TEPADINA 15 MG POWDER FOR CONCENTRATE FOR PERFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

TEPADINA 15 mg powder for concentrate for solution for infusion

tiotepa

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor.
• If you experience any side effects, talk to your doctor, even if they are not listed in this leaflet. See section 4.

Contents of the pack

1. What is TEPADINA and what is it used for
2. What you need to know before you use TEPADINA
3. How to use TEPADINA
4. Possible side effects
5. Storage of TEPADINA
6. Contents of the pack and other information

1. What is TEPADINA and what is it used for

TEPADINA contains tiotepa as the active substance, a medicine that belongs to the group of alkylating agents.

TEPADINA is used to prepare the patient for a bone marrow transplant. It works by destroying the cells in the bone marrow. This allows the patient to receive a transplant of new bone marrow cells (hematopoietic stem cells), which in turn enable the body to produce healthy blood cells.

TEPADINA can be used in adults, children, and adolescents.

2. What you need to know before you use TEPADINA

Do not use TEPADINA

• if you are allergic to tiotepa,
• if you are pregnant or think you may be pregnant,
• if you are breast-feeding,
• if you are going to receive the yellow fever vaccine with live virus and bacterial vaccines.

Warnings and precautions

Tell your doctor if you have:

• liver or kidney problems,
• heart or lung problems,
• seizures/epileptic fits or have had them in the past (if you have been treated with phenytoin or fosphenytoin).

Since TEPADINA destroys the bone marrow cells responsible for producing blood cells, you will need to have regular blood tests during treatment to check your cell counts.

To prevent and treat infections, you will be given anti-infectives.

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

Using TEPADINA with other medicines

Tell your doctor if you are using, have recently used, or might use any other medicines.

Pregnancy, breast-feeding, and fertility

Tell your doctor if you are pregnant or think you may be pregnant before receiving 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 if this medicine is excreted in breast milk. As a precaution, women must not breast-feed during treatment with TEPADINA.

TEPADINA may affect male and female fertility. Male patients must use sperm conservation before starting treatment and not father a child while receiving treatment and for the year following the end of treatment.

Driving and using machines

Some adverse reactions of tiotepa, such as dizziness, headache, and blurred vision, may affect your ability to drive and use machines.

3. How to use TEPADINA

Your doctor will calculate the dose based on your body surface area or weight and your disease.

How TEPADINA is administered

TEPADINA must be administered by a qualified healthcare professional via intravenous infusion (drip into a vein) after dilution of each vial. Each infusion lasts 2-4 hours.

Frequency of administration

You will receive infusions every 12 or 24 hours. The treatment may last up to 5 days. The frequency of administration and the duration of treatment will depend on your disease.

4. Possible side effects

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

Some more serious side effects of treatment with TEPADINA or the transplant procedure are:

• decrease in blood cell counts (expected effect of the medicine as preparation for your transplant)
• infection
• liver problems, such as blockage of a liver vein
• graft-versus-host disease (attack of the transplanted cells against your body)
• respiratory complications

Your doctor will monitor your blood cell counts and liver enzymes regularly to detect and treat these events.

The side effects of TEPADINA occur with certain frequencies, which are defined below:

Very common side effects (may affect more than 1 in 10 people)

