Tretinoin

Третиноин Drug photo

The description is actual on 05.08.2014

  • Latin name: Tretinoinum
  • ATH code: L01XX14
  • Active ingredient: Tretinoin (Tretinoinum)
  • Producer: Hoffmann la Roche, Switzerland; Pierre Fabre Medicament, France; Janssen-Silag (Johnson&Johnson Corporation), India; Pierre Fabre Italia S.p.A., Italy.

Structure

Tretinoin (transretinovy acid) is active agent represents crystal powder with the expressed flower smell. Substance is well soluble in a dimethyl sulfoxide, 100% alcohol (ethanol) are hardly dissolved in polyethyleneglycol, octanol also, it is almost not soluble in water (the solubility indicator at a temperature equal of 25 °C, makes 0,126 mg/l), mineral oils and glycerin. Color of powder can vary from yellow to light orange.

Release form

Tretinoin is issued in a look:

  • lotions with concentration of active agent of 0,05%;
  • gel with concentration of active agent of 0,025%, 0,05% or 0,1%;
  • cream with concentration of active agent of 0,05% or 0,1%);
  • solution for external use with concentration of active agent of 0,1%;
  • capsules for oral administration (content of active agent in each capsule makes 10 mg).

Pharmacological action

Substance Tretinoin belongs to groups "Other Protipoopukholevy Medicines", "Dermatotropic Means", and also to "Vitamins and Vitaminopodobny Drugs" group.

Influencing an organism, it provokes:

  • antineoplastic;
  • keratolytic;
  • antiseborrheal;
  • komedonoliticheskiya;
  • immunostimulating;
  • stimulating an angenesis;
  • local antiinflammatory effect.

Also Tretinoin is used as means for treatment of vulgar eels and as provitamin A.

Pharmacodynamics and pharmacokinetics

Tretinoin refer to category of system retinoids which are inductors of cellular differentiation. On the structure it is similar to vitamin A and represents Retinolum metabolization product.

Substance promotes induction of processes of cellular differentiation, slowing down at the same time proliferation of promyelocytes (predecessors of granulocytes) which is caused by change of linkng of transretinovy acid with receptors of cellular kernels of retinoic acid (including at a myeloleukemia).

Under the influence of Tretinoin initial maturing of the primitive promyelocytes coming from a leukemic clone, and also processes of their substitution in marrow and peripheral blood not transformed normal hemopoietic polyclonal cells becomes more active.

On this background at the patient remission of a disease which averages from two to four months develops.

At topical administration Tretinoin is capable to get through membranes of cells, forming at the same time the cytoplasmatic complex coming to cellular kernels. The hormone which is formed at the same time - a receptor complex possesses ability to contact DNA and to interfere with process of a transcription, thereby breaking protein biosynthesis (hypopigmental action of Tretinoin is based on these processes).

Substance has a promoting effect on a mitosis of cells of an epidermal layer of skin, promotes increase in amount of mucopolysaccharides and the elastic fibers formed by protein elastin which are in a papillary layer of skin.

Besides, Tretinoin:

  • suppresses process of formation of melanin;
  • stimulates growth and differentiation of cells of an epithelium;
  • suppresses adhesion of cells which are formed by eels;
  • when drawing on open eels levels epidermis, without leaving at the same time inflammation signs;
  • when drawing on the closed eels promotes their opening or transformation in papular small knots and to further healing without formation of hems after removal from them a keratinaceous stopper;
  • interferes with formation of new acne rashes.

Keratolytic action of Tretinoin consists in elimination of the phenomena of a keratosis. Its mechanism is caused by suppression of proliferation of keratinotsit and improvement of processes of their peeling.

Antiseborrheal action is caused by braking of proliferation of cells of epidermis, oppression of growth of epithelial fabric of the removing channels of sebaceous glands, decrease in production of skin fat and normalization of processes of its evacuation, reduction of expressiveness of inflammatory reaction around sebaceous glands, and also stimulation of processes of regeneration of skin.

Komedonolitichesky and local antiinflammatory action narrowings of a time and elimination of signs of inflammatory process are expressed as absorption of excess quantity of a grease secret, oppression of processes of its development by sebaceous glands.

The noticeable therapeutic effect of Tretinoin's use is noted about one and a half months later after the beginning of use of drug (as a rule, on the 6 or 7 week). The maximum effect is noted 8-12 weeks of its use later.

