THIOTEPA FOR INJECTION, USP (For Intravenous, Intracavitary or Intravesical Use)

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.

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.

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.

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.

Also see WARNINGS section.

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/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.

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/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.

Thiotepa 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 (0.5 mg) inhibited implantation in female rats when instilled into the uterine cavity. Thiotepa 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 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.

See WARNINGS section.

Thiotepa can cause fetal harm when administered to a pregnant woman. Thiotepa 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 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 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 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.

It is not known whether thiotepa is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for thiotepa 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.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of thiotepa 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.

Thiotepa for injection is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised in handling and preparation of thiotepa for injection. Skin reactions associated with accidental exposure to thiotepa for injection may occur. The use of gloves is recommended. If thiotepa solution contacts the skin, immediately wash the skin thoroughly with soap and water. If thiotepa for injection contacts mucous membranes, the membranes should be flushed thoroughly with water.

Thiotepa for injection should be reconstituted with 1.5 mL of sterile water for injection resulting in a drug concentration of approximately 10 mg per mL. The actual withdrawable quantities and concentration achieved are illustrated in the following table:

The reconstituted solution is hypotonic and should be further diluted with sodium chloride injection (0. 9% sodium chloride) before use.

When reconstituted with sterile water for injection, solutions of thiotepa should be stored in a refrigerator and used within 8 hours. Reconstituted solutions further diluted with sodium chloride injection should be used immediately.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

In order to eliminate haze, filter solutions through a 0.22 micron filter^* prior to administration. Filtering does not alter solution potency. Reconstituted solutions should be clear. Solutions that remain opaque or precipitate after filtration should not be used.

^*Polysulfone membrane (Gelman's Sterile Aerodisc^®, Single Use) or triton-free mixed ester of cellulose/PVC (Millipore's MILLEX^®-GS Filter Unit).

Initially the higher dose in the given range is commonly administered. The maintenance dose should be adjusted weekly on the basis of pretreatment control blood counts and subsequent blood counts.

Thiotepa for injection may be given by rapid intravenous administration in doses of 0.3 to 0.4 mg/kg. Doses should be given at 1 to 4 week intervals.

The dosage recommended is 0.6 to 0.8 mg/kg. Administration is usually effected through the same tubing which is used to remove the fluid from the cavity involved.

Patients with papillary carcinoma of the bladder are dehydrated for 8 to 12 hours prior to treatment. Then 60 mg of thiotepa for injection in 30 to 60 mL of Sodium Chloride Injection is instilled into the bladder by catheter. For maximum effect, the solution should be retained for 2 hours. If the patient finds it impossible to retain 60 mL for 2 hours, the dose may be given in a volume of 30 mL. If desired, the patient may be positioned every 15 minutes for maximum area contact. The usual course of treatment is once a week for 4 weeks. The course may be repeated if necessary, but second and third courses must be given with caution since bone-marrow depression may be increased. Deaths have occurred after intravesical administration, caused by bone-marrow depression from systemically absorbed drug.

Follow safe cytotoxic agent handling procedures. Several guidelines on this subject have been published.^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Store refrigerated between 2° to 8°C (36° to 46°F).

Protect from light.

Discard unused portion.

Lyophilized

Sterile, Nonpyrogenic, Preservative-free.
The container closure is not made with natural rubber latex.

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