any of isoforms at the same time does not play the dominating role. Роаккутан® and its metabolites have no significant effect on activity of enzymes of the CYP system.

Removal. After intake it is radioactive a marked izotretinoin in urine and Calais is found approximately identical quantity. The elimination half-life of a terminal phase for not changed drug at patients with an acne averages 19 hours. The elimination half-life of a terminal phase for 4-oxo-izotretinoina, povidimy, more also equals on average to 29 hours.
Izotretinoin treats natural (physiological) retinoids. Endogenous concentration of retinoids are recovered approximately in 2 weeks after the end of administration of drug Roakkutan®.

Pharmacokinetics in special clinical cases. As изотретиноин it is contraindicated at an abnormal liver function, data on drug pharmacokinetics at this group of patients are limited.
The renal failure does not influence pharmacokinetics of an izotretinoin.

Indications to use:

Severe forms 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.

Route of administration and doses:

Standard mode of dosing
Inside, during food one or twice a day.
The therapeutic effectiveness of the drug Roakkutan® and its side effects depend on a dose and vary at different patients. It dictates need of individual selection of a dose during treatment.
Treatment it is necessary to begin with the drug Roakkutan® with a dose 0.5 mg/kg a day. At most of patients the dose fluctuates from 0.5 to 1.0 mg/kg of body weight a day. Or with an acne of a trunk higher daily doses — to 2.0 mg/kg can be required by patients with very severe forms of a disease. It is proved that the frequency of remission and prevention of a recurrence are optimum when using a course dose of 120-150 mg/kg (on a course of treatment) therefore therapy duration at specific patients changes depending on a daily dose. Full remission of an acne often manages to be achieved in 16-24 weeks of treatment. At the patients who are very badly transferring the recommended dose, treatment can be continued in a smaller dose, however to carry out it longer.
At the majority of sick acnes completely disappear after a single course of treatment. At an explicit recurrence the repeated course of treatment by the drug Roakkutan® in the same daily and course dose, as well as the first is shown. As improvement can continue up to 8 weeks after drug withdrawal, it is necessary to appoint a repeated course not earlier than the termination of this term.

Dosing in special cases
At patients with a heavy renal failure treatment should be begun with a smaller dose (for example, 10 mg/days) and further to increase up to 1 mg/kg/days or the most transferable (but no more maximum daily dose of 1 mg/kg). The daily dose should be rounded down to the closest smaller number of the whole capsules.

Features of use:

Роаккутан® only doctors, preferably the dermatologists having experience of use of system retinoids and aware of risk of teratogenecity of drug have to appoint. To patients both women's, and a male it is necessary to issue the copy of the brochure with information for the patient.
In order to avoid accidental impact of drug on an organism of other people, at patients who receive or shortly before it (1 month) Roakkutan® received, it is impossible to take donor blood.
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 activity of hepatic transaminases exceeds norm, it is necessary to reduce a dose of drug or to cancel it.
It is necessary to determine also concentration 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 concentration 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 of Roakkutan® it is necessary to cancel.
In rare instances at the patients receiving Roakkutan® the depression, psychotic symptomatology are described and it is very rare — suicide attempts and a suicide. 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 drug withdrawal of Roakkutan® 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.
In several years after use of the drug Roakkutan® for treatment of dyskeratoses at the general course dose and duration of therapy, above the acnes recommended for therapy, bone changes, including premature closing of epiphyseal regions of growth, a hyperostosis, calcification of sheaves and sinews developed. Therefore at purpose of drug to any patient, it is necessary to estimate previously carefully a ratio of possible advantage and risk.
The patients receiving Roakkutan® are recommended to use the moisturizing ointment or body cream, lip balm for reduction of a xeroderma and mucous at the beginning of therapy.
During post-marketing observation at use of the drug Roakkutan® cases of development of heavy skin reactions, such as a multiformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis are described. These phenomena can have serious character and lead to working capacity loss, life-threatening states, hospitalization or a fatal outcome. The patients receiving Roakkutan® need careful observation for the purpose of identification of heavy skin reactions and in need of the solution of a question of drug withdrawal.
Against the background of administration of drug of Roakkutan® muscle and joints pains, increase in activity of KFK 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 Roakkutan® and also within 5-6 months after the end of treatment because of a possibility of the strengthened scarring in atypical places and (more rare) than emergence hyper - and hypopigmentation. During treatment and within 6 months after it it is impossible to carry out by the drug Roakkutan® 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 twilight sight 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 twilight sight and 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 drug withdrawal of Roakkutan®. At intolerance of contact lenses for the period of therapy it is necessary to use points.
It is necessary to limit influence of solar and ultraviolet rays. If necessary it is necessary to use sunblock cream with high value of a protective factor not less than 15 SPF (sun protection factor).
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 Roakkutan® immediately.
At therapy by the drug Roakkutan® developing of an inflammatory disease of intestines is possible. At patients with the expressed hemorrhagic diarrhea it is necessary to cancel Roakkutan® immediately.
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 the drug Roakkutan® more frequent laboratory control of concentration 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.
Hit of medicines to the environment has to be minimized. Utilization of the drug Roakkutan® by means of sewage or together with household waste is not allowed. It is whenever possible necessary to use special systems for utilization of medicines.

