alkylating agent, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Thiotepa, a derivative of nitrogen mustard, acts as a polyfunctional alkylating agent.3 Alkylation takes place through the formation of a highly reactive ethylenimine radical.3 This radical likely forms a cross-linkage between two strands of DNA,3 interfering with DNA, RNA, and protein synthesis.1,4 These actions do not appear to be cell cycle phase- specific. Thiotepa has immunosuppressive properties.1 Intracavitary (intra-pleural, -pericardial, and -peritoneal) administration of thiotepa also produces an inflammatory reaction on serous membranes with a resulting sclerosing effect.1
| Oral Absorption | variable as unstable in acidic pH; therefore, not administered orally | |
| Distribution | peak plasma concentrations occur immediately; lipid-soluble, 5 variable absorption occurs through serous membranes and from IM injection, peritoneum (80-100%), bladder (10- 100%) IT: diffuses rapidly out of the CSF 6,7 | |
| cross blood brain barrier? 6,8,9 | yes; triethylenephosphoramide metabolite (TEPA): yes 5 | |
| volume of distribution 1,10 | 0.3-1.6 L/kg | |
| plasma protein binding | 8-29%; TEPA more extensively bound | |
| Metabolism | extensive hepatic metabolism; involves the hepatic microsomal enzyme oxidation system and glutathione conjugation 10,11 ; thiotepa is metabolized to TEPA by CYP 3A4 (major) and CYP 2B6 (minor) 11 | |
| active metabolite(s) 3 | yes; including TEPA; when given IT, TEPA is not formed in the CNS | |
| inactive metabolite(s) | yes | |
| Excretion | biphasic elimination; renal <1%; excreted in sweat to an appreciable extent with high-dose IV | |
| urine | 0.1-2%; TEPA: 4%; unidentified metabolites with alkylating activity: 13-24% | |
| feces | no information found | |
| terminal half life 3,4 | 1.2-2.9 h; TEPA: 10-21 h | |
| clearance | 180-780 mL/min/m 2 | |
Adapted from standard reference1 unless specified otherwise.
| Primary uses: | Other uses: |
| *Bladder cancer (intravesical) | *Breast cancer |
| Malignant meningeal neoplasms 1,12 (intrathecal) | High-dose for myeloablation prior to bone marrow |
DRAFT
*Health Canada approved indication
transplant10 *Intracavitary effusions secondary to malignancy *Ovarian cancer
existing hepatic or renal damage3; see DOSAGE GUIDELINES
skin reactions including depigmentation and dermatitis have occurred after accidental exposure; safe handling precautions should be followed when handling thiotepa; if skin contact occurs, wash the area thoroughly with soap and water; if mucous membrane contact occurs, flush thoroughly with water3
Carcinogenicity: 3
Thiotepa is carcinogenic.
Mutagenicity: Mutagenic in Ames test and mammalian in vitro mutation test.3 Thiotepa is clastogenic in mammalian
in vitro and in vivo chromosome tests.3
Fertility: 3
Amenorrhea and impaired spermatogenesis have been reported.
Pregnancy: FDA Pregnancy Category D.3 There is positive evidence of human fetal risk,3 but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Breastfeeding 3
is not recommended due to the potential secretion into breast milk.