Transretinovy acid represents an endogenous metabolite of vitamin A which normal is always present at a blood plasma of the person. After oral administration substance is well absorbed in a stomach and intestines, its maximum concentration in a blood plasma is noted in three hours.

Indicators of absorption of Tretinoin can vary, and both at different groups of patients, and at each separately taken patient. Substance is capable to contact substantially proteins in a blood plasma (mainly with albumine). The indicator of binding is in limits of 95%.

Duration of an elimination half-life averages 0,7 hours. After the single use of Tretinoin in the dose equal of 40 mg, its maximum concentration in a blood plasma returns to initial level approximately in 7-12 hours.

Drug does not collect in an organism and is not late in its various fabrics even after a multiple dose.

Transretinovy acid is characterized by ability to induce own metabolism that is expressed in decrease in an indicator of AUC and decrease in indicators of plasma concentration on average on a third a week later after continuous administration of drug. At the same time increase in a dose does not promote adequate increase in plasma concentration.

About 60% of Tretinoin in the form of metabolites which are formed in the course of oxidation and a glyukuronirovaniye eliminirutsya by kidneys within 3 days (72 hours). Partially metabolites are removed with intestines contents within from 3 to 6 days.

Repeated reception provokes decrease in concentration that cytochrome with - oxidases (P450 cytochrome) is caused by induction of fermental system. As a result of it the clearance increases and the indicator of bioavailability of substance after oral administration decreases.

If drug is used for cutaneous application, an indicator of absorption of Tretinoin vary ranging from 1,41-31%. First of all such parameters as exert impact on it:

  • general condition of integuments of the patient;
  • the area to the subject processing of a surface;
  • drug use duration.

After cutaneous application of 4,45% of the absorbed Tretinoin's dose about 1,6% — together with bile eliminirutsya by kidneys together with urine also.

Indications to use

Oral administration of Tretinoin is appointed to patients for whom the option of an acute myeloid leukosis which is characterized by abnormal accumulation of one of kinds of myeloid cells — promyelocytes is diagnosed.

And use of drug provokes induction of remission of a disease as at patients who did not receive medical treatment earlier, and at patients who transferred recurrence/recurrence of OPML (an acute form of a promiyelotsitarny leukosis) or are unreceptive to the standard chemotherapy which is carried out with use of a rubomitsin, Cytarabinum or their analogs.

After approach of full remission of a disease the consolidating chemotherapy in full doses is shown to patients.

The instruction of drug warns that at patients who take a course of a maintenance therapy with Tretinoin's use loss of reaction to treatment can be noted.

As outside means Tretinoin applies to treatment:

  • drain eels (that is eels who represent result of merge of several indurative eels who united among themselves by means of the deep courses);
  • vulgar eels who are followed by papulation (small knots), comedones (the traffic jams formed by skin fat in the mouth of hair sacks) or the pustules (filled with purulent contents of elements of rash);
  • Favra-Rakusho's diseases (colloid degeneration of skin which represents a dermatosis of not clear nature of an origin);
  • hyperpegmentations of skin.

Contraindications

Contraindications to Tretinoin's appointment in the form of capsules are:

  • the increased individual sensitivity to a tretinoin;
  • pregnancy (drug has teratogenic effect on a fruit, provoking serious violations of embryonic development);
  • feeding by a breast (if it is impossible to avoid purpose of drug, feeding it is necessary to stop).

External use is forbidden:

  • during pregnancy;
  • to people who have acute inflammatory defeats of an integument;
  • at eczema;
  • in the presence of wounds and burns;
  • at a skin epithelioma (including those cases when the disease was noted in the family anamnesis).

Side effects

At oral administration of drug approximately at a quarter of patients development of a so-called "syndrome of retinoic acid" which in the absence of appropriate treatment can become the reason of a lethal outcome is noted.

The main signs of "a syndrome of retinoic acid" are an asthma, a feverish condition, an acute respiratory distress syndrome, formation of infiltrates in lungs, a hyperleukocytosis (the increased maintenance of leukocytes at which the indicator of their concentration in blood exceeds 40-50 thousand in 1 cubic mm), hypotonia, pathological accumulation of liquid in a pleural cavity (a pleural exudate), hepatic, and also renal and multiorgan failure.

