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

Clinical and pharmacological group: & nbsp

Included in the formulation

АТХ:

L.01.A.C Ethylenimines

L.01.A.C.01 Thiotepa

Pharmacodynamics:

An antitumor agent that alkylates a compound from a group of nitrogen mustard gas.Related to trifunctional alkylating compounds. The action is not connected with the cellular. The activity of the drug is caused by the formation of an unstable ethyleneimine radical that alkylates many intracellular molecular structures, including nucleic acids (binds to DNA and RNA chains, disrupts the exchange of nucleic acids and protein synthesis, blocks mitosis). Oppresses hemopoiesis.

Pharmacokinetics:

To some extent absorbed in topical application. Absorption through the mucosa of the urinary bladder varies from 10 to 100% (depending on the dose, time of contact with the urinary tract epithelium, increases with severe tumor tissue infiltration, inflammation of the mucous membrane, vesicoureteral reflux, transurethral surgery or radiotherapy). Rapidly metabolized in the liver to form an active and stable metabolite - triethylene iminophosphamide. The half-life is 1.5-2 hours, the metabolite is 3-24 hours. Elimination by the kidneys is 85% (mainly in the form of metabolites, 60% - within 24-72 hours).

Indications:

Ovarian cancer, breast cancer, malignant melanoma, bladder cancer.

Exudative pericarditis, exudative peritonitis, exudative pleurisy in malignant neoplasms (for intracavitary administration).

ICD-10

II.C43-C44.C43.9 Malignant melanoma of skin, unspecified

II.C50 Malignant neoplasm of breast)

II.C51-C58.C56 Malignant neoplasm of ovary

II.C64-C68.C67 Malignant neoplasm of bladder

IX.I30-I52.I30 Acute pericarditis

X.J90-J94.J91 * Pleural effusion in conditions classified elsewhere

XI.K65-K67.K65.0 Acute peritonitis

Contraindications:

Hypersensitivity, terminal states, cachexia, leukopenia (less than 4 × 109 / L before the start of treatment), thrombocytopenia (less than 150 × 109 / L before treatment), erythrocytopenia (less than 3 × 1012 / L), aleukemic form of chronic leukemia.

Pregnancy, breast-feeding.

Carefully:Inhibition of bone marrow function (including on the background of concomitant radiation or chemotherapy.

Pregnancy and lactation:

Possible development of fetal side effects observed in adults. Thiotepa It is teratogenous for humans, but cases of birth of healthy newborns with the appointment of the drug to the mother during pregnancy are described.It is recommended to avoid the use of antitumor, especially combined, chemotherapy in pregnancy, especially in the first trimester. In the presence of indications, it is necessary to relate the risk and benefit and take into account the mutagenic and carcinogenic potential of these agents. In view of the potential threat to the fetus for women of childbearing age, it is recommended to use contraceptives during treatment with thiotep.

There is no information on the penetration into breast milk. In view of the excretion of other antitumor drugs by milk and the potential risk of adverse effects on the child during treatment with thiotepa, breast-feeding is recommended to be discontinued.

Category of recommendations FDA is not defined.

Dosing and Administration:

Method of application - intravenously drip. Doses are set depending on the indications and stage of the disease, the state of the hematopoiesis system, the scheme of antitumor therapy. The duration of intravenous infusion should be 2-4 hours.

Adults:

In autologous transplantation of hematopoietic stem cells (TSCC):

Hematological diseases

The recommended dose: from 125 mg / m2 / day (3.38 mg / kg / day) to 300 mg / m2 / day (8.10 mg / kg / day) once a day, for 2-4 days before carrying out autologous TSCC, depending on the chosen combination with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 900 mg / m2 (24,32 mg / kg) for the entire period of preparatory therapy.

Lymphoma

Lymphoma of the central nervous system

The recommended dose: 185 mg / m2 / day (5 mg / kg / day) once a day, for 2 days before autologous TSCS, depending on the combination chosen with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 370 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.