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.13
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| allergy/immunology | allergic reactions (1-10%) 4 |
| blood/bone marrow/ febrile neutropenia | myelosuppression (>10%) 4 ; cumulative 1 and dose-related; may occur up to 30 days after treatment 1 ; deaths reported |
| anemia | |
| leukopenia; nadir 1 typically days 10-14 | |
| thrombocytopenia; onset 4 typically days 7-10, nadir day 14, recovery day 28 | |
| constitutional symptoms | fatigue (1-10%) 4 |
| fever (1-10%) 4 ; secondary to tumour breakdown | |
| dermatology/skin | extravasation hazard: none 14 |
| alopecia (1-10%) 4 | |
| discharge from subcutaneous lesions; secondary to tumour breakdown | |
| hyperpigmentation 4 (1-10%) 4 ; with high-dose BMT therapy 4 | |
| rash (1-10%) 4 ; pruritis 4 (1-10%) 4 ; urticaria (1-10%) 4 ; dermatitis | |
DRAFT
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| skin reactions including contact dermatitis and depigmentation 4 ; with topical exposure 4 | |
| gastrointestinal | emetogenic potential: low 15 |
| anorexia (1-10%) 4 | |
| nausea and vomiting (1-10%) 4 | |
| stomatitis, mucositis; dose-limiting with high-dose BMT therapy 4,16 | |
| hemorrhage | hemorrhage; secondary to myelosuppression; deaths have occurred |
| infection | septicemia; deaths have occurred |
| metabolic/laboratory | serum transaminitis and hyperbilirubinemia; with high-dose BMT therapy 4 |
| hyperuricemia 1,4 (1-10%) 4 | |
| musculoskeletal | weakness (1-10%) 4 |
| neurology | confusion, inappropriate behavior; with high-dose BMT therapy 4 |
| dizziness (1-10%) 4 | |
| somnolence; with high-dose BMT therapy 4 | |
| ocular/visual | blurred vision |
| conjunctivitis (1-10%) 4 | |
| pain | abdominal pain |
| dysuria | |
| headache (1-10%) 4 | |
| injection site pain (>10%) 4 | |
| renal/genitourinary | urinary retention (1-10%) 4 |
| secondary malignancy | myelodysplastic syndrome and acute non-lymphocytic leukemia (<1%) 4 |
| sexual/reproductive function | amenorrhea (1-10%) 4 ; impaired spermatogenesis |
Adapted from standard reference3 unless specified otherwise. Intrathecal administration is typically well tolerated.5 Systemic toxicities are infrequent with the exception of myelosuppression.5 Neurologic toxicities including weakness and paresthesia17 and aseptic chemical meningitis, characterized by fever, headache, nausea and vomiting, meningismus, photophobia, and dehydration may occur.5 Better drug exposure may be achieved if given IV because thiotepa diffuses rapidly out of the CNS and the active metabolite TEPA is not formed in the CNS.5 Intravesical administration may cause systemic toxicities due to absorption, including myelosuppression18,19 (3- 54%; deaths reported3) and allergic reactions20 (3%). Absorption is variable16,18 (10-100%) and is increased by multiple tumours, tumour infiltration, mucosal inflammation, and reflux of urine from the bladder into the ureter.1,18 Dose-dependant chemical cystitis (1-69%)4,18,19 may occur; however, hemorrhagic cystitis is rare.3,19 Delay therapy or dose reduce to manage irritative symptoms.18 Rarely, eosinophilic cystitis,21 azoospermia,19 and non-lymphocytic leukemia and myelodysplastic syndrome have been reported.18
DRAFT
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| aprepitant 22 | delayed and decreased exposure to TEPA (20%) | inhibition of CYP enzymes (likely 3A4 and 2B6) | minor clinical importance due to large inter- and intra-individual variability in thiotepa clearance |
| phenytoin 23,24 | increased rate of thiotepa conversion to TEPA | strong induction of CYP 2B6 enzyme by phenytoin | avoid concurrent use; if used consider dose reduction of thiotepa |
| succinylcholine, 3 pancuronium 23 | prolonged apnea may occur | thiotepa may inhibit pseudocholinesterase activity | caution; consider avoiding concurrent use |
Thiotepa is a major CYP 2B6 inhibitor; therefore, serum levels/effects of drugs or herbs that are CYP 2B6 substrates may be increased.4
Injection3
: Bedford Laboratories supplies thiotepa as 15 mg single-use vials of nonpyrogenic, sterile, lyophilized powder.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
