Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: ADIENNE S.r.l. S.U., Via Galileo Galilei, 19, 20867 Caponago (MB) Italy, Tel: +39-02 40700445, adienne@adienne.com
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.
Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period.
Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly metabolized through the liver, caution needs to be observed when thiotepa is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. When treating such patients it is recommended that serum transaminase, alkaline phosphatase and bilirubin are monitored regularly following transplant, for early detection of hepatotoxicity.
Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk of hepatic veno-occlusive disease (see section 4.8).
Caution must be used in patients with history of cardiac diseases, and cardiac function must be monitored regularly in patients receiving thiotepa.
Caution must be used in patients with history of renal diseases and periodic monitoring of renal function should be considered during therapy with thiotepa.
Thiotepa might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic agents (busulfan, fludarabine and cyclophosphamide) (see section 4.8).
Previous brain irradiation or craniospinal irradiation may contribute to severe toxic reactions (e.g. encephalopathy).
The increased risk of a secondary malignancy with thiotepa, a known carcinogen in humans, must be explained to the patient.
Concomitant use with live attenuated vaccines (except yellow fever vaccines), phenytoin and fosphenytoin is not recommended (see section 4.5).
Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal products are present in the same conditioning treatment. TEPADINA must be delivered after the completion of any cyclophosphamide infusion (see section 4.5).
During the concomitant use of thiotepa and inhibitors of CYP2B6 or CYP3A4, patients should be carefully monitored clinically (see section 4.5).
As most alkylating agents, thiotepa might impair male or female fertility. Male patients should seek for sperm cryopreservation before therapy is started and should not father a child while treated and during the year after cessation of treatment (see section 4.6).
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.
Yellow fever vaccine: risk of fatal generalized vaccine-induced disease.
More generally, 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.
Live attenuated vaccines (except yellow fever): risk of systemic, possibly fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease.
An inactivated virus vaccine should be used instead, whenever possible (poliomyelitis).
Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicinal product or risk of toxicity enhancement and loss of efficacy of the cytotoxic medicinal product due to increased hepatic metabolism by phenytoin.
Ciclosporine, tacrolimus: excessive immunosuppression with risk of lymphoproliferation.
Alkylating chemotherapeutic agents, including thiotepa, inhibit plasma pseudocholinesterase by 35% to 70%. The action of succinyl-choline can be prolonged by 5 to 15 minutes.
Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal products are present in the same conditioning treatment. TEPADINA must be delivered after the completion of any cyclophosphamide infusion.
The concomitant use of thiotepa and other myelosuppressive or myelotoxic agents (i.e. cyclophosphamide, melphalan, busulfan, fludarabine, treosulfan) may potentiate the risk of haematologic adverse reactions due to overlapping toxicity profiles of these medicinal products.
Due to the increase of thrombotic risk in case of malignancy, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulation state during malignancy, and the potential interaction between oral anticoagulants and anticancer chemotherapy require, if it is decided to treat the patient with oral anticoagulants, to increase the frequency of the INR (International Normalised Ratio) monitoring.
Women of childbearing potential have to use effective contraception during treatment and a pregnancy test should be performed before treatment is started.
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 (see section 5.3). 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, breast-feeding is contraindicated during treatment with thiotepa.
As most alkylating agents, thiotepa might impair male and female fertility. Male patients should seek for sperm cryopreservation before therapy is started and should not father a child while treated and during the year after cessation of treatment (see section 5.3).
TEPADINA may have major influence on the ability to drive and use machines. It is likely that certain adverse reactions of thiotepa like dizziness, headache and blurred vision could affect these functions.
The safety of thiotepa has been examined through a review of adverse events reported in published data from clinical trials. In these studies, a total of 6,588 adult patients and 902 paediatric patients received thiotepa for conditioning treatment prior to haematopoietic progenitor cell transplantation.
Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process. These include infection and Graft-versus host disease (GvHD) which, although not directly related, were the major causes of morbidity and mortality, especially in allogeneic HPCT. The most frequently adverse reactions reported in the different conditioning treatments including thiotepa are: infections, cytopenia, acute GvHD and chronic GvHD, gastrointestinal disorders, haemorrhagic cystitis, mucosal inflammation.
Cases of leukoencephalopathy have been observed following treatment with thiotepa in adult and paediatric patients with multiple previous chemotherapies, including methotrexate and radiotherapy. Some cases had a fatal outcome.
The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, reported in adult patients as more than an isolated case, are listed below by system organ class and by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).
