TEPADINA 400mg powder + solvent infusion solution medication leaflet

TEPADINA 200 mg powder and solvent for solution for infusion

TEPADINA 400 mg powder and solvent for solution for infusion

TEPADINA 200 mg powder and solvent for solution for infusion

One bag contains 200 mg thiotepa.

After reconstitution with the solvent, each mL of solution contains 1 mg of thiotepa.

When reconstituted, each bag contains 709 mg (30.8 mmol) of sodium.

TEPADINA 400 mg powder and solvent for solution for infusion

One bag contains 400 mg thiotepa.

After reconstitution with the solvent, each mL of solution contains 1 mg of thiotepa.

When reconstituted, each bag contains 1 418 mg (61.6 mmol) of sodium.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for infusion.

Powder: white powder.

Solvent: clear solution, essentially free from visible particulates, pH 4.5-7.0.

TEPADINA is indicated, in combination with other chemotherapy medicinal products:

* with or without total body irradiation (TBI), as conditioning treatment prior to allogeneic orautologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adultand paediatric patients;

* when high dose chemotherapy with HPCT support is appropriate for the treatment of solidtumours in adult and paediatric patients.

TEPADINA administration must be supervised by a physician experienced in conditioning treatmentprior to haematopoietic progenitor cell transplantation.

TEPADINA is administered at different doses, in combination with other chemotherapeutic medicinalproducts, 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.

AUTOLOGOUS HPCT

Haematological diseases

The recommended dose in haematological diseases ranges from 125 mg/m2/day (3.38 mg/kg/day) to300 mg/m2/day (8.10 mg/kg/day) as a single daily infusion, administered from 2 up to 4 consecutivedays before autologous HPCT depending on the combination with other chemotherapeutic medicinalproducts, without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), duringthe 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 beforeautologous 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 timeof 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 for2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative doseof 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, withoutexceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of theentire conditioning treatment.

Solid tumours

The recommended dose in solid tumours ranges from 120 mg/m2/day (3.24 mg/kg/day) to250 mg/m2/day (6.76 mg/kg/day) divided in one or two daily infusions, administered from 2 up to5 consecutive days before autologous HPCT depending on the combination with otherchemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of800 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 beforeautologous 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 timeof 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 daysbefore autologous HPCT depending on the combination with other chemotherapeutic medicinalproducts, without exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), duringthe 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 in2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative doseof 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, withoutexceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of theentire conditioning treatment.

ALLOGENEIC HPCT

Haematological diseases

The recommended dose in haematological diseases ranges from 185 mg/m2/day (5 mg/kg/day) to481 mg/m2/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to3 consecutive days before allogeneic HPCT depending on the combination with otherchemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of555 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 infusionsbefore 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 thetime 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, withoutexceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), during the time of the entireconditioning treatment.

THALASSEMIA

The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administeredbefore allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2(10 mg/kg), during the time of the entire conditioning treatment.

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 beforeautologous 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 ofthe 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, withoutexceeding the total maximum cumulative dose of 1 050 mg/m2 (42 mg/kg), during the time of theentire conditioning treatment.

ALLOGENEIC HPCT

Haematological diseases

The recommended dose in haematological diseases ranges from 125 mg/m2/day (5 mg/kg/day) to250 mg/m2/day (10 mg/kg/day) divided in one or two daily infusions, administered from 1 up to3 consecutive days before allogeneic HPCT depending on the combination with otherchemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of375 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, administeredbefore 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 totalmaximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioningtreatment.

REFRACTORY CYTOPENIA

The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for3 consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of375 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 for2 consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of250 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, administeredbefore allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2(10 mg/kg), during the time of the entire conditioning treatment.

Studies in renally impaired patients have not been conducted. As thiotepa and its metabolites arepoorly excreted in the urine, dose modification is not recommended in patients with mild or moderaterenal insufficiency. However, caution is recommended (see sections 4.4 and 5.2).

Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainlymetabolized 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. Dosemodification is not recommended for transient alterations of hepatic parameters (see section 4.4).

The administration of thiotepa has not been specifically investigated in elderly patients. However, inclinical studies, a proportion of patients over the age of 65 received the same cumulative dose as theother patients. No dose adjustment was deemed necessary.

TEPADINA is for intravenous use only. It must be administered by a qualified healthcare professionalas a 2-4 hours intravenous infusion via a central venous catheter.

