Vesanoid, 10 mg capsules 100 pcs

Antitumor drug. Systemic retinoid, inducer of cell differentiation. Tretinoin (fully trans-retinoic acid) is a natural metabolite of retinol belonging to the class of retinoids, which includes natural and synthetic analogues. In vitro studies have shown that trans-retinoic acid induces differentiation and suppresses proliferation of transformed hematopoietic cells, including in human myeloleukemia.

The mechanism of action in acute promyelocytic leukemia may be to alter binding of trans-retinoic acid to retinoic acid nuclear receptors, and the α-receptor of retinoic acid is also altered due to fusion with PML protein.

Pharmacokinetics

Absorption

Tretinoin (fully trans-retinoic acid) is an endogenous metabolite of vitamin A normally present in plasma. It is well absorbed after oral administration. Cmax in plasma is reached after 3 hours. Absorption varies greatly from patient to patient as well as in the same patient.

Distribution

The degree of binding to plasma proteins is high. After reaching a peak, the plasma concentration decreases. After single use of the drug in dose of 40 mg, plasma concentration returns to endogenous level in 7-12 hours. There is no cumulation of the drug in multiple doses; the drug is not retained in the tissues.

Metabolism

Tretinoin (fully trans-retinoic acid) isomerizes into 13-cis-retinoic acid and is oxidized to 4-oxymetabolites.

On repeated administration, plasma concentrations of the drug may decrease significantly, possibly due to induction of the cytochrome P450 enzyme system, which increases clearance and decreases bioavailability of the drug after oral administration.

The main route of elimination (60%) is excretion by the kidneys as metabolites formed by oxidation and glucuronidation. They have a longer T_1/2 than trans-retinoic acid and can cumulate in small amounts. The average T_1/2 is 0.7 h.

Pharmacokinetics in special cases

Particular pharmacokinetics and the need for dose adjustment in patients with impaired renal or hepatic function have not been studied.

Indications

Active ingredient

Composition

1 capsule contains:

Active ingredients:

tretinoin (fully trans-retinoic acid) 10 mg.

Auxiliary Ingredients:

beeswax yellow,

soybean oil,

soybean oil hydrogenated,

partially hydrogenated soybean oil.

Capsule shell composition:

Glycerol 85%, gelatin, Carion 83 (hydrolyzed potato starch, mannitol, sorbitol), titanium dioxide (E171), iron oxide yellow dye (E172), iron oxide red dye (E172).

How to take, the dosage

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

The treatment should be continued for 30 to 90 days until complete remission is achieved. After that, immediately switch to a standard consolidation chemotherapy regimen, such as three courses of daunomycin and cytosine-arabinoside 5-6 weeks apart.

If remission has occurred with Vesanoid monotherapy, there is no need to change its dose when joining chemotherapy.

Because there is insufficient information regarding patients with renal and/or hepatic impairment, the dose should be reduced to 25 mg/m2 in this category of patients.

Interaction

Since tretinoin is metabolized by cytochrome P450 isoenzymes, there is a possibility of changing the pharmacokinetics of simultaneously taken drugs that are inducers or inhibitors of this enzyme system. Drugs that stimulate the activity of cytochrome P450 isoenzymes include rifampicin, GCS, phenobarbital and pentobarbital. Drugs that inhibit cytochrome P450 isoenzyme activity include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem, and cyclosporine. There are no data indicating a change in efficacy or toxicity of these drugs when used concomitantly with Vesanoide.

There are no data on possible pharmacokinetic interactions between tretinoin and daunomycin and cytosine-arabinoside.

In patients receiving Vesanoid and antifibrinolytic drugs (tranexamic acid, aminocaproic acid and aprotinin) simultaneously, rare cases of fatal thrombotic complications have been described. Therefore, caution should be exercised if this combination is necessary.

Vesanoide reduces the contraceptive efficacy of low-dose progestagens (“mini-pills”). Systemic retinoid therapy may lead to intracranial hypertension.

Because tetracycline drugs can also increase intracranial pressure, they should not be administered at the same time as Vesanoide.

As with other retinoids, Vesanoid should not be used in combination with vitamin A because of increased symptoms of hypervitaminosis A.

Special Instructions

In patients with hyperleukocytosis resulting from tretinoin monotherapy, the prevention of retinoic acid syndrome is to connect full-dose chemotherapy (anthracyclines) while controlling leukocyte levels. The following therapy regimen is currently recommended:

Because there is a risk of thrombosis in the first month of therapy, caution should be exercised when treating patients with a combination of Vesanoid and antifibrinolytic agents such as tranexamic acid, aminocaproic acid or aprotinin.

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

In the course of treatment of patients with acute promyelocytic leukemia with tretinoin, supportive measures such as bleeding prophylaxis and anti-infective therapy should be given. Blood counts, clotting parameters, liver function, and triglyceride and cholesterol concentrations should be monitored frequently.

Impact on ability to drive and operate vehicles and other mechanisms requiring increased concentration

The ability to drive and operate machinery may be impaired during treatment with Vesanoide, especially if patients experience dizziness or severe headaches.

Contraindications

Side effects

When treated with the drug in the recommended doses, symptoms of hypervitaminosis A, which occur with all other retinoids, were often observed.

Dermatological reactions: dry skin, erythema, rash, itching, increased sweating, alopecia, cheilitis, dry mucous membranes of the mouth, nose, conjunctiva and other mucous membranes, with or without signs of inflammation; rarely – genital mucosa ulceration, Sweet’s syndrome, erythema nodosum.

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

Sensory organs: visual and hearing disorders.

Muscular system disorders: bone pain, chest pain; rarely – myositis.

Digestive system disorders: nausea, vomiting, abdominal pain, diarrhea, constipation, decreased appetite, pancreatitis, increased transaminase activity (ALT, AST).

Metabolism disorders: increased concentration of triglycerides, cholesterol, creatinine in blood serum; in single cases – hypercalcemia.

Respiratory system: pleural effusion, dyspnea, respiratory failure, bronchospasm.

Cardiovascular system disorders: arrhythmias, hot flashes, edema; in some cases – thrombosis.

Hematopoietic system disorders: rare – thrombocytosis, marked basophilia with or without clinically manifesting hyperhistamineemia, mainly in patients with a rare variant of acute promyelocytic leukemia with basophilic differentiation.

The decision to discontinue or continue therapy should be based on an assessment of the ratio of the benefits of treatment to the severity of side effects.

Retinoic acid syndrome in acute promyelocytic leukemia

In clinical studies, hyperleukocytosis was frequently noted (75% of patients). In many patients with acute promyelocytic leukemia (up to 25%) against the background of tretinoin treatment retinoic acid syndrome (RAS) occurs, characterized by fever, shortness of breath, acute respiratory distress syndrome, occurrence of pulmonary infiltrates, arterial hypotension, pleural and pericardial effusions, edema, weight gain, liver, kidney and multiple organ failure. IBS is often accompanied by hyperleukocytosis. Without treatment, this syndrome can be fatal.

Information on the use of tretinoin in children is limited. There are reports of an increase in toxic events in children receiving tretinoin, particularly intracranial hypertension.

Overdose

Symptoms: No cases of acute overdose have been described to date. It appears that an accidental overdose of tretinoin will show reversible symptoms characteristic of hypervitaminosis A.

The dose recommended for acute promyelocytic leukemia patients is 1/4 of the maximum tolerated dose for patients with solid tumors and is lower than the maximum tolerated dose for children.

Treatment: There is no specific treatment for overdose, but it is important that the patient be admitted to a hematology unit.