Very common: Infection susceptibility increased, Sepsis
Uncommon: Toxic shock syndrome
Common: Treatment related second malignancy
Very common: Leukopenia, Thrombocytopenia, Febrile, neutropenia, Anaemia, Pancytopenia, Granulocytopenia
Very common: Acute graft versus host disease, Chronic graft versus host disease
Common: Hypersensitivity
Common: Hypopituitarism
Very common: Anorexia, Decreased appetite, Hyperglycaemia
Very common: Confusional state, Mental status changes
Common: Anxiety
Uncommon: Delirium, Nervousness, Hallucination, Agitation
Very common: Dizziness, Headache, Vision blurred, Encephalopathy, Convulsion, Paraesthesia
Common: Intracranial aneurysm, Extrapyramidal disorder, Cognitive disorder, Cerebral haemorrhage
Not known: Leukoencephalopathy
Very common: Conjunctivitis
Common: Cataract
Very common: Hearing impaired, Ototoxicity, Tinnitus
Very common: Arrhythmia
Common: Tachycardia, Cardiac failure
Uncommon: Cardiomyopathy, Myocarditis
Very common: Lymphoedema, Hypertension
Common: Haemorrhage, Embolism
Very common: Idiopathic pneumonia syndrome, Epistaxis
Common: Pulmonary oedema, Cough, Pneumonitis
Uncommon: Hypoxia
Very common: Nausea, Stomatitis, Oesophagitis, Vomiting, Diarrhoea, Dyspepsia, Abdominal pain, Enteritis, Colitis
Common: Constipation, Gastrointestinal perforation, Ileus
Uncommon: Gastrointestinal ulcer
Very common: Venoocclusive liver disease, Hepatomegaly, Jaundice
Very common: Rash, Pruritus, Alopecia
Common: Erythema
Uncommon: Pigmentation disorder, Erythrodermic psoriasis
Not known: Severe toxic skin reactions including cases of StevensJohnson syndrome and toxic epidermal necrolysis
Very common: Back pain, Myalgia, Arthralgia
Very common: Cystitis haemorrhagic
Common: Dysuria, Oliguria, Renal failure, Cystitis, Haematuria
Very common: Azoospermia, Amenorrhoea, Vaginal haemorrhage
Common: Menopausal symptoms, Infertility female, Infertility male
Very common: Pyrexia, Asthenia, Chills, Generalised oedema, Injection site inflammation, Injection site pain, Mucosal inflammation
Common: Multi-organ failure, Pain
Very common: Weight increased, Blood bilirubin increased, Transaminases increased, Blood amylase increased
Common: Blood creatinine increased, Blood urea increased, Gammaglutamyltransferase increased, Blood alkaline phosphatase increased, Aspartate aminotransferase increased
The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, reported in paediatric patients as more than an isolated case, are listed below by system organ class and by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10), common ((≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).
Very common: Infection susceptibility increased, Sepsis
Common: Thrombocytopenic purpura
Common: Treatment related second malignancy
Very common: Thrombocytopenia, Febrile neutropenia, Anaemia, Pancytopenia, Granulocytopenia
Very common: Acute graft versus host disease, Chronic graft versus host disease
Very common: Hypopituitarism, Hypogonadism, Hypothyroidism
Very common: Anorexia, Hyperglycaemia
Very common: Mental status changes
Common: Mental disorder due to a general medical condition
Very common: Headache, Encephalopathy, Convulsion, Cerebral haemorrhage, Memory impairment, Paresis
Common: Ataxia
Not known: Leukoencephalopathy
Very common: Hearing impaired
Very common: Cardiac arrest
Common: Cardiovascular insufficiency, Cardiac failure
Very common: Haemorrhage
Common: Hypertension
Very common: Pneumonitis
Common: Idiopathic pneumonia syndrome, Pulmunary haemorrage, Pulmonary oedema, Epistaxis, Hypoxia, Respiratory arrest
Not known: Pulmonary arterial hypertension
Very common: Nausea, Stomatitis, Vomiting, Diarrhoea, Abdominal pain
Common: Enteritis, Intestinal obstruction
Very common: Venoocclusive liver disease
Common: Liver failure
Very common: Rash, Erythema, Desquamation, Pigmentation disorder
Not known: Severe toxic skin reactions including cases of StevensJohnson syndrome and toxic epidermal necrolysis
Very common: Growth retardation
Very common: Bladder disorders
Common: Renal failure, Cystitis haemorrhagic
Very common: Pyrexia, Mucosal inflammation Pain, Multi-organ failure
Very common: Blood bilirubin increased, Transaminases increased, Blood creatinine increased, Aspartate aminotransferase increased, Alanine aminotransferase increased
Common: Blood urea increased, Blood electrolytes abnormal, Prothrombin time ratio increased
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
TEPADINA is unstable in acid medium.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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