Tepadina

TEPADINA administration must be supervised by a physician experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation. Posology TEPADINA is administered at different doses, in combination with other chemotherapeutic medicinal products, in patients with haematological diseases or solid tumours prior to HPCT.

TEPADINA posology is reported, in adult and paediatric patients, according to the type of HPCT (autologous or allogeneic) and disease. 32 mg/kg), during the time of the entire conditioning treatment. 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.

27 mg/kg), during the time of the entire conditioning treatment. 62 mg/kg), during the time of the entire conditioning treatment. 62 mg/kg), during the time of the entire conditioning treatment. 27 mg/kg), during the time of the entire conditioning treatment.

51 mg/kg), during the time of the entire conditioning treatment. 27 mg/kg), during the time of the entire conditioning treatment. ALLOGENEIC HPCT Haematological diseases 4 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.

Summary of the safety profile 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 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.

9 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 Thrombocytopeni a 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 Leukoencephalopath y Eye disorders Conjunctivitis Cataract 10 System organ class Very common Common Uncommon Not known Ear and labyrinth disorders Hearing impaired Ototoxicity Tinnitus Cardiac disorders Arrhythmia Tachycardia Cardiac failure Cardiomyopath y Myocarditis Vascular disorders Lymphoedema Hypertension Haemorrhage Embolism Respiratory, thoracic and mediastinal disorders Idiopathic pneumonia syndrome Epistaxis Pulmonary oedema Cough Pneumonitis Hypoxia Gastrointestina l 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 Musculoskeleta l 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 11 System organ class Very common Common Uncommon Not known Investigations Weight increased Blood bilirubin increased Transaminases increased Blood amylase increased Blood creatinine increased Blood urea increased Gamma- glutamyltransferas e 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.

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.

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.

8). g. encephalopathy). The increased risk of a secondary malignancy with thiotepa, a known carcinogen in humans, must be explained to the patient. 5). Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal products are present in the same conditioning treatment.

Hypersensitivity to the active substance. 6). 5).