4.1. Therapeutic indications

Thiotepa Riemser 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.

4.2. Posology and method of administration

Thiotepa Riemser administration must be supervised by a physician experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation.

Posology

Thiotepa Riemser is administered at different doses, in combination with other chemotherapeutic medicinal products, in patients with haematological diseases or solid tumours prior to HPCT.

Thiotepa Riemser posology is reported, in adult and paediatric patients, according to the type of HPCT (autologous or allogeneic) and disease.

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 from 2 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 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 from 2 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 900 mg/m2 (24.32 mg/kg), during the time of the entire conditioning treatment.

CENTRAL NERVOUS SYSTEM (CNS) 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 from 2 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.

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.

Paediatric population

AUTOLOGOUS HPCT

Solid tumours

The recommended dose in solid tumours ranges from 150 mg/m2/day (6 mg/kg/day) to 350 mg/m2/day (14 mg/kg/day) as a single daily infusion, administered from 2 up to 3 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 1 050 mg/m2 (42 mg/kg), during the time of the entire conditioning treatment.

CNS TUMOURS

The recommended dose ranges from 250 mg/m2/day (10 mg/kg/day) to 350 mg/m2/day (14 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 1 050 mg/m2 (42 mg/kg), during the time of the entire conditioning treatment.

ALLOGENEIC HPCT

Haematological diseases

The recommended dose in haematological diseases ranges from 125 mg/m2/day (5 mg/kg/day) to 250 mg/m2/day (10 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 375 mg/m2 (15 mg/kg), during the time of the entire conditioning treatment.

LEUKAEMIA

The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.

THALASSEMIA

The recommended dose ranges from 200 mg/m2/day (8 mg/kg/day) to 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered before allogeneic HPCT without exceeding the total maximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.

REFRACTORY CYTOPENIA

The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 3 consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 375 mg/m2 (15 mg/kg), during the time of the entire conditioning treatment.

GENETIC DISEASES

The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 2 consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.

SICKLE CELL ANAEMIA

The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.

Special populations

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 (see sections 4.4 and 5.2).

Hepatic impairment

Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly metabolised 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 (see section 4.4).

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.

Method of administration

Thiotepa Riemser is for intravenous use. It must be administered by a qualified healthcare professional as a 2 - 4 hours intravenous infusion via a central venous catheter.

Each vial of 15 mg thiotepa must be reconstituted with 1.5 mL of sterile water for injections.

The total volume of reconstituted vials to be administered should be further diluted in 500 mL of sodium chloride 9 mg/mL (0.9%) solution for injection prior to administration (1 000 mL if the dose is higher than 500 mg). In paediatric patients, if the dose is lower than 250 mg, an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection may be used in order to obtain a final Thiotepa Riemser concentration between 0.5 and 1 mg/mL. For instructions on reconstitution and further dilution prior to administration, see section 6.6.

Precautions to be taken before handling or administering the medicinal product

Topical reactions associated with accidental exposure to thiotepa may occur. Therefore, the use of gloves is recommended in preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, the skin must be immediately thoroughly washed with soap and water. If thiotepa accidentally contacts mucous membranes, they must be flushed thoroughly with water (see section 6.6).

4.3. Contraindications

Hypersensitivity to the active substance.

Pregnancy and lactation (see section 4.6).

Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines (see section 4.5).

4.4. Special warnings and precautions for use

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 metabolised 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. Thiotepa Riemser 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 for at least 3 months after cessation of treatment (see section 4.6).

4.5. Interaction with other medicinal products and other forms of interaction

Specific interactions with thiotepa

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 catalyses 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.

Contraindications of concomitant use

Yellow fever vaccine: risk of fatal generalised 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.

Concomitant use not recommended

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.

Concomitant use to take into consideration

Cyclosporine, 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. Thiotepa Riemser 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.

Interaction common to all cytotoxic 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential have to use effective contraception during treatment and for at least 6 months after cessation of treatment. A pregnancy test should be performed before treatment is started. Male patients should not father a child while treated and for at least 3 months after cessation of treatment (see section 5.3).

Pregnancy

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.

Breast-feeding

It is unknown whether thiotepa/metabolites are 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.

Fertility

As most alkylating agents, thiotepa might impair male and female fertility.

Male patients should seek for sperm cryopreservation before therapy is started (see section 5.3).

4.7. Effects on ability to drive and use machines

Thiotepa Riemser has 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.

4.8. Undesirable effects

Summary of the safety profile

The safety of thiotepa has been examined through a review of adverse events reported in published data from clinical studies. 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, and mucosal inflammation.

Leukoencephalopathy

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.

Tabulated list of adverse reactions

Adults

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).