The bag must only be removed from the aluminum wrapper immediately before the use.

TEPADINA 200 mg

If necessary, dose adjustment of TEPADINA must be operated as per specific application.

In case the calculated dose required is higher than 200 mg but less than a multiple thereof, the user isrequested to add the required mg from TEPADINA vials by using a dedicated port of TEPADINA200 mg.

In case the calculated dose required is lower than 200 mg, the user is requested to remove theunnecessary mg of fully reconstituted 1 mg/mL solution or to set an infusion pump with the amount ofmedicinal product to be administered in mL.

TEPADINA 400 mg

If necessary, dose adjustment of TEPADINA must be operated as per specific application.

In case the calculated dose required is higher than 400 mg but less than a multiple thereof, the user isrequested to add the required mg from TEPADINA vials by using a dedicated port of TEPADINA400 mg.

In case the calculated dose required is lower than 400 mg, the user is requested to remove theunnecessary mg of fully reconstituted 1 mg/mL solution or to set an infusion pump with the amount ofmedicinal product to be administered in mL.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Topical reactions associated with accidental exposure to thiotepa may occur. Therefore, the use ofgloves is recommended in preparing the solution for infusion. If thiotepa solution accidentally contactsthe skin, the skin must be immediately thoroughly washed with soap and water. If thiotepaaccidentally contacts mucous membranes, they must be flushed thoroughly with water (see section6.6).

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).

The consequence of treatment with thiotepa at the recommended dose and schedule is profoundmyelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia orany combination thereof may develop. Frequent complete blood counts, including differential whiteblood cell counts, and platelet counts need to be performed during the treatment and until recovery isachieved. 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 cellcounts and platelet counts are recommended during therapy with thiotepa and after transplant for atleast 30 days.

Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for theprevention and management of infections during the neutropenic period.

Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainlymetabolized 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. Whentreating such patients it is recommended that serum transaminase, alkaline phosphatase and bilirubinare monitored regularly following transplant, for early detection of hepatotoxicity.

Patients who have received prior radiation therapy, greater than or equal to three cycles ofchemotherapy, or prior progenitor cell transplant may be at an increased risk of hepatic veno-occlusivedisease (see section 4.8).

Caution must be used in patients with history of cardiac diseases, and cardiac function must bemonitored regularly in patients receiving thiotepa.

Caution must be used in patients with history of renal diseases and periodic monitoring of renalfunction should be considered during therapy with thiotepa.

Thiotepa might induce pulmonary toxicity that may be additive to the effects produced by othercytotoxic 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 beexplained to the patient.

Concomitant use with live attenuated vaccines (except yellow fever vaccines), phenytoin andfosphenytoin is not recommended (see section 4.5).

Thiotepa must not be concurrently administered with cyclophosphamide when both medicinalproducts are present in the same conditioning treatment. TEPADINA must be delivered after thecompletion of any cyclophosphamide infusion (see section 4.5).

During the concomitant use of thiotepa and inhibitors of CYP2B6 or CYP3A4, patients should becarefully monitored clinically (see section 4.5).

As most alkylating agents, thiotepa might impair male or female fertility. Male patients should seekfor sperm cryopreservation before therapy is started and should not father a child while treated andduring the year after cessation of treatment (see section 4.6).

TEPADINA 400 mg contains 1 418 mg (61.6 mmol) sodium per bag, equivalent to 70.9% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

TEPADINA 200 mg contains 709 mg (30.8 mmol) sodium per bag, equivalent to 35.5% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Specific interactions with thiotepa

Live virus and bacterial vaccines must not be administered to a patient receiving animmunosuppressive chemotherapeutic agent and at least three months must elapse betweendiscontinuation 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 theplasma 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 ofthe 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 concentrationsof substances metabolised via CYP2B6, such as ifosfamide, tamoxifen, bupropion, efavirenz andcyclophosphamide. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide to its activeform 4-hydroxycyclophosphamide (4-OHCP) and co-administration of thiotepa may therefore lead todecreased concentrations of the active 4-OHCP. Therefore, a clinical monitoring should be exercisedduring the concomitant use of thiotepa and these medicinal products.

Contraindications of concomitant use

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 animmunosuppressive chemotherapeutic agent and at least three months must elapse betweendiscontinuation of therapy and vaccination.

