(thye oh TEP a)
Treatment of superficial papillary bladder cancer; palliative treatment of adenocarcinoma of breast or ovary; controlling intracavitary effusions caused by metastatic tumors
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
Note: Thiotepa is associated with a moderate emetic potential in adults (depending on dose/indication); antiemetics may be recommended to prevent nausea and vomiting (MASCC 2016).
Bladder cancer: Intravesical: 60 mg in 30 to 60 mL NS retained for 2 hours once weekly for 4 weeks
Ovarian, breast cancer: IV: 0.3 to 0.4 mg/kg every 1 to 4 weeks
Effusions: Intracavitary: 0.6 to 0.8 mg/kg
Leptomeningeal metastases (off-label use/route): Intrathecal: 10 mg twice a week (on days 1 and 4 each week) for 8 weeks (Grossman 1993)
Hematopoietic stem cell transplant (HSCT) for CNS malignancy (off-label use; combination chemotherapy): IV: 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)
Refer to adult dosing.
Note: In children, thiotepa is associated with a high emetic potential at doses ≥300 mg/m2; antiemetics are recommended to prevent nausea and vomiting (Dupuis, 2011).
Hematopoietic stem cell transplant (HSCT) for CNS malignancy (off-label use; combination chemotherapy): IV: 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)
There are no dosage adjustments provided in the manufacturer 's labeling. Use with caution; reduced dose may be warranted. Use may be contraindicated with existing renal impairment and should be limited to cases where benefit outweighs risk.
There are no dosage adjustments provided in the manufacturer 's labeling. Use with caution; reduced dose may be warranted. Use may be contraindicated with existing hepatic impairment and should be limited to cases where benefit outweighs risk.
Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Note: Due to drug shortage in the U.S., the FDA is allowing temporary importation of a European product (Tepadina). Verify product, storage, and preparation instructions prior to dispensation and administration. Refer to specific product labeling for details.
Tepadina: Reconstitute each 15 mg vial with 1.5 mL SWFI, or each 100 mg vial with 10 mL SWFI, to a concentration of 10 mg/mL. Gently mix by repeated inversions. Solution may be clear or opalescent; do not use if particulate matter is present. Further dilute reconstituted solution for IV infusion in 500 mL NS (1000 mL NS if dose >500 mg). If dose is <250 mg, dilute in an appropriate volume of NS to achieve a final concentration of 0.5 to 1 mg/mL.
Generic product labeling (US): Reconstitute each 15 mg vial with 1.5 mL SWFI to a concentration of 10 mg/mL. Solutions for IV use should be further diluted in NS 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 to 60 mL NS.
Solutions for intrathecal administration (off-label use) should be diluted to a concentration of 1 mg/mL in preservative-free buffered solution (Grossman 1993). Intrathecal medications should not be prepared during the preparation of any other agents.
In children, thiotepa is associated with a high emetic potential at doses ≥300 mg/m2 (Dupuis 2011) and is associated with a moderate emetic potential (depending on dose/indication) in adults (MASCC 2016); antiemetics may be recommended to prevent nausea and vomiting.
IV: Administer as a rapid injection. Infusion times may be longer for high-dose (off-label use) treatment; refer to specific protocols. Tepadina: Administer using a 0.2 micron in-line filter; flush line prior to and after infusion with ~5 mL NS.
Intravesical instillation: Instill directly into the bladder and retain for 2 hours; patient should be repositioned every 15 to 30 minutes for maximal exposure
Intrathecal route (off-label use/route): Was administered in 10 mL (preservative free) buffered solutions (Grossman 1993)
Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).
Note: Due to drug shortage in the United States, the FDA is allowing temporary importation of a European product (Tepadina). Verify product, storage, and preparation instructions prior to dispensation and administration. Refer to specific product labeling for details.
Tepadina: Store intact vials under refrigeration at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F). Protect from light; do not freeze. Reconstituted solution (10 mg/mL) is stable for 8 hours when stored at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F). Solution further diluted for infusion in NS is stable for 24 hours when stored at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F), or for 4 hours when stored at 25 ‚ °C (77 ‚ °F).
Generic product labeling (U.S.): Store intact vials under refrigeration at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F). Protect from light. Reconstituted solutions (10 mg/mL) are stable for up to 8 hours when stored under refrigeration. Solutions further diluted for infusion in NS should be used immediately.
After preparation, keep intrathecal medications in an isolated location or container clearly marked with a label identifying as intrathecal" use only.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Generic: 15 mg (1 ea)
Variable stability (consult detailed reference) in D5W, NS.
Y-site administration: Incompatible with cisplatin, filgrastim, minocycline, vinorelbine.
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
CYP2B6 Substrates: Thiotepa may increase the serum concentration of CYP2B6 Substrates. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). 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. Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). 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. Avoid combination
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
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
Concerns related to adverse effects:
- Fertility effects: May be mutagenic and teratogenic.
- Gastrointestinal toxicity: In children, thiotepa is associated with a high emetic potential at doses ≥300 mg/m2 (Dupuis 2011) and is associated with a moderate emetic potential (depending on dose/indication) in adults (MASCC 2016); antiemetics may be recommended to prevent nausea and vomiting.
- 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; death due to septicemia and hemorrhage has occurred. Myelosuppression (including fatal cases) has also been reported with intravesicular administration (due to systemic absorption). Monitor blood counts closely.
- 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.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special handling:
- Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).
Other warnings/precautions:
- Intrathecal safety: When used for intrathecal administration (off-label route), should not be prepared during the preparation of any other agents. After preparation, keep 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).
- Product availability: Due to the shortage of the US generic product, the FDA is allowing temporary importation of a European product (brand name Tepadina) to fulfill clinical need. Indications and dosing vary greatly between the US and European products; verify product, dosing, and preparation instructions prior to dispensation and administration.
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Adverse events were observed in animal reproduction studies. May cause harm if administered during pregnancy. Effective contraception is recommended for men and women of childbearing potential.
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
Variable absorption through serous membranes and from IM injection sites; bladder mucosa: 10% to 100% and is increased with mucosal inflammation or tumor infiltration
Vdss: 0.7-1.6 L/kg; distributes into CSF
Hepatic via oxidative desulfuration (cytochrome P450 microsomal enzyme system) primarily to TEPA (active metabolite)
Very little thiotepa or active metabolite are excreted unchanged in urine (1.5% of thiotepa dose)
Terminal: Thiotepa: 109 minutes (51.6-212 minutes) with dose-dependent clearance; TEPA: 10-21 hours
8% to 13%
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, dizziness, hair loss, lack of appetite, nausea, vomiting, or abdominal pain. Have patient report immediately to prescriber signs of infections, signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that will not stop), shortness of breath, severe loss of strength and energy, blurred vision, amenorrhea, urinary retention, or change in amount of urine passed (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.