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Thiotepa

Pronunciation

(thye oh TEP a)

Index Terms

  • TESPA
  • Thiophosphoramide
  • Thioplex
  • Triethylenethiophosphoramide
  • TSPA

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection:

Generic: 15 mg (1 ea)

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent

Pharmacology

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

Absorption

Variable absorption through serous membranes and from IM injection sites; bladder mucosa: 10% to 100% and is increased with mucosal inflammation or tumor infiltration

Distribution

Vdss: 0.7-1.6 L/kg; distributes into CSF

Metabolism

Hepatic via oxidative desulfuration (cytochrome P450 microsomal enzyme system) primarily to TEPA (active metabolite)

Excretion

Very little thiotepa or active metabolite are excreted unchanged in urine (1.5% of thiotepa dose)

Half-Life Elimination

Terminal: Thiotepa: 109 minutes (51.6-212 minutes) with dose-dependent clearance; TEPA: 10-21 hours

Protein Binding

8% to 13%

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

Hematopoietic stem cell transplant (HSCT) for CNS malignancy; intrathecal treatment of leptomeningeal metastases

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

Dosing: Adult

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)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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)

Dosing: Renal Impairment

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.

Dosing: Hepatic Impairment

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.

Dosing: Adjustment for Toxicity

IV: Note: Use may be contraindicated with pre-existing marrow damage and should be limited to cases where benefit outweighs risk.

WBC ≤3000/mm3: Discontinue treatment

Platelets ≤150,000/mm3: Discontinue treatment

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes HSCT dosing): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area in thiotepa dosing for hematopoietic stem cell transplant conditioning regimens in adult patients weighing ≤120% of their ideal body weight (IBW). In patients weighing >120% IBW, utilize adjusted body weight 40% (ABW40) to calculate BSA (Bubalo, 2014).

ABW40: Adjusted wt (kg) = Ideal body weight (kg) + 0.4 [actual wt (kg) - ideal body weight (kg)]

Reconstitution

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.

Administration

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]).

Compatibility

Variable stability (consult detailed reference) in D5W, NS.

Y-site administration: Incompatible with cisplatin, filgrastim, minocycline, vinorelbine.

Storage

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 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 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.

Drug Interactions

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

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

Warnings/Precautions

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.

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

Pregnancy Risk Factor

D

Pregnancy Considerations

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.

Patient Education

• 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.

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