Live attenuated vaccines (except yellow fever): risk of systemic, possibly fatal disease. This risk isincreased 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 digestiveabsorption by cytotoxic medicinal product or risk of toxicity enhancement and loss of efficacy of thecytotoxic medicinal product due to increased hepatic metabolism by phenytoin.

Concomitant use to take into consideration

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 medicinalproducts are present in the same conditioning treatment. TEPADINA must be delivered after thecompletion 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 ofhaematologic adverse reactions due to overlapping toxicity profiles of these medicinal products.

Interaction common to all cytotoxics

Due to the increase of thrombotic risk in case of malignancy, the use of anticoagulative treatment isfrequent. The high intra-individual variability of the coagulation state during malignancy and thepotential interaction between oral anticoagulants and anticancer chemotherapy require, if it is decidedto 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 pregnancytest should be performed before treatment is started. Male patients should not father a child whiletreated and during the year after cessation of treatment (see section 5.3).

There are no data on the use of thiotepa during pregnancy. In pre-clinical studies thiotepa, as mostalkylating 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 andits potential toxicity for breast-fed newborns/infants, breast-feeding is contraindicated duringtreatment with thiotepa.

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).

TEPADINA has major influence on the ability to drive and use machines. It is likely that certainadverse 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 publisheddata from clinical trials. In these studies, a total of 6 588 adult patients and 902 paediatric patientsreceived thiotepa for conditioning treatment prior to haematopoietic progenitor cell transplantation.

Serious toxicities involving the haematologic, hepatic and respiratory systems were considered asexpected consequences of the conditioning regimen and transplant process. These include infectionand Graft-versus host disease (GvHD) which, although not directly related, were the major causes ofmorbidity and mortality, especially in allogeneic HPCT.

The most frequently adverse reactions reported in the different conditioning treatments includingthiotepa 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 andpaediatric 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 byfrequency. Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness. 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 Very common Common Uncommon Not knownclass

Infections and Infection Toxic shockinfestations susceptibility syndromeincreased

Neoplasms Treatment relatedbenign, secondmalignant and malignancyunspecified(incl cysts andpolyps)

Blood and Leukopenialymphatic Thrombocytopenisystem adisorders Febrileneutropenia

Pancytopenia

Granulocytopenia

Immune Acute graft versus Hypersensitivitysystem host diseasedisorders

System organclass Very common Common Uncommon Not known

Chronic graftversus hostdisease

Endocrine Hypopituitarismdisorders

Metabolism Anorexiaand nutrition Decreaseddisorders appetite

Psychiatric Confusional state Anxiety Deliriumdisorders Mental status Nervousnesschanges Hallucination

Agitation

Nervous Dizziness Intracranial Leukoencephalopathsystem Headache aneurysm ydisorders Vision blurred Extrapyramidal

Encephalopathy disorder

Convulsion Cognitive disorder

Paraesthesia Cerebralhaemorrhage

Eye disorders Conjunctivitis Cataract

Ear and Hearing impairedlabyrinth Ototoxicitydisorders Tinnitus

Cardiac Arrhythmia Tachycardia Cardiomyopathdisorders Cardiac failure y

Vascular Lymphoedema Haemorrhagedisorders Hypertension Embolism

Respiratory, Idiopathic Pulmonary Hypoxiathoracic and pneumonia oedemamediastinal syndrome Coughdisorders Epistaxis Pneumonitis

Gastrointestina Nausea Constipation Gastrointestinall disorders Stomatitis Gastrointestinal ulcer

Oesophagitis perforation

Vomiting Ileus

Dyspepsia

Abdominal pain

Enteritis

Hepatobiliary Venoocclusivedisorders liver disease

Hepatomegaly

Jaundice

Skin and Rash Erythema Pigmentation Severe toxic skinsubcutaneous Pruritus disorder reactions includingtissue disorders Alopecia Erythrodermic cases of Stevens-psoriasis Johnson syndromeand toxic epidermalnecrolysis

System organ Very common Common Uncommon Not knownclass

Musculoskeleta Back painl and Myalgiaconnective Arthralgiatissue disorders

Renal and Cystitis Dysuriaurinary haemorrhagic Oliguriadisorders Renal failure

Cystitis

Haematuria

Reproductive Azoospermia Menopausalsystem and Amenorrhoea symptomsbreast disorders Vaginal Infertility femalehaemorrhage Infertility male

