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thiotepa

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Thiotepa

Thiotepa

WARNINGS

Death has occurred after intravesical administration, caused by bone-marrow depression from systematically absorbed drug.

Death from septicemia and hemorrhage has occurred as a direct result of hematopoietic depression by thiotepa (thiotepa injection) .

Thiotepa (thiotepa (thiotepa injection) injection) is highly toxic to the hematopoietic system. A rapidly falling white blood cell or platelet count indicates the necessity for discontinuing or reducing the dosage of thiotepa (thiotepa (thiotepa injection) injection) . Weekly blood and platelet counts are recommended during therapy and for at least 3 weeks after therapy has been discontinued.

Thiotepa (thiotepa (thiotepa injection) injection) can cause fetal harm when administered to a pregnant woman. Thiotepa (thiotepa (thiotepa injection) injection) given by the intraperitoneal (IP) route was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m2), approximately 8-fold less than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m2), based on body-surface area. Thiotepa (thiotepa (thiotepa injection) injection) given by the IP route was teratogenic in rats at doses ≥ 3 mg/kg (21 mg/m2), approximately equal to the maximum recommended human therapeutic dose, based on body-surface area. Thiotepa (thiotepa (thiotepa injection) injection) was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m2), approximately two times the maximum recommended human therapeutic dose based on body-surface area.

Effective contraception should be used during thiotepa (thiotepa (thiotepa injection) injection) therapy if either the patient or partner is of childbearing potential. There are no adequate and well-controlled studies in pregnant women. If thiotepa (thiotepa (thiotepa injection) injection) is used during pregnancy, or if pregnancy occurs during thiotepa (thiotepa (thiotepa injection) injection) therapy, the patient and partner should be apprised of the potential hazard to the fetus.

Thiotepa (thiotepa (thiotepa injection) injection) is a polyfunctional alkylating agent, capable of cross-linking the DNA within a cell and changing its nature. The replication of the cell is, therefore, altered, and thiotepa (thiotepa (thiotepa injection) injection) may be described as mutagenic. An in vitro study has shown that it causes chromosomal aberrations of the chromatid type and that the frequency of induced aberrations increases with the age of the subject.

Like many alkylating agents, thiotepa (thiotepa (thiotepa injection) injection) has been reported to be carcinogenic when administered to laboratory animals. Carcinogenicity is shown most clearly in studies using mice, but there is some evidence of carcinogenicity in man. In patients treated with thiotepa (thiotepa (thiotepa injection) injection) , cases of myelodysplastic syndromes and acute non-lymphocytic leukemia have been reported.

PRECAUTIONS

General

The serious complication of excessive thiotepa (thiotepa (thiotepa injection) injection) therapy, or sensitivity to the effects of thiotepa (thiotepa (thiotepa injection) injection) , is bone-marrow depression. If proper precautions are not observed thiotepa (thiotepa (thiotepa injection) injection) may cause leukopenia, thrombocytopenia, and anemia.

Laboratory Tests

The most reliable guide to thiotepa (thiotepa (thiotepa injection) injection) toxicity is the white blood cell count. If this falls to 3000 or less, the dose should be discontinued. Another good index of thiotepa (thiotepa (thiotepa injection) injection) toxicity is the platelet count; if this falls to 150,000, therapy should be discontinued. Red blood cell count is a less accurate indicator of thiotepa (thiotepa (thiotepa injection) injection) toxicity. If the drug is used in patients with hepatic or renal damage (see CONTRAINDICATIONS section), regular assessment of hepatic and renal function tests are indicated.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Also see WARNINGS section.

