Tretinoin - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Other antineoplastic agents

Included in the formulation

Weightoids

capsules inwards

Chaplafarm Artsynmittel GmbH Germany

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

ONLS

АТХ:

L.01.X.X Other antineoplastic agents

L.01.X.X.14 Tretinoin

Pharmacodynamics:

The exact mechanism of all the effects of tretinoin is unknown. Perhaps a change in the gene, leading to suppression of protein synthesis. Local (anti-acne and keratolytic): an increase in the mitosis of the epidermal cells (renewal) and skin permeability, weakening of the connection between the keratinized cells (removal of existing acne and an obstacle to the formation of new ones), an increase in the synthesis of follicular epithelium and inhibition of keratin synthesis (an impediment to the formation of keratin blockage of excretory ducts). Locally (hypopigmental): a decrease in melanin in the epidermis (inhibition of melanogenesis), compaction of the granular layer (thickening). Locally (photoprotective): inhibition of the UV-induced effect of stimulation of the gene-transcription factor (AP-1), inhibition of the production of melanoproteinase enzymes that cause damage to the skin matrix.

Systemically: induction of differentiation and a decrease in the proliferation of leukemic promyelocytes, activation of the initial maturation of promyelocytes, and repetition of bonebrain with normal polyclonal hemopoietic cells.

Pharmacokinetics:

Aabsorption by absorption 50 %, fast, dependence on food intake is not revealed, suggest the potentiation of absorption of other retinoids. The connection with plasma proteins is more than 95% (mainly with albumin). Biotransformation in the liver with the participation of cytochrome P450 isozymes and with the formation of isotretiostine, 4-oxo-trans retinoic acid, 4-oxo-cis retinoic acid. The half-life is0.5-2 hours Time to reach the maximum concentration1-2 hours (if taken orally). Elimination by the kidneys (63% for 72 hours), with feces (31% for 6 days).

When topical application is absorbed up to 8% of the dose from anhydrous forms and up to 1.41% from aqueous forms, absorption increases with considerable treatment areas and a longer exposure time for chronic dermatosis. Elimination by the kidneys (4.45% dose), with feces (1.58% dose).

Indications:

Induction of remission with acute promyelocytic leukemia (classification according to FAB - AML-M3). The drug can be administered to previously untreated patients and patients with relapses or refractory to standard chemotherapy (daunomycin and cytosine arabinoside or their analogues).

ICD-10

II.C81-C96.C92.4 Acute promyelocytic leukemia

Contraindications:

Hypersensitivity, pregnancy, breast-feeding, age to 12 years for all indications, age to 18 years and over 50 years old in the treatment of adverse effects of sunlight.

Carefully:

Carefully! Local application, ingestion.

Pregnancy and lactation:

Contraindicated in pregnancy and during lactation.

Recommendations for FDA for systemic use categories D, for topical application category C.

Dosing and Administration:

The drug is administered internally in a daily dose of 45 mg / m2 body surface in 2 divided doses (for adults - about 8 capsules). For children, the same dose is recommended, unless severe toxic effects occur (in particular, the dose should be reduced if the child has intolerable headaches).

Treatment should be continued from 30 to 90 days until a complete remission is achieved. After this, immediately go to the standard regimen of consolidating chemotherapy, for example, three courses of daunomycin and cytosine arabinoside at intervals of 5-6 weeks.

Side effects:

Dermatological reactions: dry skin, erythema, rash, itching, increased sweating, alopecia, cheilitis,dryness of the mucous membranes of the mouth, nose, conjunctiva and other mucous membranes, with or without inflammation; rarely - the formation of ulcers on the mucous membrane of the genital organs, Svit's syndrome, erythema nodosum.

From the side CNS and peripheral nervous system: headache, intracranial hypertension (mainly in children), fever, chills, dizziness, confusion, anxiety, agitation, depression, paresthesia, insomnia, weakness.

From the side sense organs: impaired vision and hearing.

From the side musculoskeletal system: pain in the bones, pain in the chest; rarely - myositis.

From the side digestive system: nausea, vomiting, abdominal pain, diarrhea, constipation, decreased appetite, pancreatitis, increased activity of transaminases (ALT, AST).