• increased risk of infections
• generalized inflammation (septicemia)
• decrease in white blood cell, platelet, and red blood cell count (anemia)
• graft-versus-host disease (attack of the transplanted cells against your body)
• dizziness, headache, blurred vision
• uncontrolled body tremors (seizures)
• tingling, pinching, or numbness (paresthesia)
• partial loss of mobility
• cardiac arrest
• nausea, vomiting, diarrhea
• inflammation of the oral mucosa (mucositis)
• irritation of the stomach, esophagus, intestine
• inflammation of the colon
• loss of appetite, anorexia
• elevated blood glucose
• rash, itching, peeling
• change in skin color (not to be confused with jaundice - see below)
• redness of the skin (erythema)
• hair loss
• back and abdominal pain, pain
• muscle and joint pain
• abnormal heart rhythm (arrhythmia)
• inflammation of lung tissue
• enlargement of the liver
• altered function of some organs
• blockage of a liver vein (veno-occlusive disease, VOD)
• yellowing of the skin and eyes (jaundice)
• hearing impairment
• lymphatic obstruction
• high blood pressure
• enlargement of the liver, elevated kidney and digestive enzymes
• abnormal blood electrolyte values
• weight gain
• fever, general weakness, chills
• bleeding (hemorrhage)
• nosebleeds
• general swelling due to fluid retention (edema)
• pain or inflammation at the injection site
• eye infection (conjunctivitis)
• decreased sperm count
• vaginal bleeding
• absence of menstrual periods (amenorrhea)
• memory loss
• delayed weight and height gain
• bladder problems
• insufficient production of testosterone
• insufficient production of thyroid hormones
• reduced activity of the pituitary gland
• state of confusion

Common side effects (may affect up to 1 in 10 people)

• anxiety, confusion
• abnormal dilation of one of the arteries in the brain (intracranial aneurysm)
• elevated creatinine
• allergic reactions
• blockage of a blood vessel (embolism)
• abnormal heart rhythm
• heart failure
• cardiovascular disability
• oxygen deficiency
• fluid accumulation in the lungs (pulmonary edema)
• lung bleeding
• respiratory arrest
• blood in the urine (hematuria) and moderate kidney failure
• inflammation of the urinary bladder
• discomfort while urinating and decreased urine production (dysuria and oliguria)
• increased amount of nitrogen components in the blood (elevated BUN)
• cataracts
• liver failure
• brain bleeding
• cough
• constipation and stomach discomfort
• intestinal obstruction
• stomach perforation
• changes in muscle tone
• general lack of coordination of muscle movements
• bruises associated with low platelet count
• menopausal symptoms
• cancer (secondary primary malignancies)
• altered brain function
• male and female infertility

Uncommon side effects (may affect up to 1 in 100 people)

• inflammation and peeling of the skin (erythrodermic psoriasis)
• delirium, nervousness, hallucinations, agitation
• gastrointestinal ulcer
• inflammation of the heart muscle (myocarditis)
• abnormal heart disease (myocardial disease)

Frequency not known: frequency cannot be estimated from the available data

• increase in blood pressure in the arteries (blood vessels) of the lungs (pulmonary arterial hypertension)
• severe skin damage (e.g. severe lesions, blisters, etc.) that can affect the entire body surface, which can be fatal
• damage to a component of the brain (so-called white matter) that can be potentially fatal (leukoencephalopathy).

Reporting of side effects

If you experience any side effects, talk to your doctor or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of TEPADINA

Keep out of the sight and reach of children.

Do not use TEPADINA after the expiry date which is stated on the carton after "EXP". The expiry date is the last day of the month shown.

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 and for 4 hours when stored at 25°C. From a microbiological point of view, the product should be used immediately.

Disposal of unused medicine and all materials that have come into contact with it will be done according to local regulations.

6. Container Content and Additional Information

TEPADINA Composition

• The active ingredient is thiotepa. A vial contains 15 mg of thiotepa. After reconstitution, each ml contains 10 mg of thiotepa (10 mg/ml).
• TEPADINA does not contain any other components.

Product Appearance and Container Content

TEPADINA is a white crystalline powder that is supplied in a glass vial containing 15 mg of thiotepa.

Each box contains 1 vial.

Marketing Authorization Holder and Manufacturer

ADIENNE S.r.l. S.U.

Via Galileo Galilei, 19

20867 Caponago (MB) Italy

Tel: +39 02 40700445

adienne@adienne.com

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet:

Other Sources of Information

Detailed information on this medicine is available on the European Medicines Agency website http://www.ema.europa.eu/.

This information is intended only for healthcare professionals:

PREPARATION GUIDE

TEPADINA 15 mg powder for concentrate for solution for infusionThiotepa

Read this guide before preparing and administering TEPADINA.

1. Presentation

TEPADINA is supplied as 15 mg of powder for concentrate for solution for infusion.

