(thye oh TEP a)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Tepadina: 15 mg (1 ea); 100 mg (1 ea)
Solution Reconstituted, Injection [preservative free]:
Tepadina: 15 mg (1 ea); 100 mg (1 ea)
Generic: 15 mg (1 ea)
Brand Names: U.S.
- Antineoplastic Agent, Alkylating Agent
Thiotepa is an alkylating agent which produces cross-linking of DNA strands leading to inhibition of DNA, RNA, and protein synthesis; thiotepa is cell-cycle independent (Perry 2012)
Vdss: 0.3 to 1.6 L/kg; penetrates into CSF (Maanen 2000); the mean volume of distribution following a single IV dose in pediatric patients receiving a 5 mg/kg dose was 1.2 L/kg or 30 L/m2
Extensively hepatic via cytochrome P450 system, primarily to the major (active) metabolite TEPA (Maanen 2000; Perry 2012)
Urine (<2% of thiotepa dose; <11% of TEPA)
Pediatrics (5 mg/kg IV dose): Thiotepa: 1.7 hours; TEPA: 4 hours
Adults (20 mg to 250 mg/m2 IV dose): Thiotepa: 1.4 to 3.7 hours; TEPA: 4.9 to 17.6 hours
~10% to 20%
Special Populations: Renal Function Impairment
Thiotepa and TEPA exposure increased 1.5-fold and 2.6-fold, respectively, following administration of multiple doses of 120 mg/m2/day in a patient with moderate renal impairment (CrCl 38 mL/minute), compared to patients with normal renal function.
Special Populations: Hepatic Function Impairment
In two adult patients with liver metastases and moderate hepatic impairment receiving multiple thiotepa doses of 7 mg/kg (administered every 2 days with cyclophosphamide), thiotepa exposure increased by 1.6-fold and 1.8-fold compared to a patient with normal hepatic function.
Use: Labeled Indications
Beta-thalassemia, class 3: To reduce the risk of graft rejection when used in conjunction with high-dose busulfan and cyclophosphamide as a preparative regimen for allogeneic hematopoietic progenitor (stem) cell transplantation in pediatric patients with class 3 beta-thalassemia.
Off Label Uses
Hematopoietic stem cell transplant (HSCT) for CNS malignancy
Data from a prospective, multicenter clinical trial in patients with refractory or recurrent primary CNS or intraocular lymphoma supports the use of thiotepa (in combination with busulfan and cyclophosphamide) as a conditioning regimen in adult patients receiving hematopoietic stem cell transplant (HSCT) for CNS malignancy [Soussain 2008]. Data from a phase II study in patients with newly diagnosed anaplastic or aggressive oligodendroglioma also support the use of high-dose thiotepa in adult patients receiving HSCT for CNS malignancy [Abrey 2006]. Additional data also supports the use of thiotepa as a component of intensive chemotherapy prior to autologous hematopoietic stem cell transplant in pediatric patients with CNS malignancies [Dunkel 2010], [Gilheeney 2010], [Grodman 2009]. Additional trials may be necessary to further define the role of thiotepa in this condition.
Leptomeningeal metastases (intrathecal)
Data from a randomized, cooperative group study in patients with neoplastic meningitis supports the use of thiotepa given intrathecally (off-label route) for leptomeningeal metastases [Grossman 1993]. Additional trials may be necessary to further define the role of thiotepa in this condition.
Known hypersensitivity (allergy) to thiotepa or any component of the formulation; concomitant use with live or attenuated vaccines (Tepadina)
Note: Thiotepa is associated with a moderate emetic potential in adults (depending on dose/indication); antiemetics may be recommended to prevent nausea and vomiting (Roila 2016). Although included in the manufacturer's labeling as approved uses, other contemporary therapies have replaced the use of thiotepa for the treatment of papillary bladder, ovarian, and breast cancers, as well as malignant intracavitary effusions.
Hematopoietic stem cell transplant (HSCT) for CNS malignancy (off-label use): IV: 250 mg/m2/day for 3 days beginning 9 days prior to transplant (in combination with busulfan and cyclophosphamide) (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)
Leptomeningeal metastases (off-label use/route): Intrathecal: 10 mg twice a week (on days 1 and 4 each week) for 8 weeks (Grossman 1993)
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).
Beta-thalassemia, class 3 (Tepadina): Infants, Children, and Adolescents: IV: 5 mg/kg every 12 hours for 2 doses on the sixth day prior to allogeneic hematopoietic stem cell transplantation (in combination with high-dose busulfan and cyclophosphamide)
Hematopoietic stem cell transplant (HSCT) for CNS malignancy (off-label use): IV: 300 mg/m2/day for 3 days beginning 8 days prior to transplant (in combination with topotecan and carboplatin) (Gilheeney 2010) or 300 mg/m2/day for 3 days beginning 5 days prior to transplant (in combination with carboplatin and etoposide) (Dunkel 2010; Grodman 2009)
Dosing: Renal Impairment
There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; decreased renal excretion may result in increased thiotepa and TEPA plasma concentrations and increased toxicity. Monitor patients with moderate (CrCl 30 to 59 mL/minute) to severe (CrCl <30 mL/minute) impairment for toxicity.
