Thiotepa is indicated, in combination with other chemotherapy medicinal products:

• With or without total body irradiation (TBI), as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients;
• When high dose chemotherapy with HPCT support is appropriate for the treatment of solid tumours in adult and paediatric patients.

Thiotepa is a polyfunctional cytotoxic agent related chemically and pharmacologically to the nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylene imine radicals that, as in the case of irradiation therapy, disrupt the bonds of DNA, e.g. by alkylation of guanine at the N-7, breaking the linkage between the purine base and the sugar and liberating alkylated guanine.

Adults-

Autologous HPCT:

• Haematological diseases: The recommended dose in haematological diseases ranges from 125 mg/m2/day (3.38 mg/kg/day) to 300 mg/m2/day (8.10 mg/kg/day) as a single daily infusion, administered from2up to 4 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 900 mg/m2(24.32 mg/kg), during the time of the entire conditioning treatment.
• Lymphoma: The recommended dose ranges from 125 mg/m2/day (3.38 mg/kg/day) to 300 mg/m2/day (8.10 mg/kg/day) as a single daily infusion, administered from2up to 4 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 900 mg/m2(24.32 mg/kg), during the time of the entire conditioning treatment.
• Central nervous system lymphoma: The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2(10 mg/kg), during the time of the entire conditioning treatment.
• Multiple myeloma: The recommended dose ranges from 150 mg/m2/day (4.05 mg/kg/day) to 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered for 3 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 750 mg/m2(20.27 mg/kg), during the time of the entire conditioning treatment.

Solid tumours: The recommended dose in solid tumours ranges from 120 mg/m2/day (3.24 mg/kg/day) to 250 mg/m2/day (6.76 mg/kg/day) divided in one or two daily infusions, administered from2up to 5 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 800 mg/m2(21.62 mg/kg), during the time of the entire conditioning treatment.

• Breast cancer: The recommended dose ranges from 120 mg/m2/day (3.24 mg/kg/day) to 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered from 3 up to 5 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 800 mg/m2(21.62 mg/kg), during the time of the entire conditioning treatment.
• CNS tumours: The recommended dose ranges from 125 mg/m2/day (3.38 mg/kg/day) to 250 mg/m2/day (6.76 mg/kg/day) divided in one or two daily infusions, administered from 3 up to 4 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 750 mg/m2(20.27 mg/kg), during the time of the entire conditioning treatment.
• Ovarian cancer: The recommended dose is 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered in 2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative dose of 500 mg/m2(13.51 mg/kg), during the time of the entire conditioning treatment.
• Germ cell tumours: The recommended dose ranges from 150 mg/m2/day (4.05 mg/kg/day) to 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered for 3 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 750 mg/m2(20.27 mg/kg), during the time of the entire conditioning treatment.

Allogeneic HPCT:

• Haematological diseases: The recommended dose in haematological diseases ranges from 185 mg/m2/day (5 mg/kg/day) to 481 mg/m2/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 555 mg/m2(15 mg/kg), during the time of the entire conditioning treatment.
• Lymphoma: The recommended dose in lymphoma is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2(10 mg/kg), during the time of the entire conditioning treatment.
• Multiple myeloma: The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion before allogeneic HPCT, without exceeding the total maximum cumulative dose of 185 mg/m2(5 mg/kg), during the time of the entire conditioning treatment.
• Leukaemia: The recommended dose ranges from 185 mg/m2/day (5 mg/kg/day) to 481 mg/m2/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 2 consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 555 mg/m2(15 mg/kg), during the time of the entire conditioning treatment.
• Thalassemia: The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2(10 mg/kg), during the time of the entire conditioning treatment.

Live virus and bacterial vaccines must not be administered to a patient receiving an immunosuppressive chemotherapeutic agent and at least three months must elapse between discontinuation of therapy and vaccination.

Thiotepa appears to be metabolised via CYP2B6 and CYP3A4. Co-administration with inhibitors of CYP2B6 (for example clopidogrel and ticlopidine) or CYP3A4 (for example azole antifungals, macrolides like erythromycin, clarithromycin, telithromycin, and protease inhibitors) may increase the plasma concentrations of thiotepa and potentially decrease the concentrations of the active metabolite TEPA. Co-administration of inducers of cytochrome P450 (such as rifampicin, carbamazepine, phenobarbital) may increase the metabolism of thiotepa leading to increased plasma concentrations of the active metabolite. Therefore, during the concomitant use of thiotepa and these medicinal products, patients should be carefully monitored clinically.

Thiotepa is a weak inhibitor for CYP2B6, and may thereby potentially increase plasma concentrations of substances metabolised via CYP2B6, such as ifosfamide, tamoxifen, bupropion, efavirenz and cyclophosphamide. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide to its active form 4-hydroxycyclophosphamide (4-OHCP) and co-administration of thiotepa may therefore lead to decreased concentrations of the active 4 OHCP. Therefore, a clinical monitoring should be exercised during the concomitant use of thiotepa and these medicinal products.

Hypersensitivity to the active substance. Pregnancy and lactation. Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines.

There are no data on the use of thiotepa during pregnancy. In pre-clinical studies thiotepa, as most alkylating agents, has been shown to cause embryofoetal lethality and teratogenicity. Therefore, thiotepa is contraindicated during pregnancy. It is unknown whether thiotepa is excreted in human milk. Due to its pharmacological properties and its potential toxicity for breast-fed newborns/infants, breastfeeding is contraindicated during treatment with thiotepa.

The consequence of treatment with thiotepa at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts need to be performed during the treatment and until recovery is achieved. Platelet and red blood cell support, as well as the use of growth factors such as Granulocyte- colony stimulating factor (G-CSF), should be employed as medically indicated. Daily white blood cell counts and platelet counts are recommended during therapy with thiotepa and after transplant for at least 30 days.

Renal impairment: Studies in renally impaired patients have not been conducted. As thiotepa and its metabolites are poorly excreted in the urine, dose modification is not recommended in patients with mild or moderate renal insufficiency. However, caution is recommended.

Hepatic impairment: Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly metabolized through the liver, caution needs to be exercised when thiotepa is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. Dose modification is not recommended for transient alterations of hepatic parameters.

Elderly: The administration of thiotepa has not been specifically investigated in elderly patients. However, in clinical studies, a proportion of patients over the age of 65 received the same cumulative dose as the other patients. No dose adjustment was deemed necessary.

There is no experience with overdoses of thiotepa. The most important adverse reactions expected in case of overdose is myeloablation and pancytopenia. There is no known antidote for thiotepa. The haematological status needs to be closely monitored and vigorous supportive measures instituted as medically indicated.

Haematopoietic Agents

Store and transport refrigerated (2°C-8°C). Do not freeze.