Thiotepa

Trade Names:Thioplex- Powder for Injection 15 mg

Pharmacology

Thiotepa is a cell cycle nonspecific alkylating agent related to nitrogen mustard. Its radiomimetic action is believed to occur through the release of ethylenimine radicals, which disrupt the bonds of DNA. TEPA possesses cytotoxic activity.

Pharmacokinetics

Absorption

Following a 60-mg dose, thiotepa C _max is approximately 1331 ng/mL and AUC is approximately 2832 ng/h/mL.

Elimination

Following a 60-mg dose, thiotepa t _½ is approximately 2.4 h and total Cl is approximately 446 mL/min.

Indications and Usage

Bladder cancer, palliative therapy of breast and ovarian carcinoma.

Unlabeled Uses

Prevention of pterygium recurrence after postoperative β-irradiation, autologous bone marrow transplantation.

Contraindications

History of hypersensitivity reaction, hepatic disease, renal disease, or bone marrow toxicity. Administer reduced doses if therapy is necessary in these patients.

Dosage and Administration

IV 0.3 to 0.4 mg/kg every 1 to 4 wk. Alternative regimens, 0.2 mg/kg/day for 4 to 5 days every 2 to 4 wk; or 6 mg/m ² /day for 4 to 5 days every 2 to 4 wk.

Intravesically 30 to 60 mg instilled (in 60 mL of sterile water) once weekly for 4 wk. Retain fluid in bladder for 2 h. If patient cannot retain for 2 h, dilute successive doses in 30 mL of sterile water instead of 60 mL. It may be necessary to repeat course of therapy or give maintenance therapy with 30 to 60 mg intravesically once monthly for up to 1 yr. After local resection or fulguration of bladder tumors, prophylaxis with thiotepa 30 to 60 mg has been used.

General Advice

• Reconstitute powder for injection by adding 1.5 mL sterile water for injection to each 15 mg vial to yield 10 mg/mL solution.
• Reconstituted solution is hypotonic and should be further diluted with sodium chloride 0.9% before administration. Do not use solutions which are opaque or contain precipitate.
• Reconstituted 10 mg/mL solution is stable for 24 h or longer under refrigeration; however, thiotepa contains no preservative and the manufacturer recommends using the product within 8 h.
• Diluted 5 mg/mL solutions prepared with sodium chloride 0.9% are stable for up to 24 h at room temperature or under refrigeration. Diluted 0.5 mg/mL solutions must be used within 8 h.
• Prior to intravesical instillation, patients should not drink for 8 to 12 h. While thiotepa is instilled, patient may be repositioned every 15 min to maximize area of contact.

Storage/Stability

Refrigerate powder for injection and protect from light.

Drug Interactions

Prolonged apnea and paralysis because of pancuronium occurred in a patient who received thiotepa.

Prolonged apnea because of succinylcholine occurred in a patient who had received thiotepa and other antineoplastics.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Confusion and somnolence at high doses used for bone marrow transplantation. With intrathecal use lower extremity weakness or pain, spinal cord demyelination, transient paresthesias.

Dermatologic

Rash, hives, bronze hyperpigmentation after bone marrow transplantation.

GI

Low potential for nausea and vomiting, anorexia, mucositis, intestinal ulceration, lower abdominal pain with intravesical use.

Genitourinary

Chemical and hemorrhagic cystitis, hematuria with intravesical use, amenorrhea, interference with spermatogenesis.

Hematologic

Bone marrow suppression, leukocyte nadir at 10 to 30 days, bone marrow suppression from systemically absorbed thiotepa can occur after bladder instillation.

Special Senses

Eye irritation and delayed periorbital skin depigmentation with ophthalmic use.

Miscellaneous

Acute leukemia and myelodysplastic syndrome with long-term intravesical use.

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Renal Function

If the benefits outweigh the potential risks, use in low doses and monitor renal function.

Hepatic Function

If the benefits outweigh the potential risks, use in low doses and monitor hepatic function.

Mutagenesis

In vitro, it causes chromatid-type chromosomal aberations.

Fertility

Thiotepa impaired fertility in male mice and inhibited implantation in female rats.

Hematopoietic toxicity

This drug is highly toxic to the hematopoietic system. Perform weekly blood and platelet counts during therapy and for 3 wk or more after therapy discontinuation. The most serious complication of excessive therapy is bone marrow depression, causing leukopenia, thrombocytopenia, and anemia. If WBC count falls to 3,000/mm ³ or less, discontinue use. If the platelet count falls to 150,000/mm ³ , discontinue therapy.

Overdosage

Symptoms

Hematopoietic toxicity, decrease in WBC count, decrease in platelets, bleeding manifestations may develop, increased infection vulnerability.

Patient Information

• Notify the health care provider in the case of any sign of bleeding (eg, epistaxis, easy bruising, change in color of urine, black stool) or infection (eg, fever, chills).
• Notify the health care provider if patient or partner may be pregnant. Use effective contraception during therapy.

Copyright © 2009 Wolters Kluwer Health.