Thiotepa

DOSAGE AND ADMINISTRATION

Since absorption from the gastrointestinal tract is variable, thiotepa should not be administered orally. Dosage must be carefully individualized. A slow response to thiotepa does not necessarily indicate a lack of effect. Therefore, increasing the frequency of dosing may only increase toxicity.

After maximum benefit is obtained by initial therapy, it is necessary to continue the patient on maintenance therapy (1 to 4 week intervals). In order to continue optimal effect, maintenance doses should not be administered more frequently than weekly in order to preserve correlation between dose and blood counts.

Preparation and Administration Precautions:

Thiotepa is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised in handling and preparation of thiotepa. Skin reactions associated with accidental exposure to thiotepa 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 contacts mucous membranes, the membranes should be flushed thoroughly with water. 5 m L of sterile water for injection resulting in a drug concentration of approximately 10 mg/mL .

4 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. 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 AerodiscR, Single Use) or triton-free mixed ester of cellulose/PVC (Millipore’s MILLEXR-GS Filter Unit). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Initial and Maintenance Doses:

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.

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. 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.

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.