Adult: 10-60 mg in 20-60 mL sterile water instilled after aspiration. May be repeated once weekly or once every 2 weeks. Alternatively, 0.6-0.8 mg/kg at 1- to 4-week intervals; doses are usually initiated at the higher range. Dose reduction, dosing interruption, or discontinuation may be required according to individual haematologic values and tolerance, refer to detailed product guideline. Dosage recommendation may vary among countries or individual products, refer to local treatment guidelines for detailed dosing information.
Intramuscular, Intravenous Breast cancer
Adult: Recommended dose: 0.3-0.4 mg/kg at 1- to 4-week intervals given intravenously. As part of a combination regimen: 15-30 mg in divided doses given 3 times weekly via IM inj for 2 weeks as 1 course of treatment with recommended intervals of 6-8 weeks between courses to allow the bone marrow to recover. Alternatively, 15 mg daily as initial priming dose given via IM or IV inj for 4 days. Maintenance: 15 mg every 14-21 days via IM inj. Dose reduction, dosing interruption, or discontinuation may be required according to individual haematologic values and tolerance, refer to detailed product guideline. Dosage recommendations may vary among countries and individual products. Refer to local treatment guidelines for detailed dosing information.
Intramuscular, Intravenous Ovarian cancer
Adult: Recommended dose: 0.3-0.4 mg/kg at 1- to 4-week intervals given intravenously. Alternatively, 15 mg daily via IV or IM administration for 4 days then as single doses given once weekly or once every 2 weeks. Dose reduction, dosing interruption, or discontinuation may be required according to individual haematologic values and tolerance, refer to detailed product guideline. Dosage recommendations may vary among countries and individual products. Refer to local treatment guidelines for detailed dosing information.
Intravesical Bladder cancer
Adult: Up to 60 mg in 30-60 mL of sterile water or 0.9% NaCl instilled via a catheter into the bladder of a patient previously dehydrated for 8-12 hours given once weekly for 4 weeks. Solution must be retained for up to 2 hours and patient must be frequently repositioned. Continue inj to ensure bathing of the prostatic and pendulous urethra during removal of catheter after instillation. If response is observed after 1 course of 4 instillations, a 2nd course of 4 instillations may be given at a reduced dosage (e.g. 15-60 mg with intervals of 1-2 weeks between instillations). For prophylaxis of recurrence after surgical removal of superficial tumours of the bladder: 30-60 mg in 60 mL sterile water instilled into the bladder for 2 hours and repeated at intervals of 1-2 weeks, for up to 8 instillations. This may be followed by instillations of 30-60 mg every 4-6 weeks for 1 year or more. Alternatively, 90 mg in 100 mL sterile water is instilled into the bladder as single dose, with the patient in the left lateral position, transfer to the right lateral position after 15 minutes, then empty the bladder after another 15 minutes. Dose reduction, dosing interruption, or discontinuation may be required according to individual haematologic values, refer to detailed product guideline.
Ophthalmic Prophylaxis of recurrence of pterygium following surgical removal
Adult: As 0.05% solution (15 mg in 30 mL sterile Ringer’s solution): Instil 3 hourly for up to 6 weeks.
Topical/Cutaneous Condyloma acuminata
Adult: 60 mg in a gel mixture apply to the affected area(s) weekly.
Urethral Condyloma acuminata
Adult: 60 mg in a gel mixture instilled in the urethra weekly.
Special Patient Group
Patient with bone marrow damage: Use the lowest effective dose.
Renal Impairment
Intravenous; Intramuscular; Intravesical; Intracavitary; Ophthalmic:
Use the lowest effective dose.
Hepatic Impairment
Reconstitution
Initially, reconstitute vials labelled as 15 mg, 30 mg, and 100 mg with 1.5 mL, 3 mL, and 10 mL of sterile water for inj respectively. Further dilute reconstituted solution prior to administration. Solutions must be filtered through 0.22-micron filter prior to administration. Urethral: Reconstitute 60 mg with 5 mL sterile water and dilute to 15 mL using a sterile mixture of lubricating jelly and water.
Pregnancy and lactation. Concomitant administration with bacterial or live or live-attenuated viral vaccines (e.g. yellow fever vaccine).
Special Precautions
Patient with existing bone marrow damage, history of cardiac disease; who had received prior radiation therapy, chemotherapy ≥3 cycles, prior progenitor cell transplant, previous bladder radiotherapy (e.g. brain irradiation, craniospinal irradiation). Renal and hepatic impairment. Haematopoietic stem cell transplantation (HSCT) is required after administration of high doses. Consider use of anti-infectives (bacterial, fungal, viral) during neutropenic period.