Hemodialysis: Thiotepa is dialyzable.
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; thiotepa is extensively hepatically metabolized. Moderate (bilirubin >1.5 to 3 times ULN and any AST) or severe (bilirubin >3 times ULN and any AST) impairment may result in increased plasma concentrations and increased toxicity. Monitor closely.
Dosing: Adjustment for Toxicity
Central nervous system toxicity, severe or life-threatening: Discontinue thiotepa and provide supportive care.
Hypersensitivity reactions (eg, anaphylaxis or other clinically significant reaction): Discontinue thiotepa and manage as appropriate; monitor until signs/symptoms resolve.
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)]
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 (1,000 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: 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.
Intrathecal administration (off-label use/route); Dilute 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 (Roila 2016); antiemetics may be recommended to prevent nausea and vomiting.
IV: Administer over 3 hours via a central line (when administering as part of the preparative regimen for hematopoietic stem cell transplantation in class 3 beta-thalassemia). Infusion times may vary by protocol or dose for off-label uses; refer to specific protocols. Filtering does not alter thiotepa potency. Tepadina: Administer using a 0.2 micron in-line filter; flush line prior to and after infusion with ~5 mL NS.
Intrathecal route (off-label use/route): Was administered in 10 mL (preservative free) buffered solutions (Grossman 1993)
Tepadina: Store intact vials 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: Store intact vials 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.
Intrathecal thiotepa (off-label use/route): After preparation, keep intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.
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 (High risk with Inhibitors): Thiotepa may increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). 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. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. 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
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
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
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
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. Consider therapy modification
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
As a preparative regimen prior to allogeneic or autologous hemtopoietic progenitor cell transplantation:
Frequency not defined:
Central nervous system: Intracranial hemorrhage, seizure
Dermatologic: Skin rash
Hematologic & oncologic: Anemia, hemorrhage, neutropenia, thrombocytopenia
Hepatic: Increased serum ALT, increased serum AST, increased serum bilirubin
Infection: Cytomegalovirus disease
Other approved/nonapproved uses:
Frequency not defined:
Dermatologic: Alopecia, contact dermatitis, dermatitis, skin depigmentation, skin rash, urticaria
Central nervous system: Dizziness, fatigue, headache
Endocrine & metabolic: Amenorrhea
Gastrointestinal: Abdominal pain, anorexia, nausea, vomiting
Genitourinary: Cystitis, dysuria, hemorrhagic cystitis, inhibition of Spermatogenesis, urinary retention
Hypersensitivity: Anaphylactic shock, hypersensitivity reaction
Local: Pain at injection site
Neuromuscular & skeletal: Weakness
Ophthalmic: Blurred vision, conjunctivitis
Respiratory: Asthma, laryngeal edema, wheezing
Miscellaneous: Febrile reaction
<1%, postmarketing, and/or case reports: Abnormal gait, acute myelocytic leukemia, acute respiratory distress, acute sinusitis, amnesia, apathy, aphasia, arteriosclerosis (pulmonary arteriopathy), ascites, aspiration, ataxia, behavioral problems, blepharoptosis, blindness, blood coagulation disorder, blood platelet disorder (refractoriness to transfusion), bone marrow aplasia, bone marrow depression (bone marrow transplant rejection), bradycardia, brain disease, candidiasis, capillary leak syndrome, cerebrovascular accident, cognitive dysfunction, coma, confusion, congestive heart failure, cranial nerve palsy, deafness, delirium, depression, diarrhea, disorientation, drowsiness, dysphagia, dyspnea on exertion, encephalitis, enterocolitis, epstein-barr infection, fever, forgetfulness, fungal infection, gastritis, gastroenteritis, gastrointestinal hemorrhage, hallucination, hematuria, hemiplegia, hepatomegaly, hyponatremia, hypotonia, immunosuppression, infection due to enterococcus, interstitial pulmonary disease, klebsiella species, lesion (including central nervous system and white matter), leukemia (recurrent), leukoencephalopathy, lower respiratory tract infection (viral), lymphoproliferative disorder (posttransplant), malaise, malignant lymphoma (including central nervous system lymphoma), malignant neoplasm (recurrence), malignant neoplasm of breast (metastatic), memory impairment, motor dysfunction, mouth disease (palatal disorder), myelodysplastic syndrome, neoplasm (metastatic), neurotoxicity, pain, papilledema, paralysis (retrobulbar), paresis (quadriparesis), pericardial effusion, pericarditis, pneumonitis, pseudomonas infection, psychomotor retardation, pulmonary aspergillosis, pulmonary disease, pulmonary hypertension, pulmonary veno-occlusive disease, pure red cell aplasia, renal failure, respiratory distress, respiratory tract infection, sepsis, septic shock, speech disturbance, staphylococcal bacteremia, staphylococcal infection, Stevens-Johnson Syndrome, strabismus, subarachnoid hemorrhage, subdural hematoma, suicidal ideation, thrombotic thrombocytopenic purpura (cerebral), toxic epidermal necrolysis, toxic nephrosis, tremor, urinary tract infection, vasodilatation (cerebral ventricle), ventricular hypertrophy, weight gain
Concerns related to adverse effects:
• Bone marrow suppression: Myelosuppression (leukopenia, thrombocytopenia, and anemia) may commonly occur, particularly when used as part of the preparative regimen for hematopoietic stem cell transplantation (HSCT) or in patients with compromised bone marrow function. Do not initiate the HSCT conditioning regimen if a stem cell donor is not available. Monitor blood counts closely. 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).
