Tepadina 100 mg powder for concentrate for solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: Information for the user

TEPADINA 100 mg powder for concentrate for solution for infusion

tiotepa

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

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

Leaflet contents:

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

1. What TEPADINA is and what it is used for

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

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

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

2. What you need to know before starting TEPADINA

Do not use TEPADINA

• if you are allergic to thiotepa,
• if you are pregnant or think you may be pregnant,
• if you are breastfeeding,
• if you are due to receive the yellow fever vaccine or other live virus or bacterial vaccines.

Warnings and precautions

Tell your doctor if you have:

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

Since TEPADINA destroys bone marrow cells responsible for producing blood cells, you will need periodic blood tests during treatment to monitor your blood cell counts.

Antimicrobial agents will be administered to prevent and treat infections.

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

Use of TEPADINA with other medicines

Tell your doctor if you are taking, have recently taken, or might need to take any other medicines.

Pregnancy, breastfeeding and fertility

Inform 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 receiving TEPADINA must use effective contraception during treatment.

It is unknown whether this medicine is excreted in human milk. As a precaution, women should not breastfeed during treatment with TEPADINA.

TEPADINA may affect male and female fertility. Male patients should consider sperm preservation before starting treatment and must avoid fathering a child during treatment and for one year after treatment ends.

Driving and using machines

Some adverse effects of thiotepa, such as dizziness, headache and blurred vision, may affect your ability to drive or operate machinery.

3. How to use TEPADINA

The physician will calculate the dose based on your body surface area or body weight and your condition.

How TEPADINA is administered

TEPADINA must be administered by a qualified healthcare professional as an intravenous infusion (intravenous 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 duration of treatment will depend on your condition.

4. Possible adverse effects

Like all medicines, TEPADINA may cause adverse effects, although not everyone will experience them.

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

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

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

Adverse effects of TEPADINA occur at certain frequencies, defined as follows:

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

• increased susceptibility to infections
• generalized inflammation (septicemia)
• decreased counts of white blood cells, platelets, and red blood cells (anemia)
• attack by transplanted cells against your body (graft-versus-host disease)
• dizziness, headache, blurred vision
• uncontrollable body tremors (seizures)
• tingling, pricking, or numbness sensation (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
• anorexia, loss of appetite
• elevated blood glucose
• rash, pruritus, skin peeling
• skin color changes (should not be confused 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
• impaired function of certain organs
• blockage of a liver vein (veno-occlusive disease, VOD)
• yellowing of the skin and eyes (jaundice)
• hearing deterioration
• lymphatic obstruction
• high blood pressure
• enlarged liver, elevated renal and digestive enzymes
• abnormal blood electrolyte levels
• weight gain
• fever, general weakness, chills
• bleeding (hemorrhage)
• nosebleeds
• generalized 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 testosterone production
• insufficient thyroid hormone production
• reduced pituitary activity
• confusion

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

• anxiety, confusion
• abnormal dilation of a brain artery (intracranial aneurysm)
• elevated creatinine
• allergic reactions
• blockage of a blood vessel (embolism)
• irregular heartbeat
• heart failure
• cardiovascular insufficiency
• oxygen deficiency
• fluid accumulation in the lungs (pulmonary edema)
• pulmonary hemorrhage
• respiratory arrest
• blood in the urine (hematuria) and moderate renal failure
• inflammation of the urinary bladder
• discomfort during urination and reduced urine output (dysuria and oliguria)
• increased levels of nitrogen-containing components in the blood (elevated BUN)
• cataracts
• liver failure
• cerebral hemorrhage
• cough
• constipation and gastric discomfort
• intestinal obstruction
• stomach perforation
• changes in muscle tone
• general lack of coordination in muscle movements
• bruising associated with low platelet count
• menopausal symptoms
• cancer (secondary primary neoplasms)
• impaired brain function
• male and female infertility

Uncommon adverse 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 tissue (myocarditis)
• abnormal heart disease (cardiomyopathy)

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

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

Reporting of adverse effects

If you experience any adverse effect, consult your doctor or nurse, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the national reporting system listed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Conservation of TEPADINA

Keep out of the sight and reach of children.

Do not use TEPADINA after the expiry date stated on the packaging after "EXP". The expiry date refers to the last day of the month indicated.

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

Do not freeze.

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

After dilution, the medicinal product remains stable for 24 hours when stored at 2°C-8°C and for 4 hours when stored at 25°C. From a microbiological standpoint, the product should be used immediately.

Any unused medicine and materials that have come into contact with it should be disposed of in accordance with local regulations.

