Thiotepa

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).

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.

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.

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 (Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting. Thiotepa is also associated with mucositis.

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.

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.

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. Disease-related concerns:

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.

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:

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.

Do not administer live or attenuated viral or bacterial vaccines until the immunosuppressive effects of thiotepa have resolved. Other warnings/precautions:

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).