Multiple myeloma

The recommended dose: from 150 mg / m2 / day (4.05 mg / kg / day) to 250 mg / m2 / day (6.76 mg / kg / day) once a day, for 3 days prior to administration autologous TSCC, depending on the chosen combination with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 750 mg / m2 (20.27 mg / kg) for the entire period of preparatory therapy.

Solid tumors

The recommended dose: from 120 mg / m2 / day (3.24 mg / kg / day) to 250 mg / m2 / day (6.76 mg / kg / day), once a day or divided into 2 infusions per day, for 2-5 days before the autologous TSCA, depending on the combination chosen with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 800 mg / m2 (21.62 mg / kg) for the entire period of preparatory therapy.

Mammary cancer

The recommended dose: from 120 mg / m2 / day (3.24 mg / kg / day) to 250 mg / m2 / day (6.76 mg / kg / day), once a day, for 3-5 days before autologous TSCA, depending on the combination chosen with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 800 mg / m2 (21.62 mg / kg) for the entire period of preparatory therapy.

Tumors of the central nervous system

The recommended dose: from 125 mg / m2 / day (3.38 mg / kg / day) to 250 mg / m2 / day (6.76 mg / kg / day) once a day or divided into 2 infusions per day, in for 3-4 days before the autologous TSCA, depending on the chosen combination with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 750 mg / m2 (20.27 mg / kg) for the entire period of preparatory therapy.

Ovarian Cancer

The recommended dose: 250 mg / m2 / day (6.76 mg / kg / day) once a day, for 2 days before the autologous TSCA. The dose should not exceed the maximum cumulative dose of 500 mg / m2 (13.51 mg / kg) for the entire period of preparatory therapy.

Germinogenic tumors

With allogeneic TSCC:

Hematological diseases

The recommended dose: from 185 mg / m2 / day (5 mg / kg / day) to 481 mg / m2 / day (13 mg / kg / day), once a day or divided into 2 infusions per day,for 1-3 days before carrying out allogeneic TSCC, depending on the chosen combination with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 555 mgm2 (15 mg / kg) for the entire period of preparatory therapy.

Lymphoma

Recommended dose: 370 mg / m2 / day (10 mg / kg / day) divided into 2 infusions per day before allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 370 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.

Multiple myeloma

The recommended dose: 185 mg / m2 / day (5 mg / kg / day) once a day before the allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 185 mg / m2 (5 mg / kg) for the entire period of preparatory therapy.

Leukemia

The recommended dose: from 185 mg / m2 / day (5 mg / kg / day) to 481 mg / m2 / day (13 mg / kg / day), once a day or divided into 2 infusions per day for 1-2 days before the allogeneic TSCC, depending on the combination chosen with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 555 mg / m2 (15 mg / kg) for the entire period of preparatory therapy.

Thalassemia

The recommended dose: 370 mg / m2 / day (10 mg / kg / day), divided into 2 infusions per day, before the allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 370 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.

Children:

With autologous TSCC

Solid tumors

Recommended dose: from 150 mg / m2 / day (6 mg / kg / day) to 350 mg / m2 / day (14 mg / kg / day) once a day, for 2-3 days before the autologous TSCA, in depending on the chosen combination with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 1050 mg / m2 (42 mg / kg) for the entire period of preparatory therapy.

Tumors of the central nervous system

Recommended dose: from 250 mg / m2 / day (10 mg / kg / day) to 350 mg / m2 / day (14 mg / kg / day) once a day, for 3 days before autologous TSCS, depending on selected combination with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 1050 mg / m2 (42 mg / kg) for the entire period of preparatory therapy.

With allogeneic transplantation, TSCC:

Hematological diseases

The recommended dose: from 125 mg / m2 / day (5 mg / kg / day) to 250 mg / m2 / day (10 mg / kg / day), once a day or divided into 2 infusions per day, 3 days before the allogeneic TSCC, depending on the combination chosen with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 375 mg / m2 (15 mg / kg) for the entire period of preparatory therapy.