6. Contents of the container and other information

Composition of TEPADINA

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

Appearance of the product and contents of the container

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

Each carton 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

[email protected]

More information on this medicinal product can be requested by contacting the local representative of the Marketing Authorization Holder:

Belgium/Belgique/Belgien Accord Healthcare bvba Tel/Tel: +32 51 79 40 12	Lithuania Accord Healthcare AB Tel: +46 8 624 00 25
Polska Accord Healthcare Polska Sp. z o.o. Tel: +48 22 577 28 00	Luxembourg/Luxemburg Accord Healthcare bvba Tel/Tel: +32 51 79 40 12
Czech Republic Accord Healthcare Polska Sp. z o.o. Tel: +48 22 577 28 00	Hungary Accord Healthcare Polska Sp. z o.o. Tel.: +48 22 577 28 00

Denmark

Immedica Pharma AB

Tlf: +46 (0)8 533 39 500

Malta

Accord Healthcare Ireland Ltd

Tel: +44 (0) 208 901 3370

Germany

Accord Healthcare GmbH

Tel: +49 89 700 9951 0

Netherlands

Accord Healthcare B.V.

Tel: +31 30 850 6014

Estonia

Accord Healthcare AB

Tel: +46 8 624 00 25

Norway

Immedica Pharma AB

Tlf: +46 (0)8 533 39 500

Greece

aVIPHARMA International S.A.

Tel: +30-210 6194 170

Austria

Accord Healthcare GmbH

Tel: +43 (0)662 424899-0

Spain

Accord Healthcare S.L.U.

Tel: +34 93 301 00 64

Poland

Accord Healthcare Polska Sp. z o.o.

Tel.: +48 22 577 28 00

France

Accord Healthcare France SAS

Tél: +33 (0)320 401 770

Portugal

Accord Healthcare, Unipessoal Lda

Tel: +351 214 697 835

Croatia

Accord Healthcare Polska Sp. z o.o.

Tel: +48 22 577 28 00

Romania

Accord Healthcare Polska Sp. z o.o.

Tel: +48 22 577 28 00

Ireland

Accord Healthcare Ireland Ltd

Tel: +44 (0)1271 385257

Slovenia

Accord Healthcare Polska Sp. z o.o.

Tel: +48 22 577 28 00

Iceland

Immedica Pharma AB

Sími: +46 (0)8 533 39 500

Slovakia

Accord Healthcare Polska Sp. z o.o.

Tel: +48 22 577 28 00

Italy

Accord Healthcare Italia Srl

Tel: +39 02 943 23 700

Finland

Immedica Pharma AB

Puh/Tel: +46 (0)8 533 39 500

Cyprus

aVIPHARMA International S.A.

Tel: +30-210 6194 170

Sweden

Immedica Pharma AB

Tel: +46 (0)8 533 39 500

Latvia

Accord Healthcare AB

Tel: +46 8 624 00 25

United Kingdom

Accord-UK Ltd

Tel: +44 (0)1271 385257

Date of the most recent review 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 for healthcare professionals only:

PREPARATION GUIDE

TEPADINA 100 mg powder for concentrate for solution for infusion Tiotepa

Read this guide before the preparation and administration of TEPADINA.

1. PRESENTATION

TEPADINA is supplied as 100 mg of powder for concentrate for solution for infusion.

TEPADINA must be reconstituted and diluted before administration.

1. SPECIAL HANDLING PRECAUTIONS AND DISPOSAL

General

Appropriate procedures for handling and disposal of antineoplastic drugs must be followed. All transfer procedures must strictly adhere to aseptic techniques, preferably using a vertical laminar flow safety cabinet. As with other cytotoxic compounds, extreme caution should be taken during handling and preparation of TEPADINA solutions to avoid accidental contact with skin or mucous membranes. Topical reactions may occur following accidental exposure to tiotepa. Therefore, the use of gloves is recommended during the preparation of the infusion solution. If tiotepa solution comes into accidental contact with the skin, wash thoroughly with soap and water immediately. If tiotepa comes into accidental contact with mucous membranes, rinse thoroughly with water.

Calculation of TEPADINA dose

TEPADINA is administered at various doses and in combination with other chemotherapeutic agents to patients undergoing conventional hematopoietic stem cell transplantation (HSCT) for hematological disorders or solid tumors.

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

Dosage in adults

AUTLOGOUS HSCT

Hematological disorders

The recommended dose in hematological disorders ranges between 125 mg/m²/day (3.38 mg/kg/day) and 300 mg/m²/day (8.10 mg/kg/day) given as a single daily infusion administered for 2 to 4 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 900 mg/m² (24.32 mg/kg) throughout the conditioning regimen.

