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Pronunciation
(thye oh TEP a)
Generic Available (U.S.)
Yes
Index Terms
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of superficial papillary bladder cancer; palliative treatment of adenocarcinoma of breast or ovary; controlling intracavitary effusions caused by metastatic tumors
Use: Unlabeled/Investigational
Intrathecal treatment of leptomeningeal metastases
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies have demonstrated teratogenicity and fetal loss. There are no adequate and well-controlled studies in pregnant women. May cause harm if administered during pregnancy. Effective contraception is recommended for men and women of childbearing potential.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Contraindications
Hypersensitivity to thiotepa or any component of the formulation
Note: May be contraindicated in certain circumstances of hepatic, renal, and/or bone marrow failure; evaluate on an individual basis as lower dose treatment (with close monitoring) may still be appropriate if the potential benefit outweighs the risks
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Fertility effects: May be mutagenic and teratogenic.
• Myelosuppression: Myelosuppression may commonly occur; use with caution in patients with bone marrow damage, dosage reduction recommended. Use may be contraindicated with existing marrow damage and should be limited to cases where benefit outweighs risk. Monitor for infection or bleeding. Myelosuppression has also been reported with intravesicular administration (due to systemic absorption).
• Secondary malignancies: Potentially carcinogenic; myelodysplastic syndrome and acute myeloid leukemia (AML) have been reported.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction recommended. Use may be contraindicated with existing hepatic impairment and should be limited to cases where benefit outweighs risk.
• Renal impairment: Use with caution in patients with renal impairment; dosage reduction recommended. Use may be contraindicated with existing renal impairment and should be limited to cases where benefit outweighs risk.
Other warnings/precautions:
• Intrathecal safety: When used for intrathecal administration, should not be prepared during the preparation of any other agents. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only. Delivery of intrathecal medications to the patient should only be with other medications intended for administration into the central nervous system (Jacobson, 2009).
Adverse Reactions
Frequency not defined:
Central nervous system: Chills, dizziness, fatigue, fever, headache
Dermatologic: Alopecia, contact dermatitis, depigmentation (with topical treatment), dermatitis, rash, urticaria
Endocrine & metabolic: Amenorrhea, spermatogenesis inhibition
Gastrointestinal: Abdominal pain, anorexia, nausea, vomiting
Genitourinary: Dysuria, urinary retention
Hematologic: Anemia, bleeding, leukopenia, thrombocytopenia
Local: Injection site pain
Neuromuscular & skeletal: Weakness
Ocular: Blurred vision, conjunctivitis
Renal: Hematuria
Respiratory: Asthma, epistaxis, laryngeal edema, wheezing
Miscellaneous: Allergic reaction, anaphylactic shock, infection
Infrequent, postmarketing, and/or case reports: Acute myeloid leukemia (AML), chemical cystitis (bladder instillation), hemorrhagic cystitis (bladder instillation), myelodysplastic syndrome
Metabolism/Transport Effects
Inhibits CYP2B6 (strong)
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
CYP2B6 Substrates: CYP2B6 Inhibitors (Strong) may decrease the metabolism of CYP2B6 Substrates. Risk D: Consider therapy modification
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Herb/Nutraceutical: Avoid black cohosh, dong quai in estrogen-dependent tumors.
Storage
Store intact vials under refrigeration (2°C to 8°C). Protect from light. Reconstituted solutions (10 mg/mL) are stable for up to 28 days under refrigeration (4°C to 8°C) or 7 days at room temperature (25°C), although the manufacturer recommends use within 8 hours when reconstituted solutions are stored under refrigeration. Solutions further diluted (for I.V. use) in NS to 1 mg/mL are stable for 24 hours and to 3 mg/mL are stable for 48 hours at room temperature, although the manufacturer recommends immediate use. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.
Reconstitution
Use appropriate precautions for handling and disposal. Reconstitute each 15 mg vial with 1.5 mL SWFI to a concentration of 10 mg/mL. Solutions for I.V. use should be further diluted in 0.9% sodium chloride injection prior to infusion. Filter through a 0.22 micron filter (polysulfone membrane [eg, Sterile Aerodisc®] or triton-free cellulose mixed ester [eg, Millex®-GS]) prior to administration; do not use solutions which precipitate or remain opaque after filtering. Solutions for intravesicular administration should be diluted in 30-60 mL NS. Solutions for intrathecal administration should be diluted to a concentration of 1-5 mg/mL in preservative-free NS. Intrathecal medications should not be prepared during the preparation of any other agents.
Compatibility
Variable stability (consult detailed reference) in D5W, NS.