Leukemia

Recommended dose: 250 mg / m2 / day (10 mg / kg / day), divided into 2 infusions per day, before the allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 250 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.

Thalassemia

The recommended dose: 200 mg / m2 / day (8 mg / kg / day), divided into 2 infusions per day, before the allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 250 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.

Refractory cytopenia

The recommended dose: 125 mg / m2 / day (5 mg / kg / day), once a day, for 3 days before the allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 375 mg / m2 (15 mg / kg) for the entire period of preparatory therapy.

Hereditary diseases

The recommended dose: 125 mg / m2 / day (5 mg / kg / day), once a day, for 2 days before the allogeneic TSCC. The dose should not exceed the maximum cumulative dose of 250 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.

Sickle cell anemia

Recommended dose: 250 mg / m2 / day (10 mg / kg / day), divided into 2 infusions per day before allogeneic TSCC. The dose should not exceed the maximum cumulative dose of 250 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.

Side effects:

From the side hematopoiesis system: leukopenia, thrombocytopenia, anemia (possibly delayed for a month or more).

From the side digestive system: nausea, vomiting, anorexia, stomatitis, liver dysfunction.

From the side CNS: dizziness, headache.

Allergic reactions: skin rash, hives, angioedema, bronchospasm, anaphylactic shock.

Other: dermatitis, conjunctivitis; at intravesical introduction - infringement of function of kidneys.

Overdose:

Not described; it is expected the development of pronounced side effects (myelosuppression).

There is no specific antidote.

Treatment is symptomatic: colony-stimulating factors, antibacterial drugs, blood transfusion and platelet transfusions.

Interaction:

Allopurinol, colchicine, probenecid, sulfinpyrazone - The use of thiotepa increases the concentration of uric acid in the blood, which may require correction of the dose of the antifungal drug. In view of the risk of developing urinary acid nephropathy with the use of antidotal agents for the prevention and treatment of thiotepicobserved hyperuricemia, allopurinol is preferred.

Suxamethonium chloride - thiotepa can reduce the concentration of pseudocholinesterase (an enzyme that metabolizes suxamethonium chloride) in the blood plasma. It is recommended to determine the concentration of pseudocholinesterase in the blood plasma before the appointment of suxamethonium chloride to patients receiving thiotepa. Perhaps the lengthening of the paralysis time of respiratory muscles (apnea), which has little clinical significance, since such patients are on artificial ventilation. Nevertheless, in view of the possibility of incomplete recovery of neuromuscular blockade,careful monitoring of the patient in the postoperative period is required.

Urokinase - it is possible to increase the effectiveness of thiotepa in the treatment of bladder cancer (urokinase - activator of plasminogen, increasing the accumulation of thiotepa in tumor tissue).

A solution of thiotepa with a concentration of 1 mg / ml in a 5% dextrose solution is chemically incompatible with cisplatin and minocycline.

Special instructions:Do not recommend the use of thiotepu in patients with chickenpox (including recently transferred or after contact with the sick), with herpes zoster and other acute infectious diseases.

During treatment, it is necessary to control the white blood cell count in the peripheral blood every other day (or daily) and 2 times / week. - the content of platelets. A clinical blood test is performed 1 time / week. in the course of therapy and within 2-3 weeks after the end of the course of treatment. In the case of severe oppression of bone marrow hematopoiesis, the introduction of thioteps is immediately stopped; prescribe a blood transfusion (thromboplasm or thromboconcentrate), as well as hemopoiesis stimulants (lenograstim, mogratostim, filgrastim), vitamins.

During the therapy should monitor the activity of hepatic transaminases, the level of bilirubin and uric acid.

Do not recommend the vaccination of patients and their families.

In experimental studies carcinogenic and mutagenic effect of thiotepa was established.

Instructions

Thiotepa (Thiotepum)