Influence on ability to driving of vehicles and work with cars and mechanisms
During treatment it is necessary to observe extreme care at control of vehicles and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.
As at some patients decrease in sharpness of twilight sight 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 during the driving of the car and work with cars and mechanisms at night.

Side effects:

The majority of side effects of the drug Roakkutan® depend on a dose. As a rule, at purpose of the recommended doses a ratio of advantage and risk, considering disease severity, it is acceptable for the patient. 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), laryngopharynx (hoarseness of a voice), eyes (conjunctivitis, reversible opacification of a cornea and intolerance of contact lenses).
Skin and its appendages: 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, a photoallergy, an easy travmiruyemost of skin, a peeling of skin of palms and soles. In an initiation of treatment there can be an exacerbation of an acne remaining several weeks.
Musculoskeletal system: muscle pains with increase in activity of a kreatinfosfokinaza (KFK) in serum or without it, joint pains, a hyperostosis, arthritis, calcification of sheaves and sinews, reduction of density of a bone tissue, premature closing of epiphyseal regions of growth, other changes of bones, tendinites.
Central nervous system and mental sphere: behavior disorder, depression, suicide attempts, suicide, psychosis, excessive fatigue, headache, increase in intracranial pressure ("brain pseudoneoplasm": headache, nausea, vomiting, vision disorder, hypostasis of an optic nerve), spasms.
Sense bodys: visual acuity disturbance, a photophobia, disturbance of dark adaptation (decrease in sharpness of twilight sight), the disturbance of color perception (which is taking place after drug withdrawal), a lentikulyarny cataract, a keratitis, a blepharitis, conjunctivitis, irritation of eyes, a xerophthalmia, a hearing disorder at certain acoustical frequencys.
Digestive tract: nausea, diarrhea, inflammatory diseases of intestines (colitis, ileitis), bleedings, dryness of a mucous membrane of an oral cavity, odontorrhagia, inflammation of gums; pancreatitis (especially at the accompanying gipertriglitseridemiya it is higher than 800 mg/dl), including with a fatal outcome. Tranzitorny and reversible increase in activity of hepatic transaminases, 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 Roakkutan®.
Respiratory organs: 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, increase in the blood sedimentation rate (BSR).
Laboratory indicators: gipertriglitseridemiya, hypercholesterolemia, hyperuricemia, decrease in concentration of lipoproteins of high density, hyperglycemia. During administration of drug of Roakkutan® 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, dorsodynia.

Post-marketing observation
During post-marketing observation at use of the drug Roakkutan® cases of development of heavy skin reactions, such as a multiformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis are described (see also section "Special Instructions").
At drug Roakkutan® use, especially at the patients making intensive exercise stresses it was reported about the serious cases of a rabdomioliz which were often leading to hospitalization. These phenomena in all cases were safely resolved. Cases of development of a renal failure are not registered.

