TEPADINA: Uses, Dosage & Side Effects

What Is TEPADINA and What Is It Used For?

TEPADINA contains the active substance thiotepa, a polyfunctional alkylating agent that has been used in cancer medicine for more than six decades. Thiotepa belongs to the ethyleneimines subgroup of alkylating agents, and its chemical structure contains three reactive aziridine rings that open spontaneously under physiological conditions to generate electrophilic intermediates. These intermediates bind covalently to nucleophilic sites on DNA - predominantly the N7 atom of guanine - forming intrastrand and interstrand cross-links as well as DNA-protein bridges that prevent the separation of the two DNA strands necessary for replication and transcription. The result is cell-cycle arrest and programmed cell death (apoptosis) in dividing cells, and because thiotepa also damages resting cells, it is especially valuable in the context of myeloablative conditioning before stem cell transplantation.

In clinical practice, TEPADINA is never used as a single agent or as continuous chemotherapy. Instead, it is administered as part of carefully designed combination regimens - often together with busulfan, fludarabine, cyclophosphamide, melphalan, carboplatin, etoposide, or total body irradiation (TBI) - over a defined number of days immediately before the planned stem cell infusion. The dose, schedule, and combination chosen depend on the underlying disease, the patient's age and organ function, the source of stem cells, and whether the transplant is autologous (using the patient's own previously harvested cells) or allogeneic (using cells from a sibling, matched unrelated donor, or cord blood).

TEPADINA was granted orphan drug designation in the European Union in recognition of its importance in treating rare, life-threatening conditions that rely on stem cell transplantation for cure. It has been approved by the European Medicines Agency (EMA) since 2010 and by equivalent authorities in numerous other regions. Thiotepa is also included in the World Health Organization's (WHO) Model List of Essential Medicines because of its unique role in facilitating curative transplant strategies worldwide. In the United States, thiotepa has been marketed for many decades under various generic and branded formulations and is approved by the U.S. Food and Drug Administration (FDA) for similar transplant-conditioning indications as well as historical uses in certain solid tumors.

The authorized indications for TEPADINA include:

• Conditioning before allogeneic HPCT in adults: In combination with other chemotherapy medicinal products, TEPADINA is indicated as conditioning treatment prior to allogeneic haematopoietic progenitor cell transplantation for both hematologic malignancies (such as acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, and myelodysplastic syndromes) and non-malignant hematologic conditions (including thalassemia major, sickle cell disease, aplastic anemia, and certain inherited bone marrow failure syndromes).
• Conditioning before autologous HPCT in adults: TEPADINA is used with other chemotherapy when high-dose chemotherapy followed by autologous stem cell support is considered appropriate, particularly for lymphomas and multiple myeloma.
• Conditioning before allogeneic HPCT in pediatric patients: In combination with other chemotherapy agents, with or without TBI, TEPADINA is used to prepare children and adolescents for allogeneic transplantation for hematologic diseases. It plays a key role in regimens for severe genetic disorders (e.g., sickle cell disease, thalassemia, Wiskott-Aldrich syndrome, severe combined immunodeficiency) as well as for pediatric leukemias and lymphomas.
• Conditioning before autologous HPCT in pediatric solid tumors: TEPADINA is a cornerstone of high-dose chemotherapy regimens for children with high-risk neuroblastoma, medulloblastoma and other high-risk embryonal CNS tumors, retinoblastoma with extraocular spread, and certain relapsed germ cell tumors. Its ability to cross the blood-brain barrier is particularly valuable for central nervous system disease.

Historically, thiotepa has also been used at lower (non-myeloablative) doses for intravesical treatment of superficial bladder cancer and for intrathecal treatment of leptomeningeal carcinomatosis. However, TEPADINA as marketed today is specifically authorized for the conditioning indications listed above. Any other clinical use is considered off-label and should only be undertaken after careful individual assessment by an experienced oncology team.

What Should You Know Before Receiving TEPADINA?

Contraindications

TEPADINA must not be used in the following situations, which are absolute contraindications based on safety data:

• Hypersensitivity to thiotepa: Do not use TEPADINA if you have a known allergy to thiotepa or to any of the excipients. Cross-reactivity with other alkylating agents is not expected but should be considered if prior severe hypersensitivity reactions have occurred.
• Pregnancy and breastfeeding: TEPADINA is strictly contraindicated during pregnancy because of the genotoxic and teratogenic effects of thiotepa. It is also contraindicated during breastfeeding; nursing must be stopped before treatment begins and not restarted.
• Yellow fever vaccine and other live attenuated vaccines: Concomitant use with yellow fever vaccine is contraindicated because of the risk of fatal vaccine-strain disease. The use of other live attenuated vaccines is also not recommended during and for an extended period after conditioning, because the induced immunosuppression can allow disseminated infection.

