Thiotepa

Thiotepa is a polyfunctional alkylating agent, related chemically and pharmacologically to the nitrogen mustards. In conditioning treatment it is used for its strong myeloablative and immunosuppressive effect: the regimen has to reduce the tumour burden, ideally eradicating the disease, and, before an allogeneic transplant, suppress the recipient’s immune system enough to prevent rejection of the graft.

Mechanism of Action

• DNA alkylation: thiotepa is believed to release ethylene imine radicals that, like irradiation, disrupt the bonds of DNA. One result is alkylation of guanine at the N-7 position, which breaks the link between the purine base and the sugar and releases the alkylated guanine.
• Cross-linking: it attacks DNA directly and cross-links guanine bases in the double helix, so the strands can no longer uncoil and separate for replication and the cell cannot divide. The action is not specific to one cell type.
• Marrow ablation: ablation of the bone marrow is the dose-limiting toxicity, which allows large dose increases when the marrow is rescued by an autologous transplant. Thiotepa shows little toxicity outside the marrow even above myelotoxic doses and has been used for decades in conditioning regimens.
• Allogeneic transplantation: its strongly myeloablative and immunosuppressive effect helps overcome rejection of the donor graft and strengthens engraftment.
• Active metabolite: the main metabolite, TEPA (triethylenephosphoramide), is also an active alkylating agent.

Pharmacokinetics

• Absorption: thiotepa is absorbed unreliably from the gut and is unstable in acid, so it cannot be given by mouth; it is infused intravenously.
• Distribution: highly lipophilic; plasma concentrations after intravenous dosing fit a two-compartment model with a rapid distribution phase. The volume of distribution is large (40.8–75 L/m²), indicating distribution into total body water, and does not depend on dose. The fraction not bound to plasma proteins is 70–90% (albumin binding 10–30%). Exposure in cerebrospinal fluid is nearly equal to that in plasma (mean CSF to plasma AUC ratio 0.93), and CSF and plasma concentrations of TEPA exceed those of thiotepa.
• Metabolism: rapid and extensive in the liver. Oxidative desulphuration by the CYP2B and CYP3A enzyme families produces TEPA. The metabolites are active alkylating agents, although their share in the antitumour effect is not yet clear; thiotepa and its identified metabolites account for 54–100% of the total alkylating activity, so other alkylating metabolites exist.
• Elimination: total clearance 11.4–23.2 L/h/m²; elimination half-life 1.5–4.1 hours. TEPA, monochlorotepa and thiotepa-mercapturate are excreted in the urine, and urinary excretion of thiotepa and TEPA is nearly complete after 6 and 8 hours respectively. Mean urinary recovery is 0.5% for unchanged thiotepa and monochlorotepa and 11% for TEPA and thiotepa-mercapturate.
• Special populations: thiotepa has not been studied in renal or hepatic impairment. It and its metabolites are poorly excreted in urine, and it is mainly metabolised in the liver. In clinical studies, patients over 65 received the same cumulative dose as other patients.

Thiotepa is always used in combination with other chemotherapy medicinal products. The indications are the same for all four presentations (15 mg and 100 mg vials, 200 mg and 400 mg bags).

• Haematological diseases: with or without total body irradiation (TBI), as conditioning treatment before allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in adult and paediatric patients.
• Solid tumours: when high-dose chemotherapy with HPCT support is appropriate for the treatment of solid tumours in adult and paediatric patients.

• Hypersensitivity to thiotepa.
• Pregnancy and breastfeeding.
• Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines.

The safety data come from published clinical-trial reports on 6,588 adults and 902 children who received thiotepa as conditioning treatment before HPCT. Serious toxicity of the blood, liver and lungs is an expected consequence of the conditioning regimen and the transplant. Infection and graft-versus-host disease (GvHD) are not directly caused by thiotepa but were the main causes of illness and death, especially after allogeneic HPCT. The reactions reported most often with regimens that include thiotepa are infections, cytopenia, acute and chronic GvHD, gastrointestinal disorders, haemorrhagic cystitis and mucosal inflammation. The lists below are for adults.

Very common (≥1/10): increased susceptibility to infections, sepsis, leucopenia, thrombocytopenia, febrile neutropenia, anaemia, pancytopenia, granulocytopenia, acute and chronic graft-versus-host disease, anorexia, decreased appetite, hyperglycaemia, confusional state, mental status changes, dizziness, headache, blurred vision, encephalopathy, convulsions, paraesthesia, conjunctivitis, hearing impairment, ototoxicity, tinnitus, arrhythmia, lymphoedema, hypertension, idiopathic pneumonia syndrome, epistaxis, nausea, stomatitis, oesophagitis, vomiting, diarrhoea, dyspepsia, abdominal pain, enteritis, colitis, hepatic veno-occlusive disease, hepatomegaly, jaundice, rash, pruritus, alopecia, back pain, myalgia, arthralgia, haemorrhagic cystitis, azoospermia, amenorrhoea, vaginal haemorrhage, pyrexia, asthenia, chills, generalised oedema, injection site inflammation, injection site pain, mucosal inflammation, weight increase, raised blood bilirubin, transaminases and amylase.