LYMPHOMA

The recommended dose in hematological disorders ranges between 125 mg/m²/day (3.38 mg/kg/day) and 300 mg/m²/day (8.10 mg/kg/day) given as a single daily infusion administered for 2 to 4 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 900 mg/m² (24.32 mg/kg) throughout the conditioning regimen.

CENTRAL NERVOUS SYSTEM (CNS) LYMPHOMA

The recommended dose is 185 mg/m²/day (5 mg/kg/day) given as a single daily infusion administered for 2 consecutive days prior to autologous HSCT, without exceeding a maximum cumulative total dose of 370 mg/m² (10 mg/kg) throughout the conditioning regimen.

MULTIPLE MYELOMA

The recommended dose ranges between 150 mg/m²/day (4.05 mg/kg/day) and 250 mg/m²/day (6.76 mg/kg/day) given as a single daily infusion administered for 3 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 750 mg/m² (20.27 mg/kg) throughout the conditioning regimen.

Solid tumors

The recommended dose in solid tumors ranges 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 prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning regimen.

BREAST CANCER

The recommended dose ranges between 120 mg/m²/day (3.24 mg/kg/day) and 250 mg/m²/day (6.76 mg/kg/day) given as a single daily infusion administered for 3 to 5 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning regimen.

CNS TUMORS

The recommended dose ranges 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 prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 750 mg/m² (20.27 mg/kg) throughout the conditioning regimen.

OVARIAN CANCER

The recommended dose is 250 mg/m²/day (6.76 mg/kg/day) given as a single daily infusion administered for 2 consecutive days prior to autologous HSCT, without exceeding a maximum cumulative total dose of 500 mg/m² (13.51 mg/kg) throughout the conditioning regimen.

GERM CELL TUMORS

The recommended dose ranges between 150 mg/m²/day (4.05 mg/kg/day) and 250 mg/m²/day (6.76 mg/kg/day) given as a single daily infusion administered for 3 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 750 mg/m² (20.27 mg/kg) throughout the conditioning regimen.

ALLOGENEIC HSCT

Hematological disorders

The recommended dose in hematological disorders ranges 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 prior to allogeneic HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 555 mg/m² (15 mg/kg) throughout the conditioning regimen.

LYMPHOMA

The recommended dose is 370 mg/m²/day (10 mg/kg/day) divided into two daily infusions prior to allogeneic HSCT, without exceeding a maximum cumulative total dose of 370 mg/m² (10 mg/kg) throughout the conditioning regimen.

MULTIPLE MYELOMA

The recommended dose is 185 mg/m²/day (5 mg/kg/day) given as a single daily infusion prior to allogeneic HSCT, without exceeding a maximum cumulative total dose of 185 mg/m² (5 mg/kg) throughout the conditioning regimen.

LEUKEMIA

The recommended dose ranges 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 prior to allogeneic HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 555 mg/m² (15 mg/kg) throughout the conditioning regimen.

THALASSEMIA

The recommended dose is 370 mg/m²/day (10 mg/kg/day) divided into two daily infusions administered prior to allogeneic HSCT, without exceeding a maximum cumulative total dose of 370 mg/m² (10 mg/kg) throughout the conditioning regimen.

Dosage in pediatric patients

AUTLOGOUS HSCT

Solid tumors

The recommended dose in hematological disorders ranges between 150 mg/m²/day (6 mg/kg/day) and 350 mg/m²/day (14 mg/kg/day) given as a single daily infusion administered for 2 to 3 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 1,050 mg/m² (42 mg/kg) throughout the conditioning regimen.

CNS TUMORS

The recommended dose ranges between 250 mg/m²/day (10 mg/kg/day) and 350 mg/m²/day (14 mg/kg/day) given as a single daily infusion administered for 3 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 1,050 mg/m² (42 mg/kg) throughout the conditioning regimen.

ALLOGENEIC HSCT

Hematological disorders

The recommended dose in hematological disorders ranges 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 prior to allogeneic HSCT, depending on combination with other chemotherapeutic agents, without exceeding a maximum cumulative total dose of 375 mg/m² (15 mg/kg) throughout the conditioning regimen.

LEUKEMIA

The recommended dose is 250 mg/m²/day (10 mg/kg/day) divided into two daily infusions administered prior to allogeneic HSCT, without exceeding a maximum cumulative total dose of 250 mg/m² (10 mg/kg) throughout the conditioning regimen.

THALASSEMIA

The recommended dose ranges between 200 