Warnings and Precautions

Before and throughout treatment, your transplant team will perform careful monitoring for the following specific risks:

• Myelosuppression: All patients receiving conditioning doses of TEPADINA develop severe, prolonged suppression of white blood cells, red blood cells, and platelets. This is the expected pharmacologic effect - hence the need for planned stem cell rescue. Complete blood counts are monitored daily, and transfusions as well as hematopoietic growth factors are used as needed.
• Infections: The combination of mucositis, neutropenia, and cellular immune deficiency creates an extremely high risk of bacterial, viral, and fungal infections, including opportunistic pathogens such as cytomegalovirus (CMV), Pneumocystis jirovecii, and invasive aspergillosis. Prophylactic antimicrobial therapy and routine reactivation screening are standard.
• Hepatotoxicity and veno-occlusive disease (VOD / SOS): Thiotepa, particularly when combined with busulfan, can cause hepatic sinusoidal obstruction syndrome (also known as veno-occlusive disease of the liver). Warning signs include weight gain, painful enlarged liver, jaundice, and fluid retention. Liver enzymes, bilirubin, and body weight are monitored daily.
• Mucositis and gastrointestinal toxicity: Severe inflammation of the oral and gastrointestinal mucosa almost always occurs. It is managed with intensive oral care, pain control (often including opioid analgesia), antiemetics, and nutritional support (including total parenteral nutrition when needed).
• Neurotoxicity: High-dose thiotepa can cause encephalopathy, seizures, confusion, and coma, particularly at very high doses or in patients with pre-existing CNS pathology. Seizure prophylaxis is considered in regimens with neurotoxic combinations.
• Pulmonary toxicity: Interstitial pneumonitis and pulmonary fibrosis have been reported, particularly when TEPADINA is combined with other pneumotoxic agents or TBI. Any new respiratory symptoms must be investigated promptly.
• Cardiotoxicity: When given with cyclophosphamide or anthracyclines, TEPADINA may contribute to hemorrhagic myocarditis and cardiac failure. Baseline echocardiography or MUGA scan is recommended before conditioning.
• Renal and bladder effects: Nephrotoxicity is uncommon with thiotepa alone but can be additive with other agents. Hemorrhagic cystitis may occur in cyclophosphamide-containing regimens; hyperhydration and mesna are routinely used.
• Secondary malignancies: Like other alkylating agents, thiotepa is mutagenic and carcinogenic. Long-term survivors of conditioning therapy have an increased lifetime risk of therapy-related myelodysplastic syndrome (t-MDS), acute leukemia (t-AML), and solid second cancers. Lifelong oncologic follow-up is essential.
• Skin toxicity from excretion in sweat: Because thiotepa is excreted through the skin, occlusive dressings, skin folds, and the perineum may accumulate drug and develop chemical burns. Frequent bathing and dressing changes mitigate this risk.

Other Medications

Tell your transplant team about all prescription medicines, over-the-counter products, herbal remedies, and dietary supplements you use. Because thiotepa is metabolized by the CYP2B6 and CYP3A4 enzyme systems in the liver, drugs that inhibit or induce these enzymes may alter plasma exposure to thiotepa or its active metabolite TEPA. Combined use with other myelosuppressive agents, nephrotoxic medications, or hepatotoxic medications can compound side effects and is the norm rather than the exception in conditioning regimens, which is why expert management is essential.

Pregnancy, Fertility, and Breastfeeding

TEPADINA is classified as a category of medication that can cause severe birth defects and pregnancy loss. Animal studies with thiotepa have demonstrated embryolethality and teratogenic malformations at doses far below those used in conditioning. There are also case reports of human birth defects after exposure in utero. Women of childbearing potential must have a negative pregnancy test documented before the first dose and must use a highly effective method of contraception (e.g., hormonal contraception combined with a barrier method, or an intrauterine device) during treatment and for at least 6 months after the last dose.

Men receiving TEPADINA can cause genetic damage in sperm. Men must use effective contraception (e.g., condoms) during treatment and for up to 1 year after the last dose to prevent conception. Because thiotepa frequently causes azoospermia that may be permanent, men are advised to have sperm cryopreserved before treatment wherever possible. Similarly, fertility preservation options for women (oocyte or embryo cryopreservation, ovarian tissue banking) should be discussed with a reproductive medicine specialist before conditioning, because premature ovarian insufficiency is a common long-term consequence.

