Thiotepa

(BAN, rINN)
Thiotepa Chemical formula
Synonyms: NSC-6396; TESPA; Thiophosphamide; Thiotépa; Thiotepum; Tiotepa; Triethylenethiophosphoramide; TSPA; WR-45312. Phosphorothioic tri(ethyleneamide); Tris(aziridin-1-yl)phosphine sulphide.
Cyrillic synonym: Тиотепа.

💊 Chemical information

Chemical formula: C6H12N3PS = 189.2.
CAS — 52-24-4.
ATC — L01AC01.
ATC Vet — QL01AC01.

Pharmacopoeias.

In Br., Chin., Fr., Jpn, and US.

BP 2008

(Thiotepa). Fine white, crystalline flakes. M.p. 52° to 57°. Freely soluble in water, in alcohol, and in chloroform. Store at 2° to 8°. At higher temperatures it polymerises and becomes inactive.

USP 31

(Thiotepa). Fine white, crystalline flakes, having a faint odour. M.p. 52° to 57°. Soluble 1 in 13 of water, 1 in about 8 of alcohol, 1 in about 2 of chloroform, and 1 in about 4 of ether. Store at 2° to 8° in airtight containers. Protect from light.

Incompatibility.

Lyophilised thiotepa 1 mg/mL in glucose 5% was incompatible when mixed with solutions of cisplatin or minocycline hydrochloride. 1 1. Trissel LA, Martinez JF. Compatibility of thiotepa (lyophilized) with selected drugs during simulated Y-site administration. Am J Health-Syst Pharm 1996; 53: 1041–5.

Stability.

A solution of a lyophilised thiotepa preparation 0.5 mg/mL in glucose 5% was considered to be stable (less than 10% loss of thiotepa) for 8 hours at both 4° and 23°. 1 After 24 hours losses ranged between about 10 and 17%. A higher thiotepa concentration (5 mg/mL) was stable for 3 days at 23° and 14 days at 4°. Another study found that solutions containing 1 or 3 mg/mL of thiotepa in sodium chloride 0.9% were stable for 24 hours at 25° and 48 hours at 8°, but solutions containing 0.5% thiotepa needed to be used immediately. 2 1. Xu QA, et al. Stability of thiotepa (lyophilized) in 5% dextrose injection at 4 and 23°C. Am J Health-Syst Pharm 1996; 53: 2728–30. 2. Murray KM, et al. Stability of thiotepa (lyophilized) in 0.9% sodium chloride injection. Am J Health-Syst Pharm 1997; 54: 2588–91.

💊 Adverse Effects, Treatment, and Precautions

Bone-marrow depression may be delayed; the nadir of white cell and platelet counts may occur up to 30 days after therapy has been stopped. Bone-marrow depression has been reported after intravesical as well as parenteral use, and has occasionally been prolonged or fatal. Gastrointestinal disturbances, fatigue, weakness, headache and dizziness, hypersensitivity reactions, blurred vision and conjunctivitis may occur. Amenorrhoea and impaired fertility have also been reported. Local irritation, and rarely frank chemical or haemorrhagic cystitis may follow intravesical instillation. Depigmentation of periorbital skin has occurred after the use of thi otepa eye drops. As with other alkylating agents, thiotepa is potentially mutagenic, teratogenic, and carcinogenic. Thiotepa should be given with extreme care, if at all, to patients with pre-existing impairment of hepatic, renal, or bone-marrow function.

💊 Pharmacokinetics

The absorption of thiotepa from the gastrointestinal tract is incomplete and unreliable; variable absorption also occurs from intramuscular injection sites. Absorption through serous membranes such as the bladder and pleura occurs to some extent. After intravenous doses it is rapidly cleared from plasma, with an elimination half-life of about 2.4 hours. It is extensively metabolised: triethylenephosphoramide (TEPA), the primary metabolite, and some of the other metabolites have cytotoxic activity and are eliminated more slowly than the parent compound. It is excreted in the urine: less than 2% of a dose is reported to be present as unchanged drug or its primary metabolite.

💊 Uses and Administration

Thiotepa is an ethyleneimine compound whose antineoplastic effect is related to its alkylating action. It has generally been replaced by cyclophosphamide or other drugs. It is not a vesicant and may be given by all parenteral routes, as well as directly into tumour masses. Instillations of thiotepa may be used in the adjuvant treatment of superficial tumours of the bladder and in the control of malignant effusions. It has been given parenterally in the palliative treatment of various solid tumours, including those of breast and ovary. It has also been given intrathecally to patients with malignant meningeal disease, and has been used, in the form of eye drops, as an adjunct to the surgical removal of pterygium, to prevent recurrence. Thiotepa is given in a variety of dosage schedules. In general, initial doses to suit the individual patient are followed by maintenance doses given at intervals of 1 to 4 weeks. Blood counts are recommended before and during therapy and should continue for at least 3 weeks after stopping. Thiotepa should not be given if the white cell or platelet counts fall below acceptable levels and treatment should be stopped if the white cell count falls rapidly. Dosage should be reduced in patients with lesser degrees of leucopenia. In the treatment of bladder cancer thiotepa in doses up to 60 mg may be instilled in 30 to 60 mL of sterile water or sodium chloride 0.9% into the bladder of a patient previously dehydrated for 8 to 12 hours, and retained if possible for 2 hours. The instillation may be repeated weekly for up to 4 weeks. Similar instillations have been given at intervals of 1 to 2 weeks, for up to 8 instillations in the prophylaxis of recurrence after surgical removal of bladder cancer. Single doses of 90 mg in 100 mL of sterile water have also been used prophylactically. For malignant effusions, doses of up to 60 mg of thiotepa in 20 to 60 mL of sterile water may be instilled after aspiration; in the USA the licensed dose is 600 to 800 micrograms/kg, a dose similar to that suggested for injection directly into tumours. Thiotepa for local use may be mixed with solutions of procaine and adrenaline. Intramuscular and intravenous dosage regimens vary considerably; several regimens have used courses of 15 mg daily for 4 days. In the USA a licensed dose is 300 to 400 micrograms/kg given at 1- to 4-week intervals. A solution containing 1 mg/mL in sterile water has been tried intrathecally in doses of up to 10 mg given on alternate days, for up to 4 doses. Thiotepa 0.05% in sterile Ringer’s solution has been instilled as eye drops every 3 hours for up to 6 weeks after surgical removal of pterygium in order to reduce the likelihood of recurrence. A dose of 60 mg weekly has been instilled into the urethra for the treatment of condylomata acuminata (genital warts). Topical application of thiotepa has also been used for condylomata. Thiotepa is under investigation for use as conditioning therapy before haematopoietic stem cell transplantation.

💊 Preparations

BP 2008: Thiotepa Injection; USP 31: Thiotepa for Injection.

Proprietary Preparations

Gr.: Ledertepa†; Ital.: Thioplex; Neth.: Ledertepa; Spain: Onco Tiotepa†; USA: Thioplex.
Published March 11, 2019.