Additional information: Do not use reconstituted solutions that are opaque or contain a precipitate after filtration thorough a 0.22 micron filter.3 Filtration to be done by pharmacy prior to dispensing; see Chemotherapy Preparation and Stability chart for details. Reconstituted thiotepa may be mixed with lidocaine,4 2% procaine hydrochloride, or 0.1% epinephrine for local administration.25
Compatibility:
consult detailed reference
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous | has been used 4 ; no advantage over IV direct |
| Intramuscular | has been used 1 ; no advantage over IV direct |
| Direct intravenous | over 1-2 minutes 4 |
| Intermittent infusion | over 10-60 minutes 4 |
| Continuous infusion | has been used 26-28 |
| Intraperitoneal | dilute to a larger volume 1,3,8 (e.g., < 2L) |
| Intrapleural | dilute to 10-60 mL in SWI, NS, or D5W 8,29 |
BCCA administration guideline noted in bold, italics | |
|---|---|
| Intrapericardial | dilute to 10-20 mL in NS or D5W 8 |
| Intrathecal | by physician only 28 ; dilute in small volume (6 mL) or to a concentration 1 of 1 mg/mL with preservative-free NS 12 ; higher concentrations have been used 30 |
| Intra-arterial | no information found |
| Intravesical | in 30-60 mL of NS; dwell time 2 h; dehydrate patient for 8-12 h prior to treatment; may rotate position every 15 minutes for better contact 1,3 |
| Intralesional | investigational 1,25 |
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults:
| BCCA usual dose noted in bold, italics | ||
| Cycle Length: | ||
| * Intravenous: | 1-4 weeks 1,3,4 : | 0.3-0.4 mg/kg IV for one dose on day 1 (total dose per cycle 0.3-0.4 mg/kg) |
| 2-4 weeks 1,4 : | 0.2 mg/kg or 6-8 mg/m 2 IV once daily for 4-5 consecutive day starting on day 1 (total dose per cycle 0.8-1 mg/kg or 24-40 mg/m 2 ) | |
| Intracavitary: | > 1 week 3,4 : | 0.6-0.8 mg/kg or 30-60 mg instilled intracavitary for one dose on day 1 (total dose per cycle 0.6-0.8 mg/kg or 30-60 mg) 15-30 mg intrapericardially has been used |
| Intramuscular: | various schedules 1,4 : | 15-30 mg IM for one dose on day 1 |
| Intrathecal: | n/a 4,12 : | 12 mg (range 10-15 mg) IT for one dose once or twice weekly (maximum two IT injections per week) diffuses rapidly out of the CSF, 6,7 active metabolite TEPA is not formed 9 and better drug exposure may be achieved if given IV 31 |
| n/a 1,4 : | 1-11.5 mg/m 2 IT for one dose once or twice weekly | |
| Intravesical: | n/a 3,10,29 : | 60 mg (range 30-60 mg) instilled intravesically for one dose on days 1, 8,15, and 22 (total dose per cycle 240 mg) cycle may be repeated if needed; caution due to the risk of myelosuppression after initial treatment, monthly installations have also been used |
BCCA usual dose noted in bold, italics Intralesional n/a1: 0.6-0.8 mg/kg injected directly into the tumour for one dose on day 1 followed by maintenance doses of 0.07-0.8 mg/kg injected into the tumour every 1-4 weeks
Concurrent radiation: 3
has been used
Dosage in myelosuppression: modify according to protocol by which patient is being treated3; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression"; the manufacturer recommends discontinuing therapy3 if the leukocyte count falls to <3 x 109/L or if the platelet count falls <150 x 109/L Dosage in renal failure: dose reduction may be required3,4; no details found Dosage in hepatic failure: limited data suggests clearance may be decreased1; use with caution3; dose reduction may be required3; no details found
Dosage in dialysis: 3
removed by dialysis
Children:
safety and effectiveness have not been established3; has been used4,8
McEvoy GK. AHFS 2007 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc. p. 1200- 1202.
National Institute for Occupational Safety and Health (NIOSH). Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, Ohio: NIOSH - Publications Dissemination; September 2004. p. 31-40.
Bedford Laboratories(tm). Thiotepa for Injection USP Package Insert. Bedford, Ohio; April 2001.
Rose BD, editor. Thiotepa. UpToDate 15.2 ed. Waltham, Massachusetts: UpToDate(r); 2007.
Berg SL, Chamberlain MC. Systemic chemotherapy, intrathecal chemotherapy, and symptom management in the treatment of leptomeningeal metastasis. Current Oncology Reports 2003; 5(1):29-40.