Breastfeeding is contraindicated during TEPADINA therapy and must be stopped before treatment begins. It is unknown whether thiotepa is excreted into human milk, but given the severity of the expected toxicity, breastfeeding an infant during or shortly after conditioning is not safe.

Driving and Operating Machinery

TEPADINA is administered to patients who are hospitalized for transplant conditioning and who will not be driving during the acute treatment and engraftment period. After discharge and recovery, any residual fatigue, neuropathy, or cognitive effects should be carefully assessed before resuming driving or operating machinery. If you experience any of these symptoms, discuss them with your care team before returning to such activities.

Important Information About Ingredients

TEPADINA is supplied as a powder containing only the active substance thiotepa. The powder does not contain any excipients. The reconstitution solvent - water for injections - is provided or used during preparation. After reconstitution and dilution for infusion, the final preparation may contain sodium chloride from the diluent. If you are on a sodium-restricted diet, this should be taken into account by your care team when planning fluid balance around conditioning.

How Does TEPADINA Interact with Other Drugs?

Drug interactions with TEPADINA fall into three broad categories: contraindicated combinations (mainly live vaccines and anticoagulants used without careful monitoring), pharmacokinetic interactions (involving the cytochrome P450 enzymes CYP2B6 and CYP3A4), and pharmacodynamic interactions (with drugs that add to myelosuppression, mucosal toxicity, or organ damage). Because conditioning regimens are tightly controlled protocols, essentially every medication the patient receives around the time of transplantation is reviewed by the pharmacy and transplant team.

Major Interactions

Additional Interactions

Because the list of possible interactions is extensive, the transplant pharmacy routinely screens every new prescription during the conditioning and early post-transplant period. Patients and caregivers should never start or stop any medication (including over-the-counter analgesics, herbal supplements, or complementary therapies) without confirming with the transplant team first.

What Is the Correct Dosage of TEPADINA?

TEPADINA is always given as part of a multi-drug conditioning regimen in a hospital transplant unit. Doses and schedules differ considerably between indications, and the examples below reflect ranges commonly described in the EMA Summary of Product Characteristics and in published transplant protocols. The exact regimen used for an individual patient is selected by the attending transplant physician after reviewing the diagnosis, prior therapy, organ function, and planned stem cell source.

Adults

Children and Adolescents

Elderly Patients

The safety and efficacy of TEPADINA in patients older than 65 years have not been studied in dedicated trials. Older adults considered for conditioning are evaluated carefully for organ function, comorbidities, and performance status. Reduced-intensity conditioning regimens using lower thiotepa doses are sometimes selected. Dose modification may be required based on hepatic and renal function. Because transplant-related mortality increases with age, the decision to proceed with conditioning is individualized.

Renal and Hepatic Impairment

Thiotepa has not been formally studied in patients with severe renal or hepatic impairment. Because the drug and its metabolites are partly eliminated through the kidneys and are extensively metabolized by the liver, significant organ dysfunction may increase toxicity. Dose adjustment is not standardized, but conditioning regimens in such patients are frequently modified or replaced with alternative options. TEPADINA should be used with particular caution in patients with pre-existing liver disease, given the heightened risk of hepatic veno-occlusive disease.

Missed Dose

Because TEPADINA is administered under hospital supervision as part of a tightly scheduled conditioning protocol, a missed dose in the usual sense should not occur. If an infusion is delayed or interrupted because of a clinical event (e.g., hypersensitivity reaction, organ toxicity, equipment failure), the transplant team will decide whether to resume the infusion, restart the dose, or modify the schedule based on the clinical context and pharmacokinetic considerations.

Overdose

There is no specific antidote to thiotepa. Overdose would be expected to produce severe, potentially irreversible bone marrow failure, profound mucositis, severe hepatic toxicity, and CNS depression. Management of accidental overdose is supportive: aggressive transfusion support, broad-spectrum antimicrobials, growth factor support, and, if possible, rescue with a stem cell graft. Hemodialysis is not expected to remove clinically significant amounts of thiotepa because of its high tissue distribution. Any known or suspected overdose of TEPADINA must be managed in a specialized transplant or intensive care setting.

How TEPADINA Is Given

TEPADINA is a white to off-white crystalline powder supplied in single-use vials of 15 mg, 100 mg, or 200 mg. It must be reconstituted in sterile water for injections and then diluted further in 500 mL of 0.9% sodium chloride solution before intravenous administration. The final infusion concentration depends on the dose and must be used as soon as possible after preparation, because the reconstituted solution is not chemically stable for prolonged periods.

