TEPADINA 100 mg powder for concentrate for solution forinfusion

TEPADINA contains the active substance thiotepa, which belongs to a group of medicines called alkylating agents.

TEPADINA is used to prepare patients for bone marrow transplantation. It works by destroying bone marrow cells. This enables the transplantation of new bone marrow cells (haematopoietic progenitor cells), which in turn enable the body to produce healthy blood cells.
TEPADINA can be used in adults and children.

Do not use TEPADINA

• if you are allergic (hypersensitive) to thiotepa,
• if you are pregnant or think you may be pregnant (see below),
• if you are breast-feeding,
• if you are receiving yellow fever vaccination.

Take special care with TEPADINA

You should tell your doctor if you have:

• liver or kidney problems,
• heart or lung problems,
• seizures/fits (epilepsy) or have had them in the past.

You will have to take regular blood tests during treatment to check your blood cell counts.

You will have to use anti-infectives to prevent and manage infections.

TEPADINA may cause another type of cancer in the future. Your doctor will discuss this risk with you.

Pregnancy and breast-feeding

You must tell your doctor if you are or think you may be pregnant before you receive TEPADINA. You must not use TEPADINA during pregnancy.

Both women and men using TEPADINA must use effective contraceptive methods during treatment.

It is not known whether this medicinal product is excreted in breast milk. As a precautionary measure, women must not breast-feed during treatment with TEPADINA.

TEPADINA can impair male and female fertility. Male patients should seek for sperm preservation before therapy is started and should not father while treated and during the year after cessation of treatment.

Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Your doctor will calculate the dose according to your body surface or weight and your disease.

How TEPADINA is given

TEPADINA is administered by a qualified healthcare professional as an intravenous infusion (drip in a vein) after dilution of the individual vial. Each infusion will last 2-4 hours.

Frequency of administration

You will receive your infusions every 12 or 24 hours. The duration of treatment can last up to 3 days. Frequency of administration and duration of treatment depend on your disease.

Like all medicines, TEPADINA can cause side effects, although not everybody gets them.

The most serious side effects of TEPADINA therapy or the transplant procedure may include

• decrease in circulating blood cell counts (intended effect of the medicine to prepare you for your transplant infusion)
• infection
• liver disorders including blocking of a liver vein
• the graft attacks your body (graft versus host disease)
• respiratory complicationsYour doctor will monitor your blood counts and liver enzymes regularly to detect and manage these events.

Side effects of TEPADINA may occur with certain frequencies, which are defined as follows very common affects more than 1 user in 10 common affects 1 to 10 users in 100 uncommon affects 1 to 10 users in 1,000 rare affects 1 to 10 users in 10,000 very rare affects less than 1 user in 10,000 not known frequency cannot be estimated from the available data.

Very common side effects

• increased susceptibility to infection
• whole-body inflammatory state (sepsis)
• decreased counts of white blood cells, platelets and red blood cells (anaemia)
• the transplanted cells attack your body (graft versus host disease)
• dizziness, headache, blurred vision
• uncontrolled shaking of the body (convulsion)
• sensation of tingling, pricking or numbness (paraesthesia)
• partial loss of movement
• cardiac arrest
• nausea, vomiting, diarrhoea
• inflammation of the mucosa of the mouth (mucositis)
• irritated stomach, gullet, intestine
• inflammation of the colon
• anorexia, decreased appetite
• high glucose in the blood
• skin rash, itching, shedding
• skin colour disorder (do not confuse with jaundice - see below)
• redness of the skin (erythema)
• hair loss
• back and abdominal pain, pain
• muscle and joint pain
• abnormal electrical activity in the heart (arrhythmia)
• inflammation of lung tissue
• enlarged liver
• altered organ function
• blocking of a liver vein (VOD)
• yellowing of the skin and eyes (jaundice)
• hearing impaired
• lymphatic obstruction
• high blood pressure
• increased liver, renal and digestive enzymes
• abnormal blood electrolytes
• weight gain
• fever, general weakness, chills
• bleeding (haemorrhage)
• nasal bleeding
• general swelling due to fluid retention (oedema)
• pain or inflammation at the injection site
• eye infection (conjunctivitis)
• decreased sperm cell count
• vaginal bleeding
• absence of menstrual periods (amenorrhea)
• memory loss
• delaying in weight and height increase
• bladder disfunction
• underproduction of testosterone
• insufficient production of thyroid hormone
• deficient activity of the pituitary gland
• confusional state