Common (≥1/100 to <1/10): treatment-related second malignancy, hypersensitivity, hypopituitarism, anxiety, intracranial aneurysm, extrapyramidal disorder, cognitive disorder, cerebral haemorrhage, cataract, tachycardia, cardiac failure, haemorrhage, embolism, pulmonary oedema, cough, pneumonitis, constipation, gastrointestinal perforation, ileus, erythema, dysuria, oliguria, renal failure, cystitis, haematuria, menopausal symptoms, female and male infertility, multi-organ failure, pain, raised blood creatinine, urea, gamma-glutamyltransferase, alkaline phosphatase and aspartate aminotransferase.

Uncommon (≥1/1,000 to <1/100): toxic shock syndrome, delirium, nervousness, hallucination, agitation, cardiomyopathy, myocarditis, hypoxia, gastrointestinal ulcer, pigmentation disorder, erythrodermic psoriasis.

Not known: leukoencephalopathy; severe toxic skin reactions, including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis.

In children the spectrum overlaps with the adult one. Reactions listed as very common in the paediatric table that do not appear in the adult table include hypogonadism, hypothyroidism, growth retardation, bladder disorders, memory impairment, paresis and cardiac arrest; the SmPC gives the full paediatric list.

Important serious reactions: profound myelosuppression in all patients, infections and sepsis, acute and chronic GvHD, hepatic veno-occlusive disease, pulmonary toxicity, treatment-related second malignancy and severe toxic skin reactions. Leukoencephalopathy, some cases fatal, has been seen in adults and children who had received many earlier chemotherapies, including methotrexate, and radiotherapy.

Thiotepa appears to be metabolised by CYP2B6 and CYP3A4 and is a weak inhibitor of CYP2B6.

• Yellow fever vaccine: contraindicated, because of the risk of fatal generalised vaccine-induced disease.
• Other live vaccines: live virus and bacterial vaccines must not be given to a patient receiving an immunosuppressive chemotherapeutic agent, and at least three months must pass between stopping therapy and vaccination. The risk is systemic, possibly fatal, disease, greater in people already immunosuppressed by their illness; an inactivated vaccine (for example against poliomyelitis) should be used instead whenever possible.
• Phenytoin and fosphenytoin: not recommended. The SmPC describes a risk of worse convulsions, because the cytotoxic medicine reduces phenytoin absorption from the gut, or of more toxicity and less efficacy of the cytotoxic medicine because phenytoin raises its hepatic metabolism.
• CYP2B6 and CYP3A4 inhibitors (clopidogrel and ticlopidine for CYP2B6; azole antifungals, macrolides such as erythromycin, clarithromycin and telithromycin, and protease inhibitors for CYP3A4): may raise thiotepa levels and potentially lower those of the active metabolite TEPA. Monitor the patient clinically.
• Inducers of cytochrome P450 (rifampicin, carbamazepine, phenobarbital): may speed up thiotepa metabolism and raise levels of the active metabolite. Monitor the patient clinically.
• CYP2B6 substrates (for example ifosfamide, tamoxifen, bupropion, efavirenz and cyclophosphamide): their levels may rise. Because CYP2B6 converts cyclophosphamide to its active form 4-hydroxycyclophosphamide, thiotepa may lower the active metabolite. Monitor clinically.
• Cyclophosphamide: must not be given at the same time as thiotepa in one conditioning regimen; thiotepa is given after any cyclophosphamide infusion has finished.
• Ciclosporin and tacrolimus: excessive immunosuppression with a risk of lymphoproliferation.
• Suxamethonium: alkylating agents including thiotepa inhibit plasma pseudocholinesterase by 35–70%, which can prolong the action of suxamethonium by 5 to 15 minutes.
• Other myelosuppressive agents (cyclophosphamide, melphalan, busulfan, fludarabine, treosulfan): overlapping toxicity can increase the risk of blood-count reactions.
• Oral anticoagulants: malignancy raises thrombotic risk and coagulation varies widely; if an oral anticoagulant is used, INR monitoring should be more frequent.
• Food: grapefruit inhibits CYP3A4 and may raise thiotepa levels; St John’s wort induces CYP3A4 and may lower them.