Y-site administration: Compatible: Acyclovir, allopurinol, amifostine, amikacin, aminophylline, amphotericin B, ampicillin, ampicillin/sulbactam, aztreonam, bleomycin, bumetanide, buprenorphine, butorphanol, calcium gluconate, carboplatin, carmustine, cefazolin, cefepime, cefotaxime, cefotetan, cefoxitin, ceftazidime, cefuroxime, chlorpromazine, cimetidine, ciprofloxacin, clindamycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin HCl, dexamethasone sodium phosphate, diphenhydramine, dobutamine, dopamine, doxorubicin HCl, doxycycline, droperidol, enalaprilat, etoposide, etoposide phosphate, famotidine, floxuridine, fluconazole, fludarabine, fluorouracil, furosemide, gallium nitrate, ganciclovir, gemcitabine, gentamicin, granisetron, haloperidol lactate, heparin, hydrocortisone sodium succinate, hydromorphone, hydroxyzine HCl, idarubicin, ifosfamide, imipenem/cilastatin, leucovorin calcium, lorazepam, magnesium sulfate, mannitol, melphalan, meperidine, mesna, methotrexate, methylprednisolone sodium succinate, metoclopramide, metronidazole, mitomycin, mitoxantrone, morphine, nalbuphine, ofloxacin, ondansetron, paclitaxel, piperacillin, piperacillin/tazobactam, potassium chloride, prochlorperazine edisylate, promethazine, ranitidine, sodium bicarbonate, streptozocin, teniposide, ticarcillin/clavulanate, tobramycin, trimethoprim/sulfamethoxazole, vancomycin, vinblastine, vincristine, zidovudine. Incompatible: Cisplatin, filgrastim, minocycline, vinorelbine. Variable (consult detailed reference): Ceftriaxone.
Compatibility in syringe: Incompatible: Ceftriaxone.
Mechanism of Action
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
Pharmacodynamics/Kinetics
Absorption: Intracavitary instillation: Unreliable (10% to 100%) through bladder mucosa
Metabolism: Extensively hepatic; major metabolite (active): TEPA
Half-life elimination: Terminal (dose-dependent clearance): ~2 hours
Excretion: Urine (as metabolites and unchanged drug)
Dosage
Children: HSCT for CNS malignancy (unlabeled use; combination chemotherapy): I.V.: 300 mg/m2/day for 3 days beginning 8 days prior to transplant (Gilheeney, 2010) or 300 mg/m2/day for 3 days beginning 5 days prior to transplant (Dunkel, 2010; Grodman, 2009)
Adults:
Bladder cancer: Intravesical: 60 mg in 30-60 mL NS retained for 2 hours once weekly for 4 weeks
Ovarian, breast cancer: I.V.: 0.3-0.4 mg/kg by rapid I.V. administration every 1-4 weeks
Effusions: Intracavitary: 0.6-0.8 mg/kg
Leptomeningeal metastases (unlabeled use): Intrathecal: 10 mg twice a week for 4 weeks, then (if CSF cytology is negative) weekly for 4 weeks, then monthly for 4 doses (NCCN CNS cancer guidelines v.1.2010)
HSCT for CNS malignancy (unlabeled use; combination chemotherapy): I.V.: 250 mg/m2/day for 3 days beginning 9 days prior to transplant (Soussain, 2008) or 150 mg/m2/dose every 12 hours for 6 doses, followed by stem cell reinfusion 96 hours after completion of thiotepa (Abrey, 2006)
Dosage adjustment for hematologic toxicity: I.V.:
WBC ≤3000/mm3: Discontinue treatment
Platelets ≤150,000/mm3: Discontinue treatment
Note: Use may be contraindicated with pre-existing marrow damage and should be limited to cases where benefit outweighs risk.
Dosing adjustment in renal impairment: Use with extreme caution, reduced dose may be warranted. Use may be contraindicated with existing renal impairment and should be limited to cases where benefit outweighs risk.
Dosing adjustment in hepatic impairment: Use with extreme caution, reduced dose may be warranted. Use may be contraindicated with existing hepatic impairment and should be limited to cases where benefit outweighs risk.
Administration: I.V.
Administer as a rapid injection. Infusion times may be longer for high-dose (unlabeled use) treatment; refer to specific protocols.
Administration: Other
Intravesical instillation: Instill directly into the bladder and retain for 2 hours; patient should be repositioned every 15-30 minutes for maximal exposure.