Treat other possible side reactions:

  • Skin reactions which are expressed as xerodermia symptoms (the increased dryness and a peeling of integuments), the increased dryness in a mouth, a cheilosis (inflammatory defeat of a red border of skin and lips), rashes, an itch, intradermal hemorrhages, increase of sweating, a hair loss (alopecia), emergence of cellulitis, increase of sensitivity of an organism to action of ultraviolet rays (photosensitization), emergence of blisters or a crust on skin, emergence of the temporary centers hyper - or hypopigmentation.
  • Dysfunctions of the alimentary system, including nausea, vomiting, pains in epigastric area, frustration of a chair (are possible both a lock, and diarrhea), development of violent stomatitis, increase of activity of desmoenzymes of a liver of ALT and nuclear heating plant (alanine and aspartatovy aminotransferases).
  • Dysfunctions of the central nervous system which are expressed as a depression, disturbance of consciousness, hearing and sight, emergence of dizzinesses, increase of level of uneasiness, increase of indicators of intracranial pressure.
  • Disturbances of the exchange processes which are expressed as increase of plasma concentration of cholesterol and triglycerides, and also as change of body weight.
  • Dysfunctions of respiratory system which are expressed as cough, an infection of upper and lower respiratory tracts, an asthma, dispnoe, flowings off mucous a nose and a throat, emergence of a pleural exudate and rattles in lungs, developments of pharyngitis and emergence of a stridor.
  • The disturbances from the musculoskeletal device which are expressed as muscular pains and ostealgias.
  • Disturbances from function of heart and vascular system which are expressed as arrhythmias.
  • Increase of bleeding.
  • Increase of weakness and drowsiness.
  • Development of consecutive infections.
  • Emergence of pains in a breast and a back.

Depending on degree of manifestation of side effects full refusal of treatment by drug or its temporary cancellation can be recommended to the patient.

Restrictions to appointment are:

  • children's age till one year at peroral appointment;
  • children's age till twelve years at Tretinoin's appointment as outside means;
  • lack of reliable contraception at the women who are in childbearing age;
  • renal failures;
  • abnormal liver functions;
  • the increased intracranial pressure;
  • the age is more senior than fifty years;
  • leukocytosis;
  • chronic intoxication (in particular, alcoholic beverages);
  • gipertriglitseridermiya;
  • hypercholesterolemia;
  • pancreatitis;
  • diabetes mellitus.

Cream Tretinoin: application instruction, way and mode of dosing

Drug is appointed only by the doctor who has experience with hematologic and oncological diseases.

The recommended daily dose for oral administration — 45 mg of Tretinoin on each square meter of integuments of a body surface for ninety days (or within thirty days after approach of full remission of a disease; treatment is supplemented with chemotherapy with use of drugs-tsitostatikov). The dose does not depend on age of the patient and is identical both for adult patients, and for elderly people, and for children.

Maximum permissible dose the daily dose equal to 195 mg of Tretinoin on each square meter of integuments of a body surface is considered. A maximum permissible children's daily dose — 60 mg of Tretinoin on each square meter of integuments of a body surface.

If the renal and/or liver failure is diagnosed for the patient, then it is recommended to reduce a daily dose to 25 mg of Tretinoin by each square meter of integuments of a body surface.

For patients with extensive tumors the daily dose makes the third part from the most admissible, for children — below most recommended, to destination the attending physician.

Two-four months later after the termination of a course of treatment by Tretinoin recurrence of a disease is possible.

At oral administration of drug for decrease in probability of development of "a syndrome of retinoic acid" at increase of concentration of leukocytes or emergence of this state, any of signs, to the patient appoint the full chemotherapy meaning introduction of cytostatic means in adequate doses.

As local means lotion, gel or cream Tretinoin apply on affected areas of skin with very thin layer once a day and leave on them within six hours. After this time drug needs to be washed away under flowing water.

A small amount of cream is squeezed out on a finger-cushion and evenly distributed on a face, since a forehead, a chin and a neck. Further pass to other affected areas.

Cream is rubbed the easy movements. At the same time it has to become invisible or, at least, hardly noticeable at once. If flaking of cream after its drying is noted or it is swept too up on an integument, it is the certificate that the dose is exceeded.

It is important to remember that the excess amount of cream is not guarantee of the best or faster result.

At the initial stages of a course of treatment Tretinoin no more than is recommended to apply to white-skinned people, and also people on half an hour with the raised xeroderma. Then gradual increase in duration of contact of skin with drug is allowed.

In the course of treatment it is also allowed to delete gradually ripened and completely softened comedones and pustules.