General Pyrexia Multi-organdisorders and Asthenia failureadministration Chills Painsite conditions Generalisedoedema

Injection siteinflammation

Injection site pain

Mucosalinflammation

Investigations Weight increased Blood creatinine

Blood bilirubin increasedincreased Blood urea

Transaminases increasedincreased Gamma-

Blood amylase glutamyltransferasincreased e increased

Blood alkalinephosphataseincreased

Aspartateaminotransferaseincreased

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 classand by frequency. Within each frequency grouping, undesirable effects are presented in order ofdecreasing 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 Thrombocytopenicsusceptibility purpuraincreased

System organ class Very common Common Not known

Neoplasms benign, malignant Treatment relatedand unspecified (incl cysts and secondpolyps) malignancy

Blood and lymphatic system Thrombocytopeniadisorders Febrileneutropenia

Pancytopenia

Granulocytopenia

Immune system disorders Acute graft versushost disease

Chronic graftversus hostdisease

Endocrine disorders Hypopituitarism

Hypogonadism

Metabolism and nutrition Anorexiadisorders Hyperglycaemia

Psychiatric disorders Mental status Mental disorderchanges due to a generalmedical condition

Nervous system disorders Headache Ataxia Leukoencephalopathy

Convulsion

Cerebralhaemorrhage

Memoryimpairment

Paresis

Ear and labyrinth disorders Hearing impaired

Cardiac disorders Cardiac arrest Cardiovascularinsufficiency

Cardiac failure

Vascular disorders Haemorrhage Hypertension

Respiratory, thoracic and Pneumonitis Idiopathic Pulmonary arterialmediastinal disorders pneumonia hypertensionsyndrome

Pulmunaryhaemorrage

Pulmonaryoedema

Epistaxis

Hypoxia

Respiratory arrest

Gastrointestinal disorders Nausea Enteritis

Stomatitis Intestinal

Vomiting obstruction

Abdominal pain

Hepatobiliary disorders Venoocclusive Liver failureliver disease

System organ class Very common Common Not known

Skin and subcutaneous tissue Rash Severe toxic skindisorders Erythema reactions including

Desquamation cases of Stevens-

Pigmentation Johnson syndromedisorder and toxic epidermalnecrolysis

Musculoskeletal and connective Growthtissue disorders retardation

Renal and urinary disorders Bladder disorders Renal failure

Cystitishaemorrhagic

General disorders and Pyrexiaadministration site conditions Mucosalinflammation Pain

Multi-organfailure

Investigations Blood bilirubin Blood ureaincreased increased

Transaminases Blood electrolytesincreased abnormal

Blood creatinine Prothrombin timeincreased ratio increased

Aspartateaminotransferaseincreased

Alanineaminotransferaseincreased

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience with overdoses of thiotepa. The most important adverse reactions expected incase 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 institutedas medically indicated.

Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, ATC code: L01AC01

Thiotepa is a polyfunctional cytotoxic agent related chemically and pharmacologically to the nitrogenmustard. The radiomimetic action of thiotepa is believed to occur through the release of ethyleneimine radicals that, as in the case of irradiation therapy, disrupt the bonds of DNA, e.g. by alkylationof guanine at the N-7, breaking the linkage between the purine base and the sugar and liberatingalkylated guanine.

The conditioning treatment must provide cytoreduction and ideally disease eradication. Thiotepa hasmarrow ablation as its dose-limiting toxicity, allowing significant dose escalation with the infusion ofautologous HPCT. In allogeneic HPCT, the conditioning treatment must be sufficientlyimmunosuppressive and myeloablative to overcome host rejection of the graft. Due to its highlymyeloablative characteristics, thiotepa enhances recipient immunosuppression and myeloablation, thusstrengthening engraftment; this compensates for the loss of the GvHD-related GvL effects. Asalkylating agent, thiotepa produces the most profound inhibition of tumour cell growth in vitro withthe smallest increase in medicinal product concentration. Due to its lack of extramedullary toxicitydespite dose escalation beyond myelotoxic doses, thiotepa has been used for decades in combinationwith other chemotherapy medicinal products prior to autologous and allogeneic HPCT.

The results of published clinical studies supporting the efficacy of thiotepa are summarised:

Autologous HPCT

Haematological diseases

Engraftment: Conditioning treatments including thiotepa have proved to be myeloablative.

