Usage
Thiotepa is an alkylating agent indicated for:
- Adenocarcinoma of the breast or ovary.
- Controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities (e.g., pleural, pericardial, peritoneal).
- Treatment of superficial papillary carcinoma of the urinary bladder.
- Conditioning treatment prior to allogeneic or autologous hematopoietic progenitor cell transplantation (HPCT) in haematological diseases and solid tumors (in combination with other chemotherapy medicinal products, with or without total body irradiation).
Alternate Names
- Tepadina
- Tepylute
- Thioplex
- Thiotepa for Injection, USP
How It Works
Pharmacodynamics: Thiotepa is a polyfunctional alkylating agent related to nitrogen mustard. Its radiomimetic action occurs through the release of ethyleneimine radicals, which crosslink DNA strands. This disrupts DNA replication and function, ultimately leading to cell death. Thiotepa also interferes with RNA and protein synthesis.
Pharmacokinetics:
- Absorption: Varies depending on the route of administration (intravenous, intracavitary, intravesical). Intravenous administration results in rapid systemic distribution. Intracavitary administration results in localized effects with minimal systemic absorption. Intravesical administration can result in limited systemic absorption.
- Metabolism: Thiotepa is metabolized in the liver primarily by CYP3A4 and CYP2B6 to its active metabolite, TEPA.
- Elimination: Thiotepa and its metabolites are primarily eliminated through metabolism with limited renal excretion.
Dosage
Standard Dosage
Adults:
- Adenocarcinoma of the breast or ovary: 0.3 to 0.4 mg/kg intravenously every 1 to 4 weeks. Initially, the higher dose is typically administered. Maintenance doses are adjusted weekly based on blood counts.
- Malignant effusions: 0.6 to 0.8 mg/kg intracavitary every 1 to 4 weeks. Initially, the higher dose is typically administered. Maintenance doses are adjusted weekly based on blood counts.
- Superficial papillary carcinoma of the urinary bladder: 60 mg in 30 to 60 mL of Sodium Chloride Injection instilled into the bladder via catheter. Retain for 2 hours. Administer once weekly for 4 weeks. Repeat courses may be given with caution due to cumulative bone marrow suppression.
Children: Pediatric dosing information is available for Tepadina, but not always included in labeling due to marketing exclusivity. Dosing is generally based on body surface area (BSA) and disease-specific protocols, particularly in the context of HPCT. Consult specialized resources for detailed pediatric regimens.
Special Cases:
- Elderly Patients: Start at the low end of the dosing range and monitor closely due to potential age-related organ dysfunction.
- Patients with Renal Impairment: Caution is advised in moderate to severe renal impairment due to potential for increased thiotepa and TEPA plasma levels. Closely monitor for toxicity. Dosage modifications may be necessary.
- Patients with Hepatic Dysfunction: Caution is advised in moderate to severe hepatic impairment due to potential for increased plasma levels of thiotepa. Closely monitor for toxicity. Dosage modifications may be necessary.
- Patients with Comorbid Conditions: Carefully assess patients with pre-existing cardiac disease or history of prior radiation therapy, stem cell transplant or multiple cycles of chemotherapy due to potential for increased toxicity.
Clinical Use Cases
Dosing for HPCT and other specialized uses varies widely based on the specific protocol, disease, and combination with other chemotherapeutic agents. Consult specific protocol guidelines.
Dosage Adjustments
Dose adjustments may be necessary based on patient-specific factors including renal/hepatic function, hematologic parameters, and concomitant medications.