System organ class

Very common

Common

Uncommon

Not known

Infections and infestations

Infection susceptibility increased

Sepsis

Toxic shock syndrome

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Treatment related second malignancy

Blood and lymphatic system disorders

Leukopenia

Thrombocytopenia

Febrile neutropenia

Anaemia

Pancytopenia

Granulocytopenia

Immune system disorders

Acute graft versus host disease

Chronic graft versus host disease

Hypersensitivity

Endocrine disorders

Hypopituitarism

Metabolism and nutrition disorders

Anorexia

Decreased appetite

Hyperglycaemia

Psychiatric disorders

Confusional state

Mental status changes

Anxiety

Delirium

Nervousness

Hallucination

Agitation

Nervous system disorders

Dizziness

Headache

Vision blurred

Encephalopathy

Convulsion

Paraesthesia

Intracranial aneurysm

Extrapyramidal disorder

Cognitive disorder

Cerebral haemorrhage

Leukoencephalopathy

Eye disorders

Conjunctivitis

Cataract

Ear and labyrinth disorders

Hearing impaired

Ototoxicity

Tinnitus

Cardiac disorders

Arrhythmia

Tachycardia

Cardiac failure

Cardiomyopathy

Myocarditis

Vascular disorders

Lymphoedema

Hypertension

Haemorrhage

Embolism

Respiratory, thoracic and mediastinal disorders

Idiopathic pneumonia syndrome

Epistaxis

Pulmonary oedema

Cough

Pneumonitis

Hypoxia

Gastrointestinal disorders

Nausea

Stomatitis

Oesophagitis

Vomiting

Diarrhoea

Dyspepsia

Abdominal pain

Enteritis

Colitis

Constipation

Gastrointestinal perforation

Ileus

Gastrointestinal ulcer

Hepatobiliary disorders

Venoocclusive liver disease

Hepatomegaly

Jaundice

Skin and subcutaneous tissue disorders

Rash

Pruritus

Alopecia

Erythema

Pigmentation disorder

Erythrodermic psoriasis

Severe toxic skin reactions including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Back pain

Myalgia

Arthralgia

Renal and urinary disorders

Cystitis haemorrhagic

Dysuria

Oliguria

Renal failure

Cystitis

Haematuria

Reproductive system and breast disorders

Azoospermia

Amenorrhoea

Vaginal haemorrhage

Menopausal symptoms

Infertility female

Infertility male

General disorders and administration site conditions

Pyrexia

Asthenia

Chills

Generalised oedema

Injection site inflammation

Injection site pain

Mucosal inflammation

Multi-organ failure

Pain

Investigation

Weight increased

Blood bilirubin increased

Transaminases increased

Blood amylase increased

Blood creatinine increased

Blood urea increased

Gamma-glutamyltransferase increased

Blood alkaline phosphatase increased

Aspartate aminotransferase increased

Paediatric population

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).

System organ class

Very common

Common

Not known

Infections and infestations

Infection susceptibility increased

Sepsis

Thrombocytopenic purpura

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Treatment related second malignancy

Blood and lymphatic system disorders

Thrombocytopenia

Febrile neutropenia

Anaemia

Pancytopenia

Granulocytopenia

Immune system disorders

Acute graft versus host disease

Chronic graft versus host disease

Endocrine disorders

Hypopituitarism

Hypogonadism

Hypothyroidism

Metabolism and nutrition disorders

Anorexia

Hyperglycaemia

Psychiatric disorders

Mental status changes

Mental disorder due to a general medical condition

Nervous system disorders

Headache

Encephalopathy

Convulsion

Cerebral haemorrhage

Memory impairment

Paresis

Ataxia

Leukoencephalopathy

Ear and labyrinth disorders

Hearing impaired

Cardiac disorders

Cardiac arrest

Cardiovascular insufficiency

Cardiac failure

Vascular disorders

Haemorrhage

Hypertension

Respiratory, thoracic and mediastinal disorders

Pneumonitis

Idiopathic pneumonia syndrome

Pulmonary haemorrhage

Pulmonary oedema

Epistaxis

Hypoxia

Respiratory arrest

Pulmonary arterial hypertension

Gastrointestinal disorders

Nausea

Stomatitis

Vomiting

Diarrhoea

Abdominal pain

Enteritis

Intestinal obstruction

Hepatobiliary disorders

Venoocclusive liver disease

Liver failure

Skin and subcutaneous tissue disorders

Rash

Erythema

Desquamation

Pigmentation disorder

Severe toxic skin reactions including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Growth retardation

Renal and urinary disorders

Bladder disorders

Renal failure

Cystitis haemorrhagic

General disorders and administration site conditions

Pyrexia

Mucosal inflammation

Pain

Multi-organ failure

Investigation

Blood bilirubin increased

Transaminases increased

Blood creatinine increased

Aspartate aminotransferase increased

Alanine aminotransferase increased

Blood urea increased

Blood electrolytes abnormal

Prothrombin time ratio increased

Reporting of suspected adverse reactions

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.