TEPADINA must be reconstituted and diluted before administration.

1. Special Precautions for Disposal and Other Handling

Generalities

Proper procedures for handling and disposal of antineoplastic medicines will be followed. All transfer procedures will strictly follow aseptic techniques, preferably using a vertical laminar flow safety cabinet. As with other cytotoxic compounds, extreme caution will be exercised during 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. Therefore, the use of gloves is recommended during preparation of the infusion solution. If the thiotepa solution accidentally comes into contact with the skin, it should be washed thoroughly with water and soap immediately. If thiotepa accidentally comes into contact with mucous membranes, they should be washed thoroughly with water.

Calculation of TEPADINA Dose

TEPADINA is administered in different doses and in combination with other chemotherapeutic agents to patients who are to receive a conventional hematopoietic stem cell transplant (HSCT) for hematological diseases or solid tumors.

The recommended dosage of TEPADINA in adult and pediatric patients depends on the type of HSCT (autologous or allogeneic) and the disease.

Adult Dosage

AUTologous HSCT

Hematological Diseases

The recommended dose in hematological diseases varies between 125 mg/m2/day (3.38 mg/kg/day) and 300 mg/m2/day (8.10 mg/kg/day) as a single daily infusion, administered for 2 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 900 mg/m2 (24.32 mg/kg) during the entire conditioning treatment.

LYMPHOMA

The recommended dose in hematological diseases varies between 125 mg/m2/day (3.38 mg/kg/day) and 300 mg/m2/day (8.10 mg/kg/day) as a single daily infusion, administered for 2 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 900 mg/m2 (24.32 mg/kg) during the entire conditioning treatment.

LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM (CNS)

The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 2 consecutive days before an autologous HSCT, without exceeding the maximum accumulated dose of 370 mg/m2 (10 mg/kg) during the entire conditioning treatment.

MULTIPLE MYELOMA

The recommended dose varies between 150 mg/m2/day (4.05 mg/kg/day) and 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered for 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 750 mg/m2 (20.27 mg/kg) during the entire conditioning treatment.

Solid Tumors

The recommended dose in solid tumors varies between 120 mg/m2/day (3.24 mg/kg/day) and 250 mg/m2/day (6.76 mg/kg/day) divided into one or two daily infusions, administered for 2 to 5 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 800 mg/m2 (21.62 mg/kg) during the entire conditioning treatment.

BREAST CANCER

The recommended dose varies between 120 mg/m2/day (3.24 mg/kg/day) and 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered for 3 to 5 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 800 mg/m2 (21.62 mg/kg) during the entire conditioning treatment.

TUMORS OF THE CNS

The recommended dose varies between 125 mg/m2/day (3.38 mg/kg/day) and 250 mg/m2/day (6.76 mg/kg/day) divided into one or two daily infusions, administered for 3 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 750 mg/m2 (20.27 mg/kg) during 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 for 2 consecutive days before an autologous HSCT, without exceeding the maximum accumulated dose of 500 mg/m2 (13.51 mg/kg) during the entire conditioning treatment.

STEM CELL TUMORS

The recommended dose varies between 150 mg/m2/day (4.05 mg/kg/day) and 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered for 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 750 mg/m2 (20.27 mg/kg) during the entire conditioning treatment.

ALLOGENEIC HSCT

Hematological Diseases

The recommended dose in hematological diseases varies between 185 mg/m2/day (5 mg/kg/day) and 481 mg/m2/day (13 mg/kg/day) divided into one or two daily infusions, administered for 1 to 3 consecutive days before an allogeneic HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 555 mg/m2 (15 mg/kg) during the entire conditioning treatment.

LYMPHOMA

The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided into two daily infusions before an allogeneic HSCT, without exceeding the maximum accumulated dose of 370 mg/m2 (10 mg/kg) during the entire conditioning treatment.

MULTIPLE MYELOMA

The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion before an allogeneic HSCT, without exceeding the maximum accumulated dose of 185 mg/m2 (5 mg/kg) during the entire conditioning treatment.