Thiotepa treatment must be supervised by a physician experienced in conditioning treatment before haematopoietic progenitor cell transplantation. It is given with other chemotherapy medicinal products, at doses that depend on the type of HPCT (autologous or allogeneic) and on the disease. A qualified healthcare professional gives it as a 2–4 hour intravenous infusion through a central venous catheter. Doses below are per day, with the mg/kg equivalent in brackets, and the maximum is the total cumulative dose over the whole conditioning treatment.

Adults: Autologous HPCT

• Haematological diseases, including lymphoma: 125–300 mg/m² (3.38–8.10 mg/kg) as a single daily infusion for 2 to 4 consecutive days before the transplant; maximum 900 mg/m² (24.32 mg/kg).
• CNS lymphoma: 185 mg/m² (5 mg/kg) for 2 consecutive days; maximum 370 mg/m² (10 mg/kg).
• Multiple myeloma: 150–250 mg/m² (4.05–6.76 mg/kg) for 3 consecutive days; maximum 750 mg/m² (20.27 mg/kg).
• Solid tumours: 120–250 mg/m² (3.24–6.76 mg/kg) in one or two daily infusions for 2 to 5 consecutive days; maximum 800 mg/m² (21.62 mg/kg). By tumour type: breast cancer 120–250 mg/m² as a single daily infusion for 3 to 5 days (maximum 800 mg/m²); CNS tumours 125–250 mg/m² (3.38–6.76 mg/kg) in one or two daily infusions for 3 to 4 days (maximum 750 mg/m², 20.27 mg/kg); ovarian cancer 250 mg/m² (6.76 mg/kg) for 2 consecutive days (maximum 500 mg/m², 13.51 mg/kg); germ cell tumours 150–250 mg/m² (4.05–6.76 mg/kg) for 3 consecutive days (maximum 750 mg/m², 20.27 mg/kg).

Adults: Allogeneic HPCT

• Haematological diseases: 185–481 mg/m² (5–13 mg/kg) in one or two daily infusions for 1 to 3 consecutive days; maximum 555 mg/m² (15 mg/kg).
• Lymphoma: 370 mg/m² (10 mg/kg) divided in two daily infusions; maximum 370 mg/m² (10 mg/kg).
• Multiple myeloma: 185 mg/m² (5 mg/kg) as a single daily infusion; maximum 185 mg/m² (5 mg/kg).
• Leukaemia: 185–481 mg/m² (5–13 mg/kg) in one or two daily infusions for 1 to 2 consecutive days; maximum 555 mg/m² (15 mg/kg).
• Thalassaemia: 370 mg/m² (10 mg/kg) divided in two daily infusions; maximum 370 mg/m² (10 mg/kg).

Children: Autologous HPCT

• Solid tumours: 150–350 mg/m² (6–14 mg/kg) as a single daily infusion for 2 to 3 consecutive days; maximum 1,050 mg/m² (42 mg/kg).
• CNS tumours: 250–350 mg/m² (10–14 mg/kg) as a single daily infusion for 3 consecutive days; maximum 1,050 mg/m² (42 mg/kg).

Children: Allogeneic HPCT

• Haematological diseases: 125–250 mg/m² (5–10 mg/kg) in one or two daily infusions for 1 to 3 consecutive days; maximum 375 mg/m² (15 mg/kg).
• Leukaemia: 250 mg/m² (10 mg/kg) divided in two daily infusions; maximum 250 mg/m² (10 mg/kg).
• Thalassaemia: 200–250 mg/m² (8–10 mg/kg) divided in two daily infusions; maximum 250 mg/m² (10 mg/kg).
• Refractory cytopenia: 125 mg/m² (5 mg/kg) as a single daily infusion for 3 consecutive days; maximum 375 mg/m² (15 mg/kg).
• Genetic diseases: 125 mg/m² (5 mg/kg) as a single daily infusion for 2 consecutive days; maximum 250 mg/m² (10 mg/kg).
• Sickle cell anaemia: 250 mg/m² (10 mg/kg) divided in two daily infusions; maximum 250 mg/m² (10 mg/kg).

Preparation and Handling

• Vials: each vial is reconstituted with 1.5 mL (15 mg) or 10 mL (100 mg) of sterile water for injections. The total reconstituted volume is then diluted in 500 mL of sodium chloride 9 mg/mL (0.9%) solution (1,000 mL if the dose is above 500 mg). In children, if the dose is below 250 mg, an appropriate volume of the same solution may be used to reach a final concentration of 0.5–1 mg/mL.
• Bags (200 mg and 400 mg): for intravenous use only. The bag is taken out of its aluminium wrapper only immediately before use. Adjusting a dose with the bags follows the instructions in the SmPC.
• Handling: accidental exposure can cause topical reactions, so gloves are recommended when preparing the solution. If the solution touches the skin, wash it at once and thoroughly with soap and water; if it touches mucous membranes, flush them thoroughly with water.

