Vesanoid

General characteristics. Structure:

Active ingredient: 10 mg of a tretinoin.

Excipients: soybeans oil, yellow beeswax, soybeans the oil hydrogenated soybeans the oil which is partially hydrogenated.

Capsule cover: глицерол 85%, gelatin, Karionum 83 (the potato starch hydrolyzed Mannitolum, sorbitol), titanium dioxide (E171), dye ferrous oxide yellow (E172), dye ferrous oxide red (E172).

Induction of remission at an acute promiyelotsitarny leukosis (OPML; classification by FAB-AML-M3). Vesanoid can be appointed earlier not to treated patients, patients with a recurrence or refractory to standard chemotherapy (a daunorubitsin and Cytarabinum or their analogs).

Pharmacological properties:

Pharmacodynamics. Tretinoin (completely transretinoic acid) is a natural metabolite of Retinolum and belongs to a class of retinoids which includes natural and synthetic analogs. Tretinoin induces differentiation and inhibits proliferation of the transformed hemogenesis cells, including at myeloleukemias at the person. The action mechanism at an acute promiyelotsitarny leukosis can consist in change of linkng of transretinoic acid with nuclear receptors of retinoic acid, and * - the receptor of retinoic acid also changes owing to merge to PML protein.

Pharmacokinetics. Tretinoin is an endogenous metabolite of vitamin A and usually is present at plasma. After oral administration третиноин it is well soaked up, and the maximum concentration in a blood plasma are reached in 3 hours. Absorption of a tretinoin is characterized by considerable variability at same and at different patients. Communication with proteins of plasma of a tretinoin high. After achievement of peak plasma concentration decreases, the average elimination half-life equals 0.7 hours. After a single dose of 40 mg of drug concentration in plasma is returned to endogenous level in 7-12 hours. At multiple dose of cumulation of a tretinoin does not occur, in fabrics drug is not late.

The main way of elimination (60%) is removal through kidneys in the form of the metabolites which are formed at oxidation and a glyukuronization. Tretinoin is isomerized in 13 - cis-retinoic acid and is oxidized to 4-oxo-metabolites. Metabolites have more long elimination half-life, than третиноин, and their accumulation in small amounts is possible.

At long reception concentration of drug in plasma can decrease considerably, perhaps, owing to induction of fermental system of P450 cytochrome that increases clearance and reduces bioavailability of drug after oral administration.

Indications to use:

Induction of remission at an acute promiyelotsitarny leukosis (OPML; classification by FAB-AML-M3). Vesanoid can be appointed earlier not to treated patients, patients with a recurrence or refractory to standard chemotherapy (a daunorubitsin and Cytarabinum or their analogs).

Route of administration and doses:

The daily dose makes 45 mg / кв.м body surfaces inside in two steps. For adults it equals to about 8 capsules. For children the same dose is recommended if there are no heavy toxic phenomena. The dose needs to be lowered if the child has expressed headaches.

It is necessary to continue treatment from 30 to 90 days, before achievement of full remission. After that it is necessary to pass immediately to the standard scheme of the consolidating chemotherapy, for example, three courses of a daunorubitsin and Cytarabinum with an interval of 5-6 weeks.

If remission occurred at monotherapy by Vesanoid, it is not necessary to change his dose at purpose of chemotherapy.

Dosing in special cases. Due to the lack of pharmacokinetic data of Vesanoid at patients with a renal and/or liver failure, it is necessary to reduce a drug dose for this category of patients to 25 mg/sq.m.

Features of use:

Vesanoid has to be appointed only to patients with an acute promiyelotsitarny leukosis under careful observation of the hematologist or oncologist.

Prevention of the syndrome of retinoic acid (SRA) at patients with the hyperleukocytosis arising against the background of monotherapy by Vesanoid consists in connection of chemotherapy anthracyclines in adequate doses under control of an indicator of leukocytes according to the following scheme:
- co-administration of chemotherapy and therapy by Vesanoid at the quantity of leukocytes exceeding 5000 in 1 мкл at the time of an initiation of treatment;
- connection of chemotherapy in adequate doses to treatment by Vesanoid at patients with number of leukocytes less than 5000 in 1 мкл at the time of Vesanoid's appointment and at increase of quantity of leukocytes against the background of its reception to:
≥ 6000 in 1 мкл - for 1-6 days of therapy
≥ 10 000 in 1 мкл - for 7-10 days of therapy
≥ 15 000 in 1 мкл - for 11-28 days of therapy

At emergence of the most precursory symptoms of SRK it is necessary to begin a course of treatment with dexamethasone (on 10 mg every 12 hours within at most 3 days or before stopping of SRK).

At a moderate and heavy current of SRK it is necessary to consider a question of temporary interruption of therapy by Vesanoid.

As in the first month of therapy there is a risk of thrombosis, it is necessary to be careful at treatment of patients with Vesanoid's combination and anti-fibrinolitic drugs, such as traneksamovy acid, aminocapronic acid or Aprotininum.

System therapy by retinoids can lead to intracranial hypertensia. Vesanoid it is not necessary to appoint in a combination with the drugs increasing intracranial pressure, for example with tetracyclines.

During therapy by Vesanoid to patients with an acute promiyelotsitarny leukosis symptomatic therapy, for example, prevention of bleeding and infections has to be carried out. It is necessary to control often a blood count, coagulation indicators, function of a liver and concentration of triglycerides and cholesterol.

At a concomitant use of Vesanoid and the tableted gestagensoderzhashchy contraceptives (mini-drank), the last are not a reliable method of contraception.