Pizzo P, Poplack D. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2006. p. 345-346.
Witham TF, Fukui MB, Meltzer CC, et al. Survival of patients with high grade glioma treated with intrathecal thiotriethylenephosphoramide for ependymal or leptomeningeal gliomatosis. Cancer 1999; 86(7):1347-53.
Rose BD, editor. Thiotepa: Pediatric drug information. UpToDate 15.2 ed. Waltham, Massachusetts: UpToDate(r); 2007.
Fleischhack G, Jaehde U, Bode U. Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clinical Pharmacokinetics 2005; 44(1):1-31.
DRUGDEX(r) Evaluations (database on the Internet). Thiotepa. Thomson MICROMEDEX(r), Available at: http://www.micromedex.com/, 25 October 2007.
Jacobson PA, Green K, Birnbaum A, et al. Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA. Cancer Chemotherapy and Pharmacology 2002; 49(6):461-467.
BC Cancer Agency Miscellaneous Origin Tumour Group. (MOIT) BCCA Protocol Summary for Soild Tumours using Intrathecal Methotrexate and/or Thiotepa and/or Cytarabine. Vancouver, British Columbia: BC Cancer Agency; 1 July 2005.
Susan Ellard MD. Personal communication. BC Cancer Agency Breast Tumour Group; 26 August 2008.
BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 September 2006.
BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.
Solimando D.A. Updates of melphalan and thiotepa. Hosp Pharm 1997; 32(8):1082-1088.
Martin Algarra S, Henriquez I, Rebollo J, et al. Severe polyneuropathy and motor loss after intrathecal thiotepa combination chemotherapy: description of two cases. Anti-Cancer Drugs 1990; 1(1):33-5.
Thrasher JB, Crawford ED, Thrasher JB, et al. Complications of intravesical chemotherapy. Urologic Clinics of North America 1992; 19(3):529-39.
Lamm DL, McGee WR, Hale K, et al. Bladder cancer: current optimal intravesical treatment. Urologic Nursing ; 25(5):323-6.
Lee M, Sharifi R, Lee M, et al. Generalized hypersensitivity reaction to intravesical thiotepa and doxorubicin. Journal of Urology 1987; 138(1):143-4.
Choe JM, Kirkemo AK, Sirls LT. Intravesical thiotepa-induced eosinophilic cystitis. Urology 1995; 46(5):729-731.
De Jonge ME, Huitema ADR, Holtkamp MJ, et al. Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemotherapy and Pharmacology 2005; 56(4):370-378.
Drug Interaction Facts (database on the Internet). Thiotepa. Facts and Comparisons 4.0, 2007. Available at: http://online.factsandcomparisons.com, 1 August 2007.
De Jonge ME, Huitema ADR, Van Dam SM, et al. Significant induction of cyclophosphamide and thiotepa metabolism by phenytoin. Cancer Chemotherapy and Pharmacology 2005; 55(5):507-510.
Trissel LA. Handbook on Injectable Drugs. 13th ed. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2005. p. 1395-1403.
Henner WD, Shea TC, Furlong EA, et al. Pharmacokinetics of continuous-infusion high-dose thiotepa. Cancer Treatment Reports 1987; 71(11):1043-1047.
Holland HK, Dix SP, Geller RB, et al. Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell transplantation and comprehensive supportive care. Journal of Clinical Oncology 1996; 14(4):1156-1164.
BC Cancer Agency Provincial Systemic Therapy Program. BCCA-Approved Parenteral Routes-Antineoplastic Drugs. Vancouver, British Columbia: BC Cancer Agency; 15 July 2004.
MARTINDALE- The Complete Drug Reference (database on the Internet). Thiotepa. Thomson MICROMEDEX(r), Available at: http://www.micromedex.com/, 25 October 2007.
Rubenstein EB, Peterson DE, Schubert M, et al. Clinical Practice Guidelines for the Prevention and Treatment of Cancer Therapy-Induced Oral and Gastrointestinal Mucositis. Supplement to Cancer 2004:2026-2046.
DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998; 38(2-3):245-52.