According to the instruction duration of a course of treatment can vary ranging from one-two weeks about three months. For prevention of emergence of acne rash Tretinoin put after a heat bath from one to three times within a day throughout a long interval of time.

Overdose

Effects of exceeding of the recommended Tretinoin's dose are the symptoms of "a syndrome of retinoic acid" described above.

In case of their emergence therapy in means passing of a course of treatment dexamethasone. It is necessary to administer the drug for three days, on 10 mg every twelve hours).

Interaction

Metabolization Tretinoina is carried out in a liver under the influence of enzymes of system cytochrome with - oxidases. For this reason combined use with drug of the medicines exerting impact on this fermental system can provoke change of pharmacokinetic parameters of Tretinoin.

Against simultaneous use of Tretinoin and contraceptives which basis is made by progesterone efficiency of the last significantly decreases.

The simultaneous use of Tretinoin with tetracyclines at patients can be noted increase of intracranial pressure.

The simultaneous use with drugs of vitamin A provokes development of symptoms of a hypervitaminosis.

Special instructions

Using creams, gels and lotions for external use, it is necessary to avoid hit of drug in eyes, in an oral cavity, nose corners, open wounds and on mucous membranes. If it occurred, it is necessary to wash away at once carefully Tretinoin water.

During passing of a course of treatment drug recommends to avoid stay on the sun. Those patients who managed to sunbathe should begin treatment after suntan weakens a little.

Over the damaged sites of skin it is necessary to put sun-protection means or to cover them with clothes. In a usage time of drugs of Tretinoin for external application it is not recommended to be found on wind or on cold.

In the first days of use by Tretinoin strengthening of acne rash is possible that is caused by impact of drug on the skin localized in deep layers eels who remained imperceptible prior to the beginning of a course of treatment.

At oral administration of drug by women of childbearing age (even if infertility is diagnosed for them) it is recommended to use reliable contraceptives. Their reception is begun at least a month before the beginning of therapy, continued throughout all course of treatment and then within a month after drug withdrawal.

Treatment is begun, as a rule, for the second or third day of a normal menstrual cycle. In two weeks prior to therapy laboratory confirmation that the woman is not pregnant has to be made. In the subsequent tests on definition of pregnancy are recommended to be made monthly.

If pregnancy comes during passing of a course of treatment by Tretinoin because of high teratogenecity of drug the risk of the birth of the child with uglinesses and other malformations is very high.

There is an insufficient amount of information concerning efficiency and safety of treatment of children by Tretinoin. Children who passed treatment by drug have, however, data on increase of toxic symptoms (in particular, cases of increase of intracranial pressure were noted). For this reason it is recommended to abstain from Tretinoin's use in pediatrics.

Treatment by drug can provoke disturbance of ability to steer vehicles and to work with potentially dangerous mechanisms and devices. It is caused by the fact that quite often Tretinoin's reception is followed by severe headaches and dizzinesses.

Drug in the form of cream is highly inflammable therefore during its use it is necessary to avoid naked flame and smoking.

At emergence of symptoms of strongly expressed irritation use of drug as outside means should be stopped.

In some cases incompatibility of drug with separate means for local use can be noted: soap (both usual, and medical), gels for washing, cosmetics etc.

It is also necessary to observe extra care, using in parallel with Tretinoin of drugs which contain sulfur, resorcin or salicylic acid.

Terms of sale

Tretinoin in the tableted form is released in drugstores strictly according to the recipe.

Drugs of a tretinoin for external use belong to the category of OTC medicines.

Storage conditions

Tretinoin is recommended to store in the dry, cool and well protected from hit of sunshine place. Admissible temperature — no more than 25 °C.

Period of validity

Drug is good for use within 3 years.

About Tretinoin

Drug deservedly has reputation of an effective remedy for problem skin. Numerous positive About cream Tretinoin demonstrate that at observance of all recommendations listed in the instruction acne rashes and spots almost completely disappear in two weeks of treatment.

However, according to responses of druggists, Tretinoin has a number of serious side effects. Having passed treatment by Tretinoin, at the patient there comes retinoidny dermatitis. It is normal and it is even good. Drug means begins to work! But at Tretinoin this dermatitis passes very sharply and can leave hems, and still this acting is not brought out of a liver. Use effects are still not investigated. Therefore in the Russian Federation Tretinoin is not resolved.

Section: Dermatological Others
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