Carcinogenesis

In mice, repeated IP administration of thiotepa (thiotepa (thiotepa injection) injection) (1.15 or 2.3 mg/kg three times per week for 52 or 43 weeks, respectively) produced a significant increase in the combined incidence of squamous-cell carcinomas of the skin, preputial gland, and ear canal, and combined incidence of lymphoma and lymphocytic leukemia. In other studies in mice, repeated IP administration of thiotepa (thiotepa (thiotepa injection) injection) (4 or 8 mg/kg three times per week for 4 weeks followed by a 20-week observation period or 1.8 mg/kg three times per week for 4 weeks followed by a 35-week observation period) resulted in an increased incidence of lung tumors. In rats, repeated IP administration of thiotepa (thiotepa (thiotepa injection) injection) (0.7 or 1.4 mg/kg three times per week for 52 or 34 weeks, respectively) produced significant increases in the incidence of squamous-cell carcinomas of the skin or ear canal, combined hematopoietic neoplasms, and uterine adenocarcinomas. Thiotepa (thiotepa (thiotepa injection) injection) given intravenously (IV) to rats (1 mg/kg once per week for 52 weeks) produced an increased incidence of malignant tumors (abdominal cavity sarcoma, lymphosarcoma myelosis, seminoma, fibrosarcoma, salivary gland hemangioendothelioma, mammary sarcoma, pheochromocytoma) and benign tumors.

The lowest reported carcinogenic dose in mice (1.15 mg/kg, 3.68 mg/m2) is approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area. The lowest reported carcinogenic dose in rats (0.7 mg/kg, 4.9 mg/m2) is approximately 6-fold less than the maximum recommended human therapeutic dose based on body-surface area.

Mutagenesis

Thiotepa (thiotepa (thiotepa injection) injection) was mutagenic in in vitro assays in Salmonella typhimurium, E coli, Chinese hamster lung and human lymphocytes. Chromosomal aberrations and sister chromatid exchanges were observed in vitro with thiotepa (thiotepa (thiotepa injection) injection) in bean root tips, human lymphocytes, Chinese hamster lung, and monkey lymphocytes. Mutations were observed with oral thiotepa (thiotepa (thiotepa injection) injection) in mouse at doses > 2.5 mg/kg (8 mg/m2). The mouse micronucleus test was positive with IP administration of > 1 mg/kg (3.2 mg/m2). Other positive in vivo chromosomal aberration or mutation assays included Drosophila melanogaster, Chinese hamster marrow, murine marrow, monkey lymphocyte, and murine germ cell.

Impairment of Fertility

Thiotepa (thiotepa (thiotepa injection) injection) impaired fertility in male mice at PO or IP doses ≥ 0.7 mg/kg (2.24 mg/m2), approximately 12-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa (thiotepa (thiotepa injection) injection) (0.5 mg) inhibited implantation in female rats when instilled into the uterine cavity. Thiotepa (thiotepa (thiotepa injection) injection) interfered with spermatogenesis in mice at IP doses ≥ 0.5 mg/kg (1.6 mg/m2), approximately 17-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa (thiotepa (thiotepa injection) injection) interfered with spermatogenesis in hamsters at an IP dose of 1 mg/kg (4.1 mg/m2), approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area.

Pregnancy: Teratagenic Effects - Category D

See WARNINGS section.

Thiotepa (thiotepa (thiotepa injection) injection) can cause fetal harm when administered to a pregnant woman. Thiotepa (thiotepa (thiotepa injection) injection) given by the IP route was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m2), approximately 8-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa (thiotepa (thiotepa injection) injection) given by the IP route was teratogenic in rats at doses ≥ 3 mg/kg (21 mg/m2), approximately equal to the maximum recommended human therapeutic dose based on body-surface area. Thiotepa (thiotepa (thiotepa injection) injection) was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m2), approximately 2 times the maximum recommended human therapeutic dose based on body-surface area. Patients of childbearing potential should be advised to avoid pregnancy. There are no adequate and well-controlled studies in pregnant women. If thiotepa (thiotepa (thiotepa injection) injection) is used during pregnancy, or if pregnancy occurs during thiotepa (thiotepa (thiotepa injection) injection) therapy, the patient and partner should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether thiotepa (thiotepa (thiotepa injection) injection) is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for thiotepa (thiotepa (thiotepa injection) injection) in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of thiotepa (thiotepa (thiotepa injection) injection) did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreasing hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Last reviewed on RxList: 11/20/2008
This monograph has been modified to include the generic and brand name in many instances.

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