ded 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.

ash the skin thoroughly with soap and water. if thiotepa contacts mucous membranes, the membranes should be flushed thoroughly with water. preparation of solution: thiotepa for injection should be reconstituted with 1.5 m l of sterile water for injection resulting in a drug concentration of approximately 10 mg/ml . the actual withdrawable quantities and concentration achieved are illustrated in the following table: label claim (mg/vial) actual content (mg/vial) amount of diluent to be added (ml) approximate withdrawable volume (ml) approximate withdrawable amount (mg/vial) approximate reconstituted concentration (mg/ml) 15 15.6 1.5 1.4 14.7 10.4 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. 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 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: 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. intravenous administration: thiotepa 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. intracavitary administration: 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. intravesical administration: patients with papillary carcinoma of the bladder are dehydrated for 8 to 12 hours prior to treatment. then 60 mg of thiotepa 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. handling and disposal: follow safe cytotoxic agent handling procedures. several guidelines on this subject have been published. 1-6 there is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

r 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.

�± 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.

s (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 chromosomal aberration or mutation assays included drosophila melanogaster, chinese hamster marrow, murine marrow, monkey lymphocyte, and murine germ cell. impairment of fertility thiotepa impaired fertility in male mice at po or ip doses ≥ 0.7 mg/kg (2.24 mg/m 2 ), 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/m 2 ), 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/m 2 ), approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area.