No

Antineoplastic Agent, Alkylating Agent

Treatment of superficial tumors of the bladder; palliative treatment of adenocarcinoma of breast or ovary; lymphomas and sarcomas; controlling intracavitary effusions caused by metastatic tumors; I.T. use: CNS leukemia/lymphoma

D

Hypersensitivity to thiotepa or any component; severe myelosuppression with leukocyte count <3000/mm³ or platelet count <150,000 mm³, except in stem cell transplant

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. The drug is potentially mutagenic, carcinogenic, and teratogenic. Reduce dosage in patients with hepatic, renal, or bone marrow damage.

>10%:

Hematopoietic: Dose-limiting toxicity which is dose-related and cumulative; moderate to severe leukopenia and severe thrombocytopenia have occurred. Anemia and pancytopenia may become fatal, so careful hematologic monitoring is required; intravesical administration may cause bone marrow suppression as well.

Hematologic: Myelosuppressive:

WBC: Moderate

Platelets: Severe

Onset (days): 7-10

Nadir (days): 14

Recovery (days): 28

Local: Pain at injection site

1% to 10%:

Central nervous system: Dizziness, fever, headache

Dermatologic: Alopecia, rash, pruritus, hyperpigmentation with high-dose therapy

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: Anorexia, nausea and vomiting rarely occur

Emetic potential: Low (<10%)

Genitourinary: Hemorrhagic cystitis

Renal: Hematuria

Miscellaneous: Tightness of the throat, allergic reactions

<1%: Stomatitis, anaphylaxis; like other alkylating agents, this drug is carcinogenic

Symptoms of overdose include nausea, vomiting, precipitation of uric acid in kidney tubules, bone marrow suppression, bleeding

Therapy is supportive only; thiotepa is dialyzable; transfusions of whole blood or platelets have been proven beneficial

Decreased effect:

Clofibrate, phenobarbital may increase clearance of thiotepa

Increased toxicity:

Other alkylating agents or irradiation concomitantly with thiotepa intensifies toxicity rather than enhancing therapeutic response

Prolonged muscular paralysis and respiratory depression may occur when neuromuscular blocking agents are administered

Succinylcholine and other neuromuscular blocking agents' action can be prolonged due to thiotepa inhibiting plasma pseudocholinesterase

Store intact vials under refrigeration (2°C to 8°C) and protect from light. Not stable at room temperature for any duration of time.

Dilute powder 1.5 mL SWI to a concentration of 10.4 mg/mL which is stable for 8 hours at refrigeration

Further dilution in NS: Thiotepa is stable for 24 hours at a concentration of 5 mg/mL in NS at 8°C and 23°C; however, stability decreases significantly at concentrations of less than or equal to 0.5 mg/mL (< 8 hours); concentrations of 1-3 mg/mL are stable 48 hours at 8°C and 24 hours at 23°C

Standard I.V. dilution:

I.V. push: Dose/syringe (concentration = 10 mg/mL)

IVPB: Dose/100-150 mL NS for a final concentration of 1.5-3.5 mg/mL

Standard intravesicular dilution: 60 mg/30-60 mL NS; solution is placed via catheter and retained for two hours for maximum effect.

Standard intrathecal dilution: Intrathecal doses of 1-10 mg/m² should be diluted to 1-5 mg/mL in preservative-free NS or LR or 1 mg/mL in preservative-free SWI

ALL solutions should be prepared fresh and administered within one hour of preparation

Alkylating agent that reacts with DNA phosphate groups to produce cross-linking of DNA strands leading to inhibition of DNA, RNA, and protein synthesis; mechanism of action has not been explored as thoroughly as the other alkylating agents, it is presumed that the aziridine rings open and react as nitrogen mustard; reactivity is enhanced at a lower pH

Absorption: Following intracavitary instillation, the drug is unreliably absorbed (10% to 100%) through the bladder mucosa; variable I.M. absorption

Metabolism: Extensively in the liver

Half-life, terminal: 109 minutes with dose-dependent clearance

Elimination: As metabolites and unchanged drug in urine

Refer to individual protocols; dosing must be based on the clinical and hematologic response of the patient

Adults:

I.M., I.V., S.C.: 30-60 mg/m ² once per week

I.V. doses of 0.3-0.4 mg/kg by rapid I.V. administration every 1-4 weeks, or 0.2 mg/kg or 6-8 mg/m²/day for 4-5 days every 2-4 weeks

High-dose therapy for bone marrow transplant: I.V.: 500 mg/m²; up to 900 mg/m²

I.M. doses of 15-30 mg in various schedules have been given

Intracavitary: 0.6-0.8 mg/kg

Intrapericardial dose: Usually 15-30 mg

Dosing comments/adjustment in renal impairment: Use with extreme caution, reduced dose may be warranted. Less than 3% of alkylating species are detected in the urine in 24 hours.