Disease free survival (DFS): An estimated 43% at five years has been reported, confirming thatconditioning treatments containing thiotepa following autologous HPCT are effective therapeuticstrategies for treating patients with haematological diseases.

Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have beenreported as being 60% or lower, which was considered by the physicians as the threshold to proveefficacy. In some of the conditioning treatments evaluated, relapse rates lower than 60% have alsobeen reported at 5 years.

Overall survival (OS): OS ranged from 29% to 87% with a follow-up ranging from 22 up to63 months.

Regimen related mortality (RRM) and Transplant related mortality (TRM): RRM values ranging from2.5% to 29% have been reported. TRM values ranged from 0% to 21% at 1 year, confirming the safetyof the conditioning treatment including thiotepa for autologous HPCT in adult patients withhaematological diseases.

Solid tumours

Engraftment: Conditioning treatments including thiotepa have proved to be myeloablative.

Disease free survival (DFS): Percentages reported with follow-up periods of more than 1 year confirmthat conditioning treatments containing thiotepa following autologous HPCT are effective choices fortreating patients with solid tumours.

Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have beenreported as being lower than 60%, which was considered by the physicians as the threshold to proveefficacy. In some cases, relapse rates of 35% and of 45% have been reported at 5 years and 6 yearsrespectively.

Overall survival: OS ranged from 30% to 87% with a follow-up ranging from 11.7 up to 87 months.

Regimen related mortality (RRM) and Transplant related mortality (TRM): RRM values ranging from0% to 2% have been reported. TRM values ranged from 0% to 7.4% confirming the safety of theconditioning treatment including thiotepa for autologous HPCT in adult patients with solid tumours.

Allogeneic HPCT

Haematological diseases

Engraftment: Engraftment has been achieved (92%-100%) in all reported conditioning treatments andit was considered to occur at the expected time. Therefore, it can be concluded that conditioningtreatments including thiotepa are myeloablative.

GvHD (graft versus host disease): all conditioning treatments evaluated assured a low incidence ofacute GvHD grade III-IV (from 4% to 24%).

Disease free survival (DFS): Percentages reported with follow-up periods of more than 1 year and upto 5 years confirm that conditioning treatments containing thiotepa following allogeneic HPCT areeffective choices for treating patients with haematological diseases.

Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have beenreported as being lower than 40% (which was considered by the physicians as the threshold to proveefficacy). In some cases, relapse rates lower than 40% have also been reported at 5 years and 10 years.

Overall survival: OS ranged from 31% to 81% with a follow-up ranging from 7.3 up to 120 months.

Regimen related mortality (RRM) and Transplant related mortality (TRM): low values have beenreported, confirming the safety of the conditioning treatments including thiotepa for allogeneic HPCTin adult patients with haematological diseases.

Autologous HPCT

Solid tumours

Engraftment: It has been achieved with all reported conditioning regimens including thiotepa.

Disease free survival (DFS): With a follow-up of 36 to 57 months, DFS ranged from 46% to 70% inthe reported studies. Considering that all patients were treated for high risk solid tumours, DFS resultsconfirm that conditioning treatments containing thiotepa following autologous HPCT are effectivetherapeutic strategies for treating paediatric patients with solid tumours.

Relapse: In all the reported conditioning regimens containing thiotepa, relapse rates at 12 to 57 monthsranged from 33% to 57%. Considering that all patients suffer of recurrence or poor prognosis solidtumours, these rates support the efficacy of conditioning regimens based on thiotepa.

Overall survival (OS): OS ranged from 17% to 84% with a follow-up ranging from 12.3 up to99.6 months.

Regimen related mortality (RRM) and Transplant related mortality (TRM): RRM values ranging from0% to 26.7% have been reported. TRM values ranged from 0% to 18% confirming the safety of theconditioning treatments including thiotepa for autologous HPCT in paediatric patients with solidtumours.

Allogeneic HPCT

Haematological diseases

Engraftment: It has been achieved with all evaluated conditioning regimens including thiotepa with asuccess rate of 96% - 100%. The haematological recovery is in the expected time.

Disease free survival (DFS): Percentages of 40% - 75% with follow-up of more than 1 year have beenreported. DFS results confirm that conditioning treatment containing thiotepa following allogeneic

HPCT are effective therapeutic strategies for treating paediatric patients with haematological diseases.