Common side effects

• anxiety, confusion
• abnormal bulging outward of one of the arteries in the brain (intracranial aneurysm)
• creatinine elevated
• allergic reactions
• occlusion of a blood vessel (embolism)
• heart rhythm disorder
• heart inability
• cardiovascular inability
• oxygen deficiency
• fluid accumulation in the lungs (pulmonary oedema)
• pulmonary bleeding
• respiratory arrest
• blood in the urine (haematuria) and moderate renal insufficiency
• inflammation of the urinary bladder
• discomfort in urination and decrease in urine output (disuria and oliguria)
• increase in the amount of nitrogen components in the blood stream (BUN increase)
• cataract
• inability of the liver
• cerebral haemorrhage
• cough
• constipation and upset stomach
• obstruction of the bowel
• perforation of stomach
• changes in muscle tone
• gross lack of coordination of muscle movements
• bruises due to a low platelet count
• menopausal symptoms
• cancer (second primary malignancies)
• abnormal brain function

Uncommon side effects

• inflammation and exfoliation of the skin (erythrodermic psoriasis)
• delirium, nervousness, hallucination, agitation
• gastrointestinal ulcer
• inflammation of the muscular tissue of the heart (myocarditis)
• abnormal heart condition (cardiomyopathy)
• male and female infertility

If any of the side effects gets serious, or if you notice any side effects not mentioned in this leaflet, please tell your doctor or nurse.

Keep out of the reach and sight of children.

Do not use TEPADINA after the expiry date which is stated on the carton and vial label, after EXP. The expiry date refers to the last day of that month.

Store and transport refrigerated (2°C-8°C).
Do not freeze.

After reconstitution the product is stable for 8 hours when stored at 2°C -8°C.

After dilution the product is stable for 24 hours when stored at 2°C -8°C. From a microbiological point of view, the product should be used immediately.

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

What TEPADINA contains

• The active substance is thiotepa. One vial contains 100 mg thiotepa. After reconstitution, each ml contains 10 mg thiotepa (10 mg/ml).
• TEPADINA does not contain any other ingredients.

What TEPADINA looks like and contents of the pack

TEPADINA is a white crystalline powder supplied in a glass vial containing 100 mg thiotepa.

Each carton contains 1 vial.

Marketing Authorisation Holder
ADIENNE S.r.l.
Via Broseta 64/B
24128 Bergamo
Italy

+39 035 19964047
adienne@adienne.com

Manufacturer

RIEMSER Arzneimittel AG
7 An der Wiek
17493 Greifswald
Insel Riems
Germany

This leaflet was last approved in: {MM/YYYY}

The following information is intended for medical or healthcare professionals only.

PREPARATION GUIDE

TEPADINA 100 mg powder for concentrate for solution for infusion

Thiotepa

Read this guide prior to the preparation and administration of TEPADINA.

1. PRESENTATION

TEPADINA is supplied as 100 mg powder for concentrate for solution for infusion. TEPADINA must be reconstituted and diluted prior to administration.

2. SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING

General
Procedures for proper handling and disposal of anticancer medicinal products should be considered. All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood.As with other cytotoxic compounds, caution need to be exercised in handling and preparation of TEPADINA solutions to avoid accidental contact with skin or mucous membranes. Topical reactions associated with accidental exposure to thiotepa may occur. In fact, the use of gloves is recommended in preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, immediately the skin must be thoroughly washed with soap and water. If thiotepa accidentally contacts mucous membranes, they must be flushed thoroughly with water.

Calculation of dose of TEPADINA
TEPADINA is administered at different doses in combination with other chemotherapeutic medicinal products in patients prior to conventional haematopoietic progenitor cell transplantation (HPCT) for haematological diseases or solid tumours.
TEPADINA posology is reported, in adult and paediatric patients, according to the type of HPCT (autologous or allogeneic) and disease.

Posology in adults

AUTOLOGOUS HPCT:

Haematological diseases

The recommended dose in haematological diseases ranges from 125 mg/m 2/day (3.38 mg/kg/day) to 300 mg/m 2/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/m 2 (24.32 mg/kg), during the time of the entire conditioning treatment.

LYMPHOMA

The recommended dose ranges from 125 mg/m 2/day (3.38 mg/kg/day) to 300 mg/m 2/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/m 2 (24.32 mg/kg), during the time of the entire conditioning treatment.
CNS LYMPHOMAThe recommended dose is 185 mg/m 2/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/m 2 (10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose ranges from 150 mg/m 2/day (4.05 mg/kg/day) to 250 mg/m 2/day

Solid tumours

The recommended dose in solid tumours ranges from 120 mg/m 2/day (3.24 mg/kg/day) to 250 mg/m 2/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/m 2 (21.62 mg/kg), during the time of the entire conditioning treatment.
BREAST CANCER
The recommended dose ranges from 120 mg/m 2/day (3.24 mg/kg/day) to 250 mg/m 2/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/m 2 (21.62 mg/kg), during the time of

The recommended dose ranges from 125 mg/m 2/day (3.38 mg/kg/day) to 250 mg/m 2/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/m 2 (20.27 mg/kg), during the time of the entire conditioning treatment.