• CNS effects: Fatal encephalopathy has been reported in patients receiving high-dose thiotepa. Headache, apathy, psychomotor retardation, disorientation, confusion, amnesia, hallucinations, drowsiness, somnolence, seizures, coma, inappropriate behavior, and forgetfulness have also been reported (may be dose dependent). If severe or life-threatening central nervous system toxicity occurs, discontinue treatment and manage as necessary. CNS toxicity, including seizures and intracranial hemorrhage was reported in pediatric patients who receive the recommended dose in combination with busulfan and cyclophosphamide as a stem cell conditioning regimen for beta thalassemia; do not exceed the recommended dose.
• Dermatologic toxicity: In patients receiving high-dose thiotepa, the parent drug and/or its active metabolites may be partially excreted through the skin. Thiotepa may cause skin discoloration, pruritus, blistering, desquamation, and peeling (may be more severe in skin folds, groin, axillae, and neck areas, and under dressings). Change occlusive dressing and clean covered skin at least twice daily during and for 48 hours after thiotepa administration (when used as a component of the HSCT preparative regimen). Patients should shower/bathe in water twice daily through 48 hours after receiving thiotepa. Change bed sheets daily. Accidental thiotepa exposure is also associated with skin reactions; wash skin thoroughly with soap and water and flush mucous membranes if skin and/or mucous membrane contact occurs.
• GI 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 (Roila 2016); antiemetics are recommended to prevent nausea and vomiting. Thiotepa is also associated with mucositis.
• Hepatic sinusoidal obstruction syndrome: Hepatic sinusoidal obstruction syndrome (SOS, also called veno-occlusive disease [VOD]) may occur in patients receiving thiotepa in combination with busulfan and cyclophosphamide as a preparative regimen prior to HSCT. Monitor serum transaminases, bilirubin and for signs/symptoms of hepatic SOS through day +28 of stem cell transplant; provide supportive care if SOS develops.
• Hypersensitivity: Clinically significant hypersensitivity reactions (including anaphylaxis) have occurred. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, discontinue thiotepa treatment and initiate appropriate supportive management. Monitor until resolution of symptoms.
• Secondary malignancies: Thiotepa is potentially carcinogenic; myelodysplastic syndrome and acute myeloid leukemia (AML) have been reported. There is an increased risk of secondary malignancies with thiotepa use.
• Hepatic impairment: Use with caution in patients with hepatic impairment; thiotepa is extensively hepatically metabolized; moderate (bilirubin >1.5 to 3 times ULN and any AST) or severe (bilirubin >3 times ULN and any AST) impairment may result in increased plasma concentrations and increased toxicity. Monitor closely.
• Renal impairment: Use with caution in patients with renal impairment; decreased renal excretion may result in increased thiotepa and TEPA plasma concentrations and increased toxicity. Monitor closely.
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.
• Vaccines: Do not administer live or attenuated viral or bacterial vaccines until the immunosuppressive effects of thiotepa have resolved.
• 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 also intended for administration into the central nervous system (Jacobson 2009).
CBC with differential and platelet count frequently throughout therapy; renal and liver function tests; signs/symptoms of hypersensitivity reactions, dermatologic toxicity, hepatic sinusoidal obstruction syndrome, and CNS toxicity
Pregnancy Risk Factor
Adverse events were observed in animal reproduction studies. Based on the mechanism of action, thiotepa may cause fetal harm if used in pregnant women. Verify pregnancy status in women of reproductive potential prior to therapy initiation. Effective contraception should be used during treatment and for at least 6 months after the final dose. Males with female partners of reproductive potential should use effective contraception during therapy and for at least 1 year after the final dose. Both male and female fertility may be affected by thiotepa administration.
• 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 diarrhea, dizziness, hair loss, lack of appetite, nausea, vomiting, abdominal pain, or injection site irritation. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), severe loss of strength and energy, amenorrhea, mouth irritation, mouth sores, difficult urination, vision changes, eye pain, severe eye irritation, severe fatigue, confusion, behavioral changes, hallucinations, memory impairment, seizures, difficulty moving, or severe headache (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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- Drug class: alkylating agents
Other brands: Tepadina