Tepadina

Approved Indications:

• Breast Cancer: Palliative treatment for advanced or recurrent breast carcinoma, especially after failure of standard regimens.
• Ovarian Cancer: Palliative therapy for advanced epithelial ovarian carcinoma.
• Bladder Cancer: Intravesical use in superficial transitional cell carcinoma of the bladder.
• Hodgkin’s Lymphoma and Non-Hodgkin’s Lymphoma: As part of combination chemotherapy regimens.
• Malignant Effusions: Management of malignant pleural, peritoneal, and pericardial effusions.
• Hematopoietic Stem Cell Transplantation (HSCT): High-dose conditioning agent prior to autologous or allogeneic transplantation, particularly in pediatric patients with solid tumors and hematologic malignancies.

Clinically Accepted Off-Label Uses:

• Carcinomatous Meningitis: Intrathecal use in the treatment of leptomeningeal metastases.
• Melanoma (Advanced): Rare use in experimental protocols for disseminated melanoma.
• High-Dose Conditioning in Adults: In HSCT regimens where other alkylators are contraindicated or ineffective.

Route of Administration:

• Intravenous (IV)
• Intravesical
• Intrathecal (off-label in specialized protocols only)

Adult Dosage:

• Systemic IV (Solid Tumors): 0.3 to 0.4 mg/kg every 1 to 4 weeks depending on patient response and hematologic tolerance.
• Intravesical for Bladder Cancer: 30–60 mg in 30–60 mL sterile saline, instilled directly into the bladder. Retain for 1–2 hours, repeat weekly or as indicated.
• Conditioning Regimen (HSCT): 5–10 mg/kg/day IV for 3 consecutive days, usually combined with other agents (e.g., busulfan, fludarabine).

Pediatric Dosage:

• Conditioning for HSCT: 5–10 mg/kg/day IV for 3 days.
• Intrathecal (off-label for CNS involvement): 2 mg/m² once weekly in select protocols.

Elderly:

• Use with caution; dose reduction may be necessary due to reduced hepatic/renal function.

Renal Impairment:

• No formal guidelines; use with caution. Monitor for toxicity and adjust dose if needed.

Hepatic Impairment:

• Contraindicated in severe impairment. For mild to moderate dysfunction, monitor liver function closely.

Dose Modifications:

• Delay or reduce dosage in cases of severe myelosuppression (neutropenia or thrombocytopenia).

Thiotepa is a polyfunctional alkylating agent of the ethylenimine class. It exerts cytotoxic effects by alkylating DNA, specifically by introducing alkyl groups at the N7 position of guanine bases, causing inter- and intra-strand cross-links. These DNA adducts inhibit DNA replication and transcription, resulting in cell cycle arrest and apoptosis. Its active metabolite, triethylenephosphoramide (TEPA), further enhances its cytotoxic activity. Thiotepa is non–cell cycle specific and is most effective against rapidly dividing cancer cells.

• Absorption: Not applicable (non-oral formulation).
• Distribution: Wide distribution in body tissues and fluids, including cerebrospinal fluid (CSF).
• Protein Binding: Approximately 10–20%.
• Metabolism: Hepatic metabolism primarily via CYP3A4 to active metabolite TEPA.
• Half-life:
• Thiotepa: 1.5–3 hours
• TEPA: 10–25 hours
• Excretion: Renal elimination (approximately 10% unchanged); metabolites primarily excreted in urine.

• Pregnancy: Thiotepa is teratogenic and embryotoxic. Use is contraindicated during pregnancy unless no alternatives are available. Women of childbearing potential must use effective contraception during treatment and for at least 6 months afterward.
  Pregnancy Category: D (known risk to fetus).
• Lactation: Excreted into breast milk. Breastfeeding is contraindicated during and for at least 1 week after the final dose due to potential toxicity to the infant.
• Fertility Warning: May cause irreversible infertility in both male and female patients.

• Primary Class: Antineoplastic Agent
• Subclass: Alkylating Agent – Ethylenimine Class
• Generation: First-generation alkylating agent

• Known hypersensitivity to Thiotepa or any formulation excipients
• Severe bone marrow suppression
• Active, uncontrolled systemic infection
• Severe hepatic impairment
• Concurrent use of live vaccines
• Pregnancy and breastfeeding
• Intrathecal use in patients receiving concurrent high-dose systemic chemotherapy (outside of protocols)

• Myelosuppression: Severe leukopenia, thrombocytopenia, and anemia may occur. Monitor CBC frequently.
• Secondary Malignancies: Long-term use may increase the risk of therapy-related leukemia or myelodysplastic syndromes.
• Dermatologic Reactions: High-dose therapy can cause severe skin reactions including desquamation and erythema.
• Hepatotoxicity: Monitor liver function; discontinue if significant transaminase elevations occur.
• Neurotoxicity (Intrathecal): Rare CNS toxicity with off-label intrathecal use; must be administered under specialist protocols.
• Reproductive Toxicity: Infertility, teratogenic effects, and amenorrhea may result.
• Immunosuppression: Increased susceptibility to infections; avoid live vaccines.
• Bladder Toxicity (Intravesical): Dysuria and hematuria; monitor for hemorrhagic cystitis.

Common Adverse Effects:

• Hematologic: Leukopenia, thrombocytopenia, anemia
• Gastrointestinal: Nausea, vomiting, anorexia, stomatitis
• Dermatologic: Rash, hyperpigmentation, desquamation
• Genitourinary (Intravesical): Dysuria, frequency, hematuria

Serious or Rare Adverse Effects:

• Severe myelosuppression leading to infection or bleeding
• Hepatic dysfunction or failure
• Secondary malignancies (e.g., leukemia)
• Pulmonary fibrosis (rare)
• Infertility or amenorrhea
• Neurotoxicity (headache, dizziness, CNS depression)
• Severe cutaneous reactions (e.g., toxic epidermal necrolysis—rare)

• Live Vaccines: Avoid due to increased infection risk from immunosuppression.
• CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir): May increase plasma levels and toxicity.
• CYP3A4 Inducers (e.g., rifampin, carbamazepine): May reduce therapeutic efficacy.
• Other Myelosuppressive Agents (e.g., cisplatin, cyclophosphamide): Additive hematologic toxicity.
• Warfarin: Monitor INR closely due to potential enhancement or reduction in anticoagulant effect.

• FDA Update: Granted orphan drug status for use in conditioning regimens in pediatric HSCT.
• EMA: Included Thiotepa as part of conditioning protocols for both pediatric and adult stem cell transplant regimens.
• ASCO/EBMT Guidelines: Recognize its role in reduced-toxicity and high-dose conditioning prior to HSCT in pediatric cancers.
• WHO: Thiotepa is listed in select protocols for CNS and hematologic malignancies requiring CNS penetration.

• Temperature: Store unopened vials at 2°C to 8°C (refrigerated).
• Protect from Light: Keep vials in original carton until use.
• Do Not Freeze.
• Reconstitution Instructions:
• Reconstitute with sterile water for injection.
• Reconstituted solution should be used within 1 hour if kept at room temperature or 24 hours if refrigerated (2°C to 8°C).
• Handling: Cytotoxic agent – use gloves and safety measures during handling and disposal.
• Disposal: Dispose of according to local guidelines for cytotoxic drugs.