Side Effects
Common Side Effects
- Neutropenia
- Anemia
- Thrombocytopenia
- Elevated liver enzymes (ALT, AST, bilirubin)
- Mucositis
- Nausea and vomiting
- Anorexia
- Fatigue and weakness
- Headache
- Dizziness
Rare but Serious Side Effects
- Severe myelosuppression with resulting infection or bleeding
- Secondary malignancies (MDS, AML)
- Hepatic veno-occlusive disease
- Pulmonary toxicity
- Neurotoxicity
- Severe skin reactions (e.g., Stevens-Johnson syndrome)
- Allergic reactions
Long-Term Effects
- Infertility
- Secondary malignancies
Adverse Drug Reactions (ADR)
- Severe myelosuppression
- Anaphylaxis
Contraindications
- Severe hypersensitivity to thiotepa
- Concomitant use with live or attenuated vaccines (except under specific circumstances like yellow fever vaccine)
Drug Interactions
- CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) may increase thiotepa toxicity.
- CYP3A4 inducers (e.g., rifampin, phenytoin) may decrease thiotepa efficacy.
- Numerous other potential interactions exist. Consult a drug interaction checker for a comprehensive assessment.
Pregnancy and Breastfeeding
- Pregnancy: Thiotepa is contraindicated in pregnancy. It is teratogenic and can cause fetal harm. Effective contraception is essential during and after treatment (at least 6 months for females, 1 year for males).
- Breastfeeding: Thiotepa is contraindicated during breastfeeding. It is unknown if it is excreted in breast milk, but potential harm to the infant exists.
Drug Profile Summary
- Mechanism of Action: Alkylating agent; crosslinks DNA, disrupts DNA/RNA function, and causes cell death.
- Side Effects: Myelosuppression, nausea, vomiting, mucositis, hepatic dysfunction, pulmonary toxicity, neurotoxicity.
- Contraindications: Hypersensitivity to thiotepa, concomitant use with live vaccines, pregnancy, breastfeeding.
- Drug Interactions: CYP3A4 inhibitors and inducers, numerous other potential interactions.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Varies based on indication and route of administration. See detailed dosage section.
- Monitoring Parameters: Complete blood counts (including differential and platelets), liver function tests, renal function tests.
Popular Combinations
Thiotepa is often used in combination regimens for HPCT conditioning. The specific combinations and dosages are determined by disease and treatment protocol.
Precautions
- Monitor blood counts closely during and after treatment.
- Monitor liver and renal function.
- Avoid concomitant use of live vaccines.
- Counsel patients on contraception and fertility preservation.
- Use safe handling precautions to avoid skin contact.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Thiotepa?
A: Dosage varies depending on indication and route of administration. See detailed dosage section above.
Q2: What are the major side effects of Thiotepa?
A: Myelosuppression (neutropenia, anemia, thrombocytopenia), nausea, vomiting, mucositis, and increased liver enzymes.
Q3: Is Thiotepa safe to use during pregnancy or breastfeeding?
A: No, Thiotepa is contraindicated in both pregnancy and breastfeeding.
Q4: What are the primary drug interactions with Thiotepa?
A: CYP3A4 inhibitors and inducers can significantly affect thiotepa levels and toxicity. Many other drug interactions are possible; consult a drug interaction checker.
Q5: How does Thiotepa work at the cellular level?
A: It acts as an alkylating agent, forming crosslinks in DNA and disrupting DNA replication and function, leading to cell death.
Q6: What are the key monitoring parameters during Thiotepa treatment?
A: Complete blood counts (including differential and platelets), liver function tests, and renal function tests are essential.
Q7: What precautions should be taken when administering Thiotepa?
A: Use safe handling techniques to avoid skin contact. Closely monitor blood counts and organ function. Counsel patients on contraception and fertility preservation.
Q8: What is the role of Thiotepa in HPCT?
A: It’s used as part of the conditioning regimen prior to HPCT, often in combination with other chemotherapy drugs, to suppress the bone marrow and prepare for transplant.
Q9: How is Thiotepa administered for bladder cancer?
A: It’s instilled directly into the bladder via a catheter.
Q10: Are there any long-term risks associated with Thiotepa?
A: Yes, infertility and secondary malignancies are potential long-term risks.