Relapse: In all the reported conditioning regimens containing thiotepa, the relapse rate was in therange of 15%-44%. These data support the efficacy of conditioning regimens based on thiotepa in allhaematological diseases.

Overall survival (OS): OS ranged from 50% to 100% with a follow-up ranging from 9.4 up to121 months.

Regimen related mortality (RRM) and Transplant related mortality (TRM): RRM values ranging from0% to 2.5% have been reported. TRM values ranged from 0% to 30% confirming the safety of theconditioning treatment including thiotepa for allogeneic HPCT in paediatric patients withhaematological diseases.

Thiotepa is unreliably absorbed from the gastrointestinal tract: acid instability prevents thiotepa frombeing administered orally.

Thiotepa is a highly lipophilic compound. After intravenous administration, plasma concentrations ofthe active substance fit a two compartment model with a rapid distribution phase. The volume ofdistribution of thiotepa is large and it has been reported as ranging from 40.8 l/m2 to 75 l/m2,indicating distribution to total body water. The apparent volume of distribution of thiotepa appearsindependent of the administered dose. The fraction unbound to proteins in plasma is 70-90%;insignificant binding of thiotepa to gamma globulin and minimal albumin binding (10-30%) has beenreported.

After intravenous administration, CSF medicinal product exposure is nearly equivalent to thatachieved in plasma; the mean ratio of AUC in CSF to plasma for thiotepa is 0.93. CSF and plasmaconcentrations of TEPA, the first reported active metabolite of thiotepa, exceed the concentrations ofthe parent compound.

Thiotepa undergoes rapid and extensive hepatic metabolism and metabolites could be detected inurine within 1 hour after infusion. The metabolites are active alkylating agents but the role they playin the antitumor activity of thiotepa remains to be elucidated. Thiotepa undergoes oxidativedesulphuration via the cytochrome P450 CYP2B and CYP3A isoenzyme families to the major andactive metabolite TEPA (triethylenephosphoramide). The total excreted amount of thiotepa and itsidentified metabolites accounts for 54-100% of the total alkylating activity, indicating the presence ofother alkylating metabolites. During conversion of GSH conjugates to N-acetylcysteine conjugates,

GSH, cysteinylglycine, and cysteine conjugates are formed. These metabolites are not found in urine,and, if formed, are probably excreted in bile or as intermediate metabolites rapidly converted intothiotepa-mercapturate.

The total clearance of thiotepa ranged from 11.4 to 23.2 l/h/m2. The elimination half-life varied from1.5 to 4.1 hours. The identified metabolites TEPA, monochlorotepa and thiotepa-mercapturate are allexcreted in the urine. Urinary excretion of thiotepa and TEPA is nearly complete after 6 and 8 hoursrespectively. The mean urinary recovery of thiotepa and its metabolites is 0.5% for the unchangedmedicinal product and monochlorotepa, and 11% for TEPA and thiotepa-mercapturate.

There is no clear evidence of saturation of metabolic clearance mechanisms at high doses of thiotepa.

The pharmacokinetics of high dose thiotepa in children between 2 and 12 years of age do not appearto vary from those reported in children receiving 75 mg/m2 or adults receiving similar doses.

The effects of renal impairment on thiotepa elimination have not been assessed.

The effects of hepatic impairment on thiotepa metabolism and elimination have not been assessed.

No conventional acute and repeat dose toxicity studies were performed.

Thiotepa was shown to be genotoxic in vitro and in vivo, and carcinogenic in mice and rats.

Thiotepa was shown to impair fertility and interfere with spermatogenesis in male mice, and to impairovarian function in female mice. It was teratogenic in mice and in rats, and foeto-lethal in rabbits.

These effects were seen at doses lower than those used in humans.

None

Sodium chloride

Water for injections

TEPADINA is unstable in acid medium.

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Inactivated bag2 years.

After activation of the bag and reconstitution

From a microbiological point of view, the product should be used immediately after activation andreconstitution.

Chemical and physical stability of the reconstituted product in the activated bag has beendemonstrated for up to 48 hours when stored at 2 °C-8 °C and for up to 6 hours at 25 °C temperature.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of theuser and would normally not be longer than the above-mentioned conditions when reconstitution hastaken place in controlled and validated aseptic conditions.

Store and transport refrigerated (2°C - 8°C).

Do not freeze.

