Thiotepa 15 mg/1.5mL Injection, Powder, Lyophilized, For Solution, 1 vial — NDC 25021-246-02 (Billing 25021-0246-02)

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/m 2 ), approximately 8-fold less than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m 2 ), based on body-surface area. Thiotepa given by the IP route was teratogenic in rats at doses ≥3 mg/kg (21 mg/m 2 ), 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/m 2 ), 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.

ADVERSE REACTIONS In addition to its effect on the blood-forming elements (see WARNINGS and PRECAUTIONS sections), thiotepa may cause other adverse reactions. General: Fatigue, weakness. Febrile reaction and discharge from a subcutaneous lesion may occur as the result of breakdown of tumor tissue.

Hypersensitivity Reactions: Allergic reactions - rash, urticaria, laryngeal edema, asthma, anaphylactic shock, wheezing. Local Reactions: Contact dermatitis, pain at the injection site. Gastrointestinal: Nausea, vomiting, abdominal pain, anorexia.

Renal: Dysuria, urinary retention. There have been rare reports of chemical cystitis or hemorrhagic cystitis following intravesical, but not parenteral administration of thiotepa. Respiratory: Prolonged apnea has been reported when succinylcholine was administered prior to surgery, following combined use of thiotepa and other anticancer agents.

It was theorized that this was caused by decrease of pseudocholinesterase activity caused by the anticancer drugs. Neurologic: Dizziness, headache, blurred vision. Skin: Dermatitis, alopecia.

Skin depigmentation has been reported following topical use. Special Senses: Conjunctivitis. Reproductive: Amenorrhea, interference with spermatogenesis.

Drug Interactions It is not advisable to combine, simultaneously or sequentially, cancer chemotherapeutic agents or a cancer chemotherapeutic agent and a therapeutic modality having the same mechanism of action. Therefore, thiotepa combined with other alkylating agents such as nitrogen mustard or cyclophosphamide or thiotepa combined with irradiation would serve to intensify toxicity rather than to enhance therapeutic response. If these agents must follow each other, it is important that recovery from the first agent, as indicated by white blood cell count, be complete before therapy with the second agent is instituted.

Other drugs which are known to produce bone-marrow depression should be avoided.

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. Laboratory Tests The most reliable guide to thiotepa toxicity is the white blood cell count. If this falls to 3,000 or less, the dose should be discontinued.

Another good index of thiotepa 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 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.

Drug Interactions It is not advisable to combine, simultaneously or sequentially, cancer chemotherapeutic agents or a cancer chemotherapeutic agent and a therapeutic modality having the same mechanism of action. Therefore, thiotepa combined with other alkylating agents such as nitrogen mustard or cyclophosphamide or thiotepa combined with irradiation would serve to intensify toxicity rather than to enhance therapeutic response. If these agents must follow each other, it is important that recovery from the first agent, as indicated by white blood cell count, be complete before therapy with the second agent is instituted.

Other drugs which are known to produce bone-marrow depression should be avoided. Carcinogenesis, Mutagenesis, Impairment of Fertility Also see WARNINGS section. Carcinogenesis In mice, repeated IP administration of thiotepa (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 (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 (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 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/m 2 ) 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/m 2 ) is approximately 6-fold less than the maximum recommended human therapeutic dose based on body-surface area.

Mutagenesis Thiotepa 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 in bean root tips, human lymphocytes, Chinese hamster lung, and monkey lymphocytes. Mutations were observed with oral thiotepa in mouse at doses >2.5 mg/kg (8 mg/m 2 ).

The mouse micronucleus test was positive with IP administration of >1 mg/kg (3.2 mg/m 2 ). Other positive in vivo c… [Excerpted — this section continues on DailyMed.]