Adverse Reactions
Significant: Secondary malignancies (e.g. myelodysplastic syndrome, acute myeloid leukaemia), bone marrow ablation with resulting infection or bleeding (high dose); hepatic veno-occlusive disease; impaired fertility; skin discolouration, blistering, pruritus, desquamation, peeling (high dose); hypersensitivity reactions (including anaphylaxis). Blood and lymphatic system disorders: Febrile neutropenia, granulocytopenia. Cardiac disorders: Arrhythmia, tachycardia, cardiac failure, cardiomyopathy. Ear and labyrinth disorders: Tinnitus, ototoxicity, impaired hearing. Endocrine disorders: Hypopituitarism. Eye disorders: Blurred vision, conjunctivitis, cataract. Gastrointestinal disorders: Nausea, vomiting, mucositis, oesophagitis, stomatitis, diarrhoea, abdominal pain, dyspepsia, enteritis, colitis, constipation, ileus, gastrointestinal perforation. General disorders and administration site conditions: Chills, asthenia, pyrexia, pain and inflammation at the injection site, generalised oedema, multiorgan failure, pain. Hepatobiliary disorders: Jaundice, hepatomegaly. Immune system disorders: Acute or chronic graft versus host disease. Infections and infestations: Increased susceptibility to infections, sepsis. Investigations: Increased weight, transaminases, blood bilirubin, blood amylase, blood urea, blood creatinine, gamma-glutamyltransferase, blood alkaline phosphatase, aspartate aminotransferase. Metabolism and nutrition disorders: Decreased appetite, anorexia, hyperglycaemia. Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, back pain. Neoplasms benign, malignant and unspecified: Tumour lysis syndrome. Nervous system disorders: Headache, dizziness, convulsion, paraesthesia, intracranial aneurysm, cognitive disorder, extrapyramidal disorder, cerebral haemorrhage. Psychiatric disorders: Confusion, mental status change, anxiety. Renal and urinary disorders: Haemorrhagic cystitis (intravesical/IV), renal failure, oliguria, cystitis, dysuria, haematuria. Reproductive system and breast disorders: Vaginal haemorrhage, azoospermia, amenorrhoea, menopausal symptoms. Respiratory, thoracic and mediastinal disorders: Epistaxis, idiopathic pneumonia syndrome, pneumonitis, cough, pulmonary oedema. Skin and subcutaneous tissue disorders: Rash, alopecia, erythema. Vascular disorders: Hypertension, lymphoedema, haemorrhage, embolism. Potentially Fatal: Bone marrow depression (e.g. leucopenia, thrombocytopenia, anaemia, pancytopenia), septicaemia, haemorrhage; encephalopathy (high dose).
Determine pregnancy status in women of reproductive potential prior to initiation of therapy. Monitor CBC with differential and platelet count at weekly intervals during therapy and for at least 3 weeks after discontinuation of therapy (except when used topically); cardiac, renal and liver function tests; uric acid, urinalysis; signs and symptoms of hypersensitivity reactions, hepatic veno-occlusive disease, dermatologic toxicity, and CNS toxicity.
Overdosage
Symptoms: Bleeding, decreased blood cell and platelet counts, myeloablation, pancytopenia. Management: Supportive treatment. Assess blood counts. May consider whole blood, platelet or leucocyte transfusions or use of dialysis.
Drug Interactions
May increase risk of pulmonary toxicity and haematologic adverse reactions with other cytotoxic agents (e.g. busulfan, fludarabine, cyclophosphamide). Enhanced toxicity with other alkylating agents (e.g. nitrogen mustard, cyclophosphamide). Enhanced effects of suxamethonium. May reduce absorption of digoxin. May decrease concentrations of the active metabolite (triethylenephosphoramide) with inhibitors of CYP2B6 (e.g. clopidogrel, ticlopidine) or CYP3A4 (e.g. itraconazole, clarithromycin, ritonavir). May increase metabolism with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital). May increase plasma concentrations of CYP2B6 substrates (e.g. ifosfamide, tamoxifen, bupropion, efavirenz, cyclophosphamide). May decrease digestive absorption of phenytoin; may diminish efficacy due to increased hepatic metabolism with phenytoin. Enhanced immunosuppressive effect with ciclosporin and tacrolimus. Potentially Fatal: Increased risk of generalised vaccine-induced disease with yellow fever vaccine. Increased risk of systemic diseases with bacterial or live or live-attenuated viral vaccines.
Action
Description: Mechanism of Action: Thiotepa is an ethyleneimine compound and polyfunctional cytotoxic agent. Its mechanism is suspected to occur through the release of ethylene imine radicals that disrupt the bonds of deoxyribonucleic acid (DNA) which is initiated by alkylation of guanine at the N-7 position thus breaking the linkage between sugar and purine base and liberating alkylated guanines. Pharmacokinetics: Absorption: Minimal absorption through serous membranes (e.g. bladder, pleura). Distribution: Plasma protein binding: Approx 10-20%. Metabolism: Rapidly and extensively metabolised in the liver via oxidative desulfuration by CYP2B6 and CYP3A4 isoenzymes to the major and active metabolite, triethylenephosphoramide (TEPA). Excretion: Via urine (<2% as unchanged drug, <11% as TEPA). Elimination half-life: 1.5-4.1 hours (thiotepa); 4.9-17.6 hours (TEPA).
Chemical Structure
Thiotepa Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5453, Thiotepa. https://pubchem.ncbi.nlm.nih.gov/compound/Thiotepa. Accessed Apr. 28, 2021.
Storage
Store between 2-8°C. Do not freeze. Protect from light. Reconstituted solutions are stable between 2-8°C for 24 hours; if precipitate forms, discard solution.
This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
L01AC01 - thiotepa ; Belongs to the class of alkylating agents, ethylene imines. Used in the treatment of cancer.
References
Anon. Thiotepa. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 01/09/2020.Anon. Thiotepa. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 01/09/2020.Buckingham R (ed). Thiotepa. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/09/2020.Tepadina Powder, for Solution (Amneal Pharmaceuticals LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 01/09/2020.Thiotepa 15 mg Sterile Powder for Solution for Injection (Mercury Pharmaceuticals Ltd). MHRA. https://products.mhra.gov.uk. Accessed 01/09/2020.
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