Thiotepa

THIOTEPA- thiotepa injection, powder, lyophilized, for solution
Sagent Pharmaceuticals

SAGENT®
Rx only

DESCRIPTION

Thiotepa for Injection, USP is an ethylenimine-type compound. It is supplied as a non-pyrogenic, sterile lyophilized powder for intravenous, intracavitary or intravesical administration, containing 15 mg of thiotepa. Thiotepa is a synthetic product with antitumor activity. The chemical name for thiotepa is Aziridine, 1,1′,1”-phosphinothioylidynetris-, or Tris (1-aziridinyl) phosphine sulfide. Thiotepa has the following structural formula:

Structural Formula

Thiotepa has the empirical formula C6 H12 N3 PS, and a molecular weight of 189.22. When reconstituted with sterile water for injection, the resulting solution has a pH of approximately 5.5 to 7.5. Thiotepa is stable in alkaline medium and unstable in acid medium.

CLINICAL PHARMACOLOGY

Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylenimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principal bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates alkylated guanines.

The pharmacokinetics of thiotepa and TEPA in thirteen female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4 week intervals are presented in the following table:

Pharmacokinetic
Parameters
(units)
Mean ± SEM
Thiotepa TEPA
60 mg 80 mg 60 mg 80 mg
Peak Serum concentration (ng/mL) 1331 ± 119 1828 ± 135 273 ± 46 353 ± 46
Elimination half-life (h) 2.4 ± 0.3 2.3 ± 0.3 17.6 ± 3.6 15.7 ± 2.7
Area under the curve (ng/h/mL) 2832 ± 412 4127 ± 668 4789 ± 1022 7452 ± 1667
Total body clearance (mL/min) 446 ± 63 419 ± 56

TEPA, which possesses cytotoxic activity, appears to be the major metabolite of thiotepa found in human serum and urine. Urinary excretion of 14 C-labeled thiotepa and metabolites in a 34 year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. Thiotepa and TEPA in urine each accounts for less than 2% of the administered dose.

The pharmacokinetics of thiotepa in renal and hepatic dysfunction patients have not been evaluated. Possible pharmacokinetic interactions of thiotepa with any concomitantly administered medications have not been formally investigated.

INDICATIONS AND USAGE

Thiotepa for Injection has been tried with varying results in the palliation of a wide variety of neoplastic diseases. However, the most consistent results have been seen in the following tumors:

  1. Adenocarcinoma of the breast.
  2. Adenocarcinoma of the ovary.
  3. For controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities.
  4. For the treatment of superficial papillary carcinoma of the urinary bladder.

While now largely superseded by other treatments, Thiotepa for Injection has been effective against other lymphomas, such as lymphosarcoma and Hodgkin’s disease.

CONTRAINDICATIONS

Thiotepa is contraindicated in patients with a known hypersensitivity (allergy) to this preparation.

Therapy is probably contraindicated in cases of existing hepatic, renal, or bone-marrow damage. However, if the need outweighs the risk in such patients, thiotepa may be used in low dosage, and accompanied by hepatic, renal and hemopoietic function tests.

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 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. Weekly blood and platelet counts are recommended during therapy and for at least 3 weeks after therapy has been discontinued.

Thiotepa can cause fetal harm when administered to a pregnant woman. Thiotepa 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 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 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 therapy if either the patient or partner is of childbearing potential. There are no adequate and well-controlled studies in pregnant women. If thiotepa is used during pregnancy, or if pregnancy occurs during thiotepa therapy, the patient and partner should be apprised of the potential hazard to the fetus.

Thiotepa 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 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 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, cases of myelodysplastic syndromes and acute non-lymphocytic leukemia have been reported.

PRECAUTIONS

General

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

Information for Patients

The patient should notify the physician in the case of any sign of bleeding (epistaxis, easy bruising, change in color of urine, black stool) or infection (fever, chills) or for possible pregnancy to patient or partner.

Effective contraception should be used during thiotepa therapy if either the patient or the partner is of childbearing potential.

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