OVARIAN CANCER
The recommended dose is 250 mg/m 2/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/m 2 (13.51 mg/kg), during the time of the entire conditioning treatment.
GERM CELL TUMOURS
The recommended dose ranges from 150 mg/m 2/day (4.05 mg/kg/day) to 250 mg/m 2/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/m 2 (20.27 mg/kg), during the time of the entire

ALLOGENEIC HPCT:

Haematological diseases

The recommended dose in haematological diseases ranges from 185 mgm2day 5 mgkgday to 481 mgm2day 13 mgkgday divided in one or two daily infusions, administered from 1 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 555 mgm2 15 mgkg, during the time of the entire conditioning treatment. LYMPHOMA The recommended dose in lymphoma is 370 mgm2day 10 mgkgday divided in two daily infusions before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mgm210 mgkg, during the time of the entire conditioning treatment. MULTIPLE MYELOMA The recommended dose is 185 mgm2day 5 mgkgday as a single daily infusion before allogeneic HPCT, without exceeding the total maximum cumulative dose of 185 mgm2 5 mgkg, during the time of the entire conditioning treatment. LEUKEMIA The recommended dose ranges from 185 mgm2day 5 mgkgday to 481 mgm2day 13 mgkgday 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 mgm2 15 mgkg, during the time of the entire conditioning treatment. THALASSEMIA The recommended dose is 370 mgm2day 10 mgkgday divided in two daily infusions, administered before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mgm210 mgkg, during the time of the entire conditioning treatment.

Posology in paediatric patients

AUTOLOGOUS HPCT:

Solid tumours

The recommended dose in solid tumours ranges from 150 mg/m 2/day (6 mg/kg/day) to 350 mg/m 2/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 1050 mg/m 2 (42 mg/kg), during the time of the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 250 mg/m 2/day (10 mg/kg/day) to 350 mg/m 2/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 1050 mg/m 2 (42 mg/kg), during the time of the entire conditioning treatment.

ALLOGENEIC HPCT:

Haematological diseases

The recommended dose in haematological diseases ranges from 125 mgm2day 5 mgkgday to 250 mgm2day 10 mgkgday 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 mgm2 15 mgkg, during the time of the entire conditioning treatment. LEUKEMIA The recommended dose is 250 mgm2day 10 mgkgday divided in two daily infusions, administered before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mgm210 mgkg, during the time of the entire conditioning treatment. THALASSEMIA The recommended dose ranges from 200 mgm2day 8 mgkgday to 250 mgm2day 10 mgkgday divided in two daily infusions, administered before allogeneic HPCT without exceeding the total maximum cumulative dose of 250 mgm2 10 mgkg, during the time of the entire conditioning treatment. REFRACTORY CYTOPENIA The recommended dose is 125 mgm2day 5 mgkgday as a single daily infusion, administered for 3 consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 375 mgm2 15 mgkg, during the time of the entire conditioning treatment. GENETIC DISEASES The recommended dose is 125 mgm2day 5 mgkgday as a single daily infusion, administered for 2 consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mgm2 10 mgkg, during the time of the entire conditioning treatment. SICKLE CELL ANAEMIA The recommended dose is 250 mgm2day 10 mgkgday divided in two daily infusions, administered before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mgm210 mgkg, during the time of the entire conditioning treatment.

Reconstitution
TEPADINA must be reconstituted with 10 ml of sterile water for injections.
Using a syringe fitted with a needle, aseptically withdraw 10 ml of sterile water for injections. Inject the content of the syringe into the vial through the rubber stopper.
Remove the syringe and the needle and mix manually by repeated inversions.
Only clear colourless solutions, without any particulate matter, must be used.

Further dilution in the infusion bag
The reconstituted solution is hypotonic and should be further diluted prior to administration with 500 ml sodium chloride 9 mg/ml (0.9%) solution for injection.

Administration
TEPADINA infusion solution should be inspected visually for particulate matter and opalescence prior to administration. Solutions containing a precipitate should be discarded.

It is recommended that the infusion solution be administered to patients using an infusion set equipped with a 0.2 µm in-line filter.

TEPADINA should be aseptically administered as a 2-4 hours infusion under room temperature and normal light conditions.

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

Disposal
TEPADINA is for single use only.

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