Administration: I.V. Detail
pH: 5.5-7.5
Monitoring Parameters
CBC with differential and platelet count (monitor weekly during treatment and for at least 3 weeks after treatment); renal and liver function tests; uric acid, urinalysis
Patient Education
Do not take any aspirin or aspirin-containing products during therapy unless approved by prescriber. If administered by infusion, report immediately any redness, pain, swelling, or burning at infusion site. You will require regular blood tests to assess response to therapy. Maintain adequate hydration to prevent kidney damage, unless instructed to restrict fluid intake. You may have increased sensitivity to infection. May cause mild nausea, vomiting, or loss of appetite; rash; hair loss; or change in skin color (usually reversible after discontinuing treatment). Report any changes in urinary pattern or blood in your urine, unusual bleeding or bruising, persistent fever or chills, sore throat, sores in mouth or vagina, blackened stool, unusual or persistent weakness, difficulty swallowing, or respiratory difficulty.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness
Mental Health: Effects on Psychiatric Treatment
Myelosuppression is common; avoid clozapine and carbamazepine; barbiturates may increase clearance of thiotepa
Nursing: Physical Assessment/Monitoring
Use caution in presence of hepatic or renal impairment or compromised bone marrow reserve; dosing adjustment may be warranted. Evaluate results of laboratory tests regularly during treatment and for at least 3 weeks following treatment. Monitor for myelosuppression, leukopenia, dysuria, bleeding, and infection. Teach patient importance of adequate hydration.
Oncology: Emetic Potential
Low (10% to 30%)
Oncology: Vesicant
May be an irritant
Oncology: Bone Marrow - High Dose
HSCT for CNS malignancy (unlabeled use): I.V.: 750-900 mg/m2 in divided doses; in combination with other high-dose chemotherapeutic drugs (Abrey, 2006; Soussain, 2008).
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 15 mg
References
Abrey LE, Childs BH, Paleologos N, et al, “High-Dose chemotherapy With Stem Cell Rescue as Initial Therapy for anaplastic Oligodendroglioma: Long-Term Follow-Up,” J Neurooncol, 2008, 89(2):187-93.
Badalament RA and Farah RN, “Treatment of Superficial Bladder Cancer With Intravesicle Chemotherapy,” Semin Surg Oncol, 1997, 13(5):335-41.
DeAngelis LM and Butros D, “Leptomeningeal Metastasis,” Cancer Invest, 2005, 23(2):145-54.
de Lemos ML, Monfared S, Denyssevych T, et al, “Evaluation of Osmolality and pH of Various Concentrations of Methotrexate, Cytarabine, and Thiotepa Prepared in Normal Saline, Sterile Water for Injection, and Lactated Ringer's Solution for Intrathecal Administration,” J Oncol Pharm Pract, 2009, 15(1):45-52.
Dunkel IJ, Gardner SL, Garvin JH Jr, et al, “High-Dose Carboplatin, Thiotepa, and Etoposide With Autologous Stem Cell Rescue for Patients With Previously Irradiated Recurrent Medulloblastoma,” Neuro Oncol, 2010, 12(3):297-303.
Gilheeney SW, Khakoo Y, Souweidane M, et al, “Thiotepa/Topotecan/Carboplatin With Autologous Stem Cell Rescue in Recurrent/Refractory/Poor Prognosis Pediatric Malignancies of the Central Nervous System,” Pediatr Blood Cancer, 2010, 54(4):591-5.
Grodman H, Wolfe L, and Kretschmar C, “Outcome of Patients With Recurrent Medulloblastoma or Central Nervous System Germinoma Treated With Low Dose Continuous Intravenous Etoposide Along With Dose-Intensive Chemotherapy Followed by Autologous Hematopoietic Stem Cell Rescue,” Pediatr Blood Cancer, 2009, 53(1):33-6.
Grossman SA, Finkelstein DM, Ruckeschel JC, et al, “Randomized Prospective Comparison of Intraventricular Methotrexate and Thiotepa in Patients With Previously Untreated Neoplastic Meningitis. Eastern Cooperative Oncology Group,” J Clin Oncol, 1993, 11(3):561-9.
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.
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.
Jacobson JO, Polovich M, McNiff KK, et al, "American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards," J Clin Oncol, 2009, 27(32):5469-75.
Maanen MJ, Smeets CJ, and Beijnen JH, “Chemistry, Pharmacology and Pharmacokinetics of N,N',N", -Triethylenethiophosphoramide (ThioTEPA)," Cancer Treat Rev, 2000, 26(4):257-68.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Central Nervous System Cancers,” Version 1.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/cns.pdf
Soussain C, Hoang-Xuan K, Taillandier L, et al, “Intensive Chemotherapy Followed by Hematopoietic Stem-Cell Rescue for Refractory and Recurrent Primary CNS and Intraocular Lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire,” J Clin Oncol, 2008, 26(15):2512-8.
International Brand Names
Lexi-Comp.com
Last full review/revision November 2011
Content last modified November 2011
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