Interaction with other medicines:

Because of possible strengthening of symptoms of a hypervitaminosis And it is necessary to avoid co-administration of the drug Roakkutan® and vitamin A (Retinolum), and also other peroral retinoids.
As tetracyclines can also cause increase in intracranial pressure, their use in combination with the drug Roakkutan® is contraindicated.
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 or exfoliative drugs for treatment of an acne is contraindicated because of possible strengthening of local irritation.

Contraindications:

Pregnancy, the feeding period a breast (see the section "Pregnancy and Period of Breastfeeding"), a liver failure, a hypervitaminosis And, the expressed lipidemia, the accompanying therapy by tetracyclines.
Hypersensitivity to drug or its components (including to soy).
Children's age up to 12 years.

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

Pregnancy and period of breastfeeding
Pregnancy — an absolute contraindication for therapy by the drug Roakkutan®.
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.
Роаккутан® it is contraindicated to women of childbearing age if only the condition of the woman does not meet all following criteria:
- it has to have a severe form of an acne steady against usual methods of treatment;
- she has to understand and follow instructions of the doctor precisely;
- she has to be informed by the doctor on danger of approach of pregnancy during treatment by the drug Roakkutan® 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 the drug Roakkutan®, 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 with the drug Roakkutan® 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 the drug Roakkutan®, 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.

The doctor has to be sure that:
- the patient has 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 the drug Roakkutan®, 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.

Test for pregnancy
According to the existing practice, the test for pregnancy with the minimum sensitivity of 25 MME/ml should be carried 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 purpose of the drug Roakkutan® 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 the drug Roakkutan®.
During therapy:
The patient has to visit the doctor each 28 days. Need of monthly testing for pregnancy is defined according to local practice and with 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 Roakkutan® 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.
Delivery of the drug Roakkutan® in a drugstore should be carried out only within 7 days from the moment of a recipe extract.
To help doctors, to druggists and patients to avoid risk of impact of the drug Roakkutan® on a fruit, the manufacturing company created the "Program of protection from pregnancy" directed to the warning of teratogenecity of drug and underlining of absolutely obligatory use of reliable measures of contraception by women of childbearing age. The program contains the following materials:
for doctors:
- the management for the doctor to destination the drug Roakkutan® to women
- a form of the informed consent for the patient
- form of the accounting of purpose of drug to women
for the patient:
- the information brochure for the patient
- what it is necessary to know about contraception
for the druggist:
- the guide for the druggist to drug Roakkutan® issue.
The complete information about teratogenic risk and strict observance of measures for prevention of pregnancy needs to be provided both to men, and women.
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 Roakkutan® is not sufficient for emergence of teratogenic effects of the drug Roakkutan®.
Men should exclude a possibility of administration of drug by other persons, especially women.
If, despite the taken precautionary measures, during treatment by the drug Roakkutan® or within a month after its termination pregnancy nevertheless occurred, there is a high risk of very heavy malformations of a fruit (in particular, from the central nervous system, heart and large blood vessels). Besides, the risk of spontaneous abortions increases.
At pregnancy emergence therapy by the drug Roakkutan® is stopped. It is necessary to discuss expediency of its preservation with the doctor specializing in a teratology.
The heavy inborn malformations of a fruit at the person connected with purpose of the drug Roakkutan® including hydrocephaly, nanocephalia, malformations of a cerebellum, anomaly of an outside ear (microtia, narrowing or lack of outside acoustical pass), microphthalmia, cardiovascular anomalies (Fallo's tetrad, transposition of the main vessels, defects of partitions), malformations of the person (wolf mouth), a thymus, pathology of epithelial bodies are documented.
As изотретиноин has high lipophilicity, it is very probable that it gets to breast milk. Because of possible side effects of Roakkutan® nursing mothers cannot appoint.

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:

To store at a temperature not above 25 °C in the place protected from light and moisture.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules of 10 mg and 20 mg
On 10 capsules in the blister PVH/PE/PVDH/Al or PVH/PVDH/Al or PVC / Аl.
3 or 10 blisters together with the application instruction place in a cardboard pack.