From the side metabolism: increasing the concentration of triglycerides, cholesterol, creatinine in the blood serum; in some cases - hypercalcemia.

From the side respiratory system: pleural effusion, shortness of breath, respiratory failure, bronchospasm.

From the side of cardio-vascular system: rhythm disturbances, hot flushes, swelling; in some cases - thrombosis.

From the side hematopoiesis system: rarely - thrombocytosis, marked basophilia with clinically manifested hyperhistaminemia or without it, mainly in patients with a rare variant of acute promyelocytic leukemia with basophilic differentiation.

The decision to interrupt or continue therapy should be based on an assessment of the relationship between the benefits of treatment and the severity of side effects.

Syndrome of retinoic acid in acute promyelocytic leukemia.

Overdose:

To date, cases of acute overdose have not been described. It seems that a random overdose of tretinoin will be manifested by reversible symptoms characteristic of hypervitaminosis A. The dose recommended for patients with acute promyelocytic leukemia is 1/4 of the dose tolerated by patients with solid tumors and is less than the maximum tolerated dose for children .

There is no specific overdose treatment, however it is important that the patient be placed in the hematology unit.

Interaction:

Because the tretinoin is metabolized by isoenzymes of the cytochrome P450 system, it is possible to change the pharmacokinetics of concurrently taken drugs that are inducers or inhibitors of this enzyme system.The drugs that stimulate the activity of cytochrome P450 isoenzymes include rifampicin, glucocorticosteroids, phenobarbital and pentobarbital. Drugs that inhibit the activity of cytochrome P450 isoenzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and ciclosporin. Data that would indicate a change in the efficacy or toxicity of these drugs when used simultaneously with tretinoin is not present.

Information on the possible pharmacokinetic interaction between tretinoin and daunomycin and cytosine arabinoside is absent.

In patients receiving concomitantly tretinoin and antifibrinolytic drugs (tranexamic acid, aminocaproic acid and aprotinin), rare cases of thrombotic complications with a lethal outcome are described. Therefore, if this combination is necessary, care should be taken.

Tretinoin reduces the contraceptive effectiveness of small doses of progestogens (mini-pili).

Systemic therapy with retinoids can lead to intracranial hypertension.Because tetracycline drugs can also increase intracranial pressure, they should not be administered concomitantly with tretinoin.

Like other retinoids, tretinoin Do not use in combination with vitamin A because of the symptoms of hypervitaminosis A.

Special instructions:

In patients with hyperleukocytosis, which occurs against the background of monotherapy with tretinoin, the prevention of retinoic acid syndrome consists in the connection of full-dose chemotherapy (anthracyclines) while controlling the level of leukocytes. Currently, a clear scheme of therapy is developed.

1. Immediate initiation of treatment, if at the time of diagnosis or at any time against the background of combined therapy with tretinoin and chemotherapy, the number of leukocytes exceeds 5000 / μL.

2. Connection of full-dose chemotherapy to treatment with tretinoin in patients with a number of leukocytes <5000 / μl by the time of diagnosis, if the leukocytosis rises to ≥ 6000 / μL for 1-6 days of treatment, ≥ 10,000 / μL for 7-10 days of treatment, ≥ 15 000 / mkl - for 11-28 days of treatment.

3. If the earliest signs of retinoic acid are present, it is necessary to begin treatment with dexamethasone (10 mg every 12 hours for a maximum of 3 days or until the syndrome is stopped).

4.With a moderate and severe course of retinoic acid, consideration should be given to the temporary interruption of therapy with tretinoin.

Since there is a risk of developing thrombosis in the first month of therapy, care should be taken when treating patients with a combination of tretinoin and antifibrinolytic drugs such as tranexamic acid, aminocaproic acid or aprotinin.

Tretinoin should be administered only to patients with acute promyelocytic leukemia under close supervision of a hematologist or oncologist.

Supportive measures should be taken during treatment of patients with acute promyelocytic leukemia with tretinoin, for example, bleeding prophylaxis and anti-infective therapy. It is often necessary to monitor the blood picture, the clotting parameters, the liver function and the concentration of triglycerides and cholesterol.

Instructions

Tretinoin (Tretinoinum)