Keep the bag in the aluminum wrapper in order to protect from activation.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

TEPADINA 200 mg

TEPADINA is supplied as a dual chamber bag containing 200 mg of powder in one chamber and 200mL sodium chloride 9 mg/mL (0.9%) solution for injection in the other chamber.

TEPADINA 400 mg

TEPADINA is supplied as a dual chamber bag containing 400 mg of powder in one chamber and400 mL sodium chloride 9 mg/mL (0.9%) solution for injection in the other chamber.

The bag of TEPADINA 200 mg and 400 mg is made of a multilayer polyolefin/styrene - blockcopolymer and it is assembled with three tubes made of the same polyolefin/styrene material, fittedwith different closure systems:

- twist off port (polypropylene or thermoplastic elastomer);

- nip-cap connector composed of luer lock closure (silicone/polycarbonate) and cap connector(polypropylene);

- blind port which is only used during manufacturing (lyophilization) is made of polypropyleneequipped with chlorobutyl lyo stopper and sealed with aluminum flip-off seals.

Each bag is packed in an aluminum wrapper.

Pack size of 1 bag.

Preparation of TEPADINA

Procedures for proper handling and disposal of anticancer medicinal products must be considered. Alltransfer procedures require strict adherence to aseptic techniques, preferably employing a verticallaminar flow safety hood.

As with other cytotoxic compounds, caution needs to be exercised in handling and preparation of

TEPADINA solutions to avoid accidental contact with skin or mucous membranes. Topical reactionsassociated with accidental exposure to thiotepa may occur. In fact, the use of gloves is recommendedin preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, the skin mustbe immediately and thoroughly washed with soap and water. If thiotepa accidentally contacts mucousmembranes, they must be flushed thoroughly with water.

Activation and reconstitution

TEPADINA bag must be reconstituted with sodium chloride 9 mg/mL (0.9%) solution for injection.

The final reconstituted solution is obtained after breaking the peelable seal of the dual chamber bagand mixing the contents (powder and solvent) until complete dissolution of the powder.

After reconstitution with the solvent, each mL of solution contains 1 mg of thiotepa.

Only colourless solutions, without any particulate matter, must be used.

Dose adjustments calculated according to posology (section 4.2)

TEPADINA 200 mg

In order to ensure the dose to be administered, an adjustment may be needed by withdrawal or additionof the solution, as follows:

- withdrawal (if the required dose is less than 200 mg)withdraw an appropriate volume of the reconstituted solution (1 mg/mL), as needed, with agraduated syringe using the luer port (Step 5 of the Instruction for Use in the package leaflet) orset an infusion pump with the amount of medicinal product to be administered in mL;

- addition (if the required dose is greater than 200 mg)the appropriate volume of the reconstituted solution from TEPADINA 15 mg or 100 mg vials(10 mg/mL) should be transferred into the infusion bag of TEPADINA 200 mg through thededicated luer port (Step 5 of the Instruction for Use in the package leaflet).

TEPADINA 400 mg

In order to ensure the dose to be administered, an adjustment may be needed by withdrawal or additionof the solution, as follows:

- withdrawal (if the required dose is less than 400 mg)withdraw an appropriate volume of the reconstituted solution (1 mg/mL), as needed, with agraduated syringe using the luer port (Step 5 of the Instruction for Use in the package leaflet) orset an infusion pump with the amount of medicinal product to be administered in mL;

- addition (if the required dose is greater than 400 mg)the appropriate volume of the reconstituted solution from TEPADINA 15 mg or 100 mg vials(10 mg/mL) should be transferred into the infusion bag of TEPADINA 400 mg through thededicated luer port (Step 5 of the Instruction for Use in the package leaflet).

TEPADINA infusion solution should be inspected visually for particulate matter prior toadministration. Solutions containing a precipitate should be discarded.

Prior to and following each infusion, the indwelling catheter line should be flushed withapproximately 5 mL sodium chloride 9 mg/mL (0.9%) solution for injection.

The infusion solution must be administered to patients using an infusion set equipped with a 0.2 µmin-line filter. Filtering does not alter solution potency.

TEPADINA is for single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

ADIENNE S.r.l. S.U.

Via Galileo Galilei, 1920867 Caponago (MB) Italy

Tel: +39-02 40700445adienne@adienne.com

EU/1/10/622/003

EU/1/10/622/004

Date of first authorisation: 15 March 2010

Date of latest renewal: 17 November 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.