Intrathecal: Doses of 1-10 mg/m² administered 1-2 times/week in concentrations of 1 mg/mL diluted with preservative-free sterile water for injection

Intravesical: Used for treatment of carcinoma of the bladder; patients should be dehydrated for 8-12 hours prior to treatment; instill 60 mg (in 30-60 mL of NS) into the bladder and retain for a minimum of 2 hours. Patient should be positioned every 15 minutes for maximal area exposure. Instillations usually once a week for 4 weeks. Monitor for bone marrow suppression.

Intratumor: Use a 22-gauge needle to inject thiotepa directly into the tumor. Initial dose: 0.6-0.8 mg/kg (diluted to 10 mg/mL) are used every 1-4 weeks; maintenance dose: 0.07-0.8 mg/kg are administered at 1- to 4-week intervals

Ophthalmic: 0.05% solution in LR has been instilled into the eye every 3 hours for 6-8 weeks for the prevention of pterygium recurrence

CBC with differential and platelet count, uric acid, urinalysis

May cause dizziness

Myelosuppression is common; avoid clozapine and carbamazepine; barbiturates may increase clearance of thiotepa

No information available to require special precautions

No effects or complications reported

This drug can only be administered I.V. You will require regular blood tests to assess response to therapy. Avoid alcohol and aspirin or aspirin-containing medications unless approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) to prevent kidney damage. For nausea and vomiting, small frequent meals, chewing gum, or sucking lozenges may help, antiemetics may be prescribed. You may experience amenorrhea or changed sperm production, rash, hair loss, or loss of appetite (maintaining adequate nutrition is important). You may have increased sensitivity to infection (avoid crowds and infected persons). Report unusual bleeding or bruising, persistent fever or chills, sore throat, sores in mouth or vagina, blackened stool, or difficulty breathing. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Male: Do not cause a female to become pregnant. Male/female: Consult prescriber for instruction on appropriate barrier contraceptive measures. This drug may cause severe fetal defects. Breast-feeding is not recommended.

Not a vesicant

Powder for injection: 15 mg

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Badalament RA and Farah RN, "Treatment of Superficial Bladder Cancer With Intravesicle Chemotherapy," Semin Surg Oncol, 1997: 13(5):335-41.

Dimopoulos MA, Alexanian R, Przepiorka D, et al, "Thiotepa, Busulfan, and Cyclophosphamide: A New Preparative Regimen for Autologous Marrow or Blood Stem Cell Transplantation in High-Risk Multiple Myeloma," Blood, 1993, 82(8):2324-8.

Gutin PH, Weiss HD, Wiernik PH, et al, "Intrathecal N,N',N''-triethylenethiophosphoramide [thio-TEPA (NSC-6396)] in the Treatment of Malignant Meningeal Disease: Phase I-II Study," Cancer, 1976, 38(4):1471-5.

Hart RD, Perloff M, and Holland JF, "One-Day VATH (Vinblastine, Adriamycin, Thiotepa, and Halotestin) Therapy for Advanced Breast Cancer Refractory to Chemotherapy," Cancer, 1981; 48(7):1522-7.

Heideman R, Cole D, Balis F, et al, "Phase I and Pharmacokinetic Evaluation of Thiotepa in the Cerebrospinal Fluid and Plasma of Pediatric Patients: Evidence for Dose-Dependent Plasma Clearance of Thiotepa," Cancer Res, 1989, 49(3):736-41.

Herzig GP, "Phase I-II Studies of High-Dose Thiotepa and Autologous BMT in Patients With Refractory Malignancies," Adv Cancer Chemotherapy, 1987, 17-29 (proceedings of a symposium, Oct 1986)

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Saarinen UM, Hovi L, and Makipern CA, "High Dose Thiotepa With Autologous Bone Marrow Rescue in Pediatric Solid Tumors," Proc Am Soc Clin Oncol, 1989, 8:303.