LEUKEMIA

The recommended dose varies between 185 mg/m2/day (5 mg/kg/day) and 481 mg/m2/day (13 mg/kg/day) divided into one or two daily infusions, administered for 1 or 2 consecutive days before an allogeneic HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 555 mg/m2 (15 mg/kg) during the entire conditioning treatment.

THALASSEMIA

The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided into two daily infusions before an allogeneic HSCT, without exceeding the maximum accumulated dose of 370 mg/m2 (10 mg/kg) during the entire conditioning treatment.

Pediatric Dosage

AUTologous HSCT

Solid Tumors

The recommended dose in hematological diseases varies between 150 mg/m2/day (6 mg/kg/day) and 350 mg/m2/day (14 mg/kg/day) as a single daily infusion, administered for 2 to 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 1,050 mg/m2 (42 mg/kg) during the entire conditioning treatment.

TUMORS OF THE CNS

The recommended dose varies between 250 mg/m2/day (10 mg/kg/day) and 350 mg/m2/day (14 mg/kg/day) as a single daily infusion, administered for 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 1,050 mg/m2 (42 mg/kg) during the entire conditioning treatment.

ALLOGENEIC HSCT

Hematological Diseases

The recommended dose in hematological diseases varies between 125 mg/m2/day (5 mg/kg/day) and 250 mg/m2/day (10 mg/kg/day) divided into one or two daily infusions, administered for 1 to 3 consecutive days before an allogeneic HSCT, depending on the combination with other chemotherapeutic agents, without exceeding the maximum accumulated dose of 375 mg/m2 (15 mg/kg) during the entire conditioning treatment.

LEUKEMIA

The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided into two daily infusions before an allogeneic HSCT, without exceeding the maximum accumulated dose of 250 mg/m2 (10 mg/kg) during the entire conditioning treatment.

THALASSEMIA

The recommended dose varies between 200 mg/m2/day (8 mg/kg/day) and 250 mg/m2/day (10 mg/kg/day) divided into two daily infusions before an allogeneic HSCT, without exceeding the maximum accumulated dose of 250 mg/m2 (10 mg/kg) during 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 an allogeneic HSCT, without exceeding the maximum accumulated dose of 375 mg/m2 (15 mg/kg) during 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 an allogeneic HSCT, without exceeding the maximum accumulated dose of 250 mg/m2 (10 mg/kg) during the entire conditioning treatment.

SICKLE CELL ANEMIA

The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided into two daily infusions before an allogeneic HSCT, without exceeding the maximum accumulated dose of 250 mg/m2 (10 mg/kg) during the entire conditioning treatment.

Reconstitution

TEPADINA must be reconstituted with 1.5 ml of sterile water for injectable preparations.

Using a syringe with a needle, extract 1.5 ml of sterile water for injectables under aseptic conditions.

Inject the contents of the syringe into the vial by piercing the rubber stopper.

Remove the syringe and needle, and mix manually by repeated inversion of the vial.

Only clear, particle-free solutions will be used. Reconstituted solutions may occasionally show opalescence; such solutions may still be administered.

Further Dilution in the Infusion Bag

The reconstituted solution is hypotonic and must be diluted before administration with 500 ml of injectable solution containing 9 mg/ml of sodium chloride (0.9%) for injectables (1000 ml if the dose is higher than 500 mg) or with an appropriate volume of sodium chloride 9 mg/ml (0.9%) to achieve a final concentration of TEPADINA between 0.5 and 1 mg/ml.

Administration

TEPADINA infusion solution must be visually inspected for the presence of particles before administration. Solutions containing precipitates must be discarded.

The infusion solution should be administered to patients using an infusion set with a 0.2 µm in-line filter. Filtration does not alter the potency of the solution.

TEPADINA must be administered under aseptic conditions by infusion over 2-4 hours at room temperature (approximately 25 °C) and under normal lighting conditions.

Before and after each infusion, the permanent catheter should be flushed with approximately 5 ml of injectable solution containing 9 mg/ml of sodium chloride (0.9%).

Disposal

TEPADINA is for single use.

Disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.