Vesanoid possesses the expressed teratogenic action. During therapy by Vesanoid and, at least, within 3 months later it is necessary to use reliable barrier methods of contraception. Women of childbearing age during treatment should carry out tests for pregnancy at least 1 time a month.

Influence on ability to driving of transport and work with cars and mechanisms. Some side effects of Vesanoid, for example, such as dizziness or severe headaches, can negatively influence ability of patients to manage vehicles or to be engaged in other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

At treatment symptoms of a hypervitaminosis And which also arise at therapy by other retinoids were the most frequent side effects recommended by Vesanoid's doses.

From skin and its appendages: a xeroderma, an erythema, rash, an itch, the strengthened sweating, an alopecia, a cheilitis, dryness of mucous membranes of an oral cavity, nose, a conjunctiva and others mucous with signs of an inflammation or without; seldom: formation of ulcers on a mucous membrane of generative organs, syndrome Suite, knotty erythema.

From the central nervous system: a headache, intracranial hypertensia (generally at children), fever, a fever, dizziness, confusion of consciousness, alarm, excitement, a depression, paresthesias, sleeplessness, weakness.

From sense bodys: vision disorder and hearing.

From a musculoskeletal system: ostealgias, thorax pains; seldom: miositis.

From digestive tract: nausea, vomiting, abdominal pains, diarrhea, lock, loss of appetite, pancreatitis.

From a metabolism, liver and kidneys: increase in concentration of triglycerides, cholesterol, creatinine in blood serum, increase in activity of transaminases (ALT, nuclear heating plant); separate cases of a hypercalcemia.

From a respiratory organs: pleural exudate, asthma, respiratory insufficiency, bronchospasm.

From cardiovascular system: disturbances of a rhythm, inflows, hypostases, separate cases of thrombosis (venous and arterial).

From system of a hemopoiesis: exceptional cases of a thrombocytosis, the expressed basophilia with clinically shown hyper histaminemia or without it, mainly, at patients with rare option of OPML with basphilic differentiation.

From an organism in general: exceptional cases of a skin vasculitis.

"Syndrome of retinoic acid" at OPML. Many sick OPML (to 25%) against the background of treatment tretinoiny have a syndrome of retinoic acid (SRA). SRK is characterized by fever, short wind, acute respiratory a distress syndrome, emergence of pulmonary infiltrates, arterial hypotonia, a pleural and pericardiac exudate, hypostases, increases in body weight, liver, renal and multiorgan failure. SRK quite often is followed by a hyperleukocytosis and can lead to a lethal outcome.

The decision on interruption or continuation of therapy has to be based on assessment of a ratio of advantages of treatment and severity of side effects.

Information on use of a tretinoin for children is limited. The children receiving третиноин, in particular, intracranial hypertensia have messages on increase of the toxic phenomena.

Interaction with other medicines:

As Vesanoid is metabolized by hepatic system of P450 cytochrome, there is a possibility of change of pharmacokinetics at a concomitant use of the drugs which are inductors or inhibitors of this fermental system.

Rifampicin, glucocorticosteroids, phenobarbital and pentobarbital belong to the medicines stimulating activity of liver enzymes of system of P450 cytochrome. The medicines suppressing activity of liver enzymes of the P450 system include кетоконазол, Cimetidinum, erythromycin, verapamil, diltiazem and cyclosporine. Data which would confirm change of efficiency or toxicity of these drugs at simultaneous use with tretinoiny, no. Data on possible pharmacokinetic interactions between tretinoiny and daunorubitsiny and Cytarabinum are absent.

Anti-fibrinolitic means, such as traneksamovy acid, aminocapronic acid and Aprotininum: at the patients who are at the same time receiving третиноин and anti-fibrinolitic drugs, exceptional cases of trombotichesky complications with a lethal outcome are described. At purpose of a tretinoin together with these drugs it is necessary to be careful.

Tetracyclines: system therapy by retinoids can lead to intracranial hypertensia. As drugs of a tetracycline row can also increase intracranial pressure, it is not necessary to appoint them along with tretinoiny.

Vitamin A: as well as other retinoids, Vesanoid is contraindicated in combination with vitamin A because of strengthening of symptoms of a hypervitaminosis And.

The tableted gestagensoderzhashchy contraceptives (mini-drank): at a concomitant use of Vesanoid and mini-drank reliability of contraceptive action mini-saw decreases.

Contraindications:

Hypersensitivity to a tretinoin or any other component of drug.

Pregnancy and period of feeding by a breast.
Concomitant use of vitamin A.

With care. A concomitant use of tetracyclines, anti-fibrinolitic drugs and the tableted gestagensoderzhashchy contraceptives (mini-drank).

Overdose:

At overdose the reversible symptoms characteristic of a hypervitaminosis are shown And (a headache, nausea, vomiting, signs of damage of skin and mucous membranes). The dose recommended for patients with an acute promiyelotsitarny leukosis makes 1/4 from the dose which is most transferred by patients with solid tumors and the most tolerable dose for children is smaller, than. There is no specific treatment of overdose, however it is important that the patient was placed in a hematology unit

Storage conditions:

Period of validity 3 years. Not to use after the period of validity specified on packaging.

At a temperature not above 30 °C in the place protected from light. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules of 10 mg. On 100 capsules in a bottle of amber glass with the screwing-up cover from PEVP providing control of the first opening. Each bottle together with the application instruction is placed in a cardboard pack.