The diluted solution is infused over 2 to 4 hours through a central venous catheter. Peripheral administration is not recommended because extravasation can cause severe local tissue damage. Patients are kept well hydrated, and anti-emetic prophylaxis is always given. Because thiotepa is excreted through sweat, saliva, tears, and other body fluids, the skin is washed frequently to prevent chemical burns.

What Are the Side Effects of TEPADINA?

The side-effect profile of TEPADINA is dominated by the expected and severe toxicity of myeloablative conditioning. Unlike conventional chemotherapy, where side effects are graded as common or uncommon, essentially every patient receiving conditioning doses of thiotepa develops profound pancytopenia and significant mucositis. The clinical priority is therefore to anticipate these effects and manage them with intensive supportive care until the stem cell graft engrafts and hematopoiesis recovers. The categories below are based on the frequencies observed in clinical trials and post-marketing experience reported in the EMA Summary of Product Characteristics.

Side Effects by Frequency

If you or your child experience any new or concerning symptoms during or after treatment, contact your transplant team immediately. Suspected adverse reactions can also be reported to your national pharmacovigilance authority, such as the European Medicines Agency (EMA) through the national competent authority, the FDA MedWatch program in the United States, or the MHRA Yellow Card Scheme in the United Kingdom. Reporting helps monitor the ongoing benefit-risk balance of TEPADINA.

How Should TEPADINA Be Stored?

Keep this medicine out of the sight and reach of children. Do not use TEPADINA after the expiry date stated on the vial label and outer carton after EXP. The expiry date refers to the last day of the stated month.

• Unopened vials: Store in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze.
• Light protection: Keep the vial in the original outer carton to protect it from light.
• Reconstituted and diluted solution: Should be used immediately. Chemical and physical in-use stability has been demonstrated for up to 24 hours at 2-8°C for the reconstituted solution and for a more limited period after dilution; from a microbiological point of view, the product should be used immediately unless reconstitution and dilution take place under validated aseptic conditions.
• Visual inspection: Before administration, visually inspect for particulate matter or discoloration. If the solution is cloudy, contains particles, or has changed color, it must not be used.
• Waste disposal: Cytotoxic waste handling procedures apply. Unused medicine or waste material must be disposed of in accordance with local requirements for cytotoxic drugs to protect patients, staff, and the environment.

Because TEPADINA is prepared and administered only in specialized hospital settings, patients and families will not need to handle storage themselves. The hospital pharmacy and transplant unit ensure that vials are stored correctly and that preparation takes place under validated aseptic conditions using appropriate cytotoxic safety cabinets and personal protective equipment.

What Does TEPADINA Contain?

Active Substance

The active substance in TEPADINA is thiotepa, a tri-functional alkylating agent with the chemical name N,N',N''-triethylenethiophosphoramide. Each single-use vial contains either 15 mg, 100 mg, or 200 mg of thiotepa, depending on the presentation. After reconstitution with 1.5 mL (for the 15 mg vial), 10 mL (for the 100 mg vial), or 20 mL (for the 200 mg vial) of sterile water for injections, the concentration is 10 mg/mL. The reconstituted solution is then further diluted in 500 mL of 0.9% sodium chloride solution before administration.

Inactive Ingredients (Excipients)

TEPADINA is a lyophilized powder containing only the active substance. No excipients are added to the powder itself. The diluent used for reconstitution is sterile water for injections (not preserved), and the infusion solution is 0.9% sodium chloride.

Appearance

TEPADINA is supplied as a white to off-white crystalline powder or cake in a transparent glass vial with a rubber stopper and aluminum crimp. After reconstitution in water for injections, the solution is clear and colorless; any cloudy or discolored preparation must be discarded. The dissolution of the powder is usually complete within 5 minutes with gentle agitation; vigorous shaking should be avoided.

Pack Sizes

TEPADINA is available in packs containing one vial of 15 mg, 100 mg, or 200 mg thiotepa. Not all pack sizes may be marketed in every country.

Manufacturer and Marketing Authorization Holder

TEPADINA is manufactured and marketed by Adienne S.r.l. S.U. (Italy), which holds the centralized European marketing authorization. The product is distributed in multiple European countries and globally by licensed importers and distributors. Similar thiotepa formulations are marketed in other regions under different trade names by various manufacturers, but all are subject to equivalent regulatory review by the relevant national authorities.