Special Populations

• Renal impairment: not studied; because thiotepa and its metabolites are poorly excreted in urine, no dose change is recommended in mild or moderate renal insufficiency, but caution is advised.
• Hepatic impairment: not studied; caution in pre-existing liver impairment, especially severe, because thiotepa is mainly metabolised in the liver. No dose change for transient alterations of liver tests.
• Elderly: not specifically investigated; no dose adjustment was thought necessary.
• Children: dosed as above.

Myelosuppression and Infections

Profound myelosuppression occurs in all patients at the recommended dose, with severe granulocytopenia, thrombocytopenia and anaemia. Frequent full blood counts, including differential white cell and platelet counts, are needed during treatment and until recovery; daily counts are recommended during therapy and for at least 30 days after the transplant. Platelet and red cell support and growth factors such as G-CSF are used as medically indicated. Preventive or empirical anti-infectives should be considered for the neutropenic period.

Liver, Heart, Kidney, Lungs and Brain

• Liver: caution in impaired liver function; monitor transaminases, alkaline phosphatase and bilirubin regularly after the transplant to detect hepatotoxicity early. Earlier radiotherapy, three or more cycles of chemotherapy or an earlier progenitor cell transplant raise the risk of hepatic veno-occlusive disease.
• Heart and kidney: caution with a history of heart or kidney disease; monitor cardiac function regularly and consider periodic checks of kidney function.
• Lungs: thiotepa can cause pulmonary toxicity that adds to that of other cytotoxic agents (busulfan, fludarabine, cyclophosphamide).
• Brain: earlier brain or craniospinal irradiation may contribute to severe toxic reactions such as encephalopathy.

Secondary Malignancy

Thiotepa is a known human carcinogen. The increased risk of a second malignancy must be explained to the patient.

Interacting Medicines

Do not give live attenuated vaccines, phenytoin or fosphenytoin with thiotepa (see Drug Interactions). Give thiotepa only after any cyclophosphamide infusion has finished, and monitor patients clinically when they take CYP2B6 or CYP3A4 inhibitors.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: contraindicated. There are no human data; like most alkylating agents, thiotepa caused embryo-foetal lethality and malformations in preclinical studies. A pregnancy test should be done before treatment starts.
• Contraception: women of childbearing potential must use effective contraception during treatment and for at least 6 months afterwards. Men should not father a child during treatment and for at least 3 months afterwards.
• Breastfeeding: contraindicated during treatment; it is not known whether thiotepa passes into human milk.
• Fertility: thiotepa may impair male and female fertility. Men should seek sperm cryopreservation before therapy starts.

Sodium

When reconstituted, each 200 mg bag contains 709 mg (30.8 mmol) of sodium and each 400 mg bag 1,418 mg (61.6 mmol); the SmPC lists sodium as an excipient with known effect.

Effect on Driving

Thiotepa has a major influence on the ability to drive and use machines. Dizziness, headache and blurred vision are likely to affect these functions.

Store and transport refrigerated at 2–8 °C, and do not freeze. Because the product needs a cold chain, it should be kept at 2–8 °C throughout transport and storage until it is prepared. Keep the 200 mg and 400 mg bags in the aluminium wrapper to protect them from activation; storage after reconstitution and dilution is described under Shelf Life.

• Unopened: 15 mg vial 30 months; 100 mg vial 3 years; 200 mg and 400 mg bags (not activated) 3 years.
• Vials after reconstitution: chemical and physical in-use stability has been shown for 80 hours at 2–8 °C. After dilution it has been shown for up to 48 hours at 2–8 °C and up to 6 hours at 25 °C. From a microbiological point of view the product should be used immediately after dilution.
• Bags after activation and reconstitution: stability has been shown for up to 168 hours at 2–8 °C and up to 56 hours at 25 °C. From a microbiological point of view the product should be used immediately; if it is not, in-use times and conditions are the responsibility of the user and would normally not exceed these times when reconstitution was done under controlled, validated aseptic conditions.

Prescription only (Rx), subject to restricted medical prescription (Annex II B). Treatment must be supervised by a physician experienced in conditioning treatment before haematopoietic progenitor cell transplantation. Thiotepa is given by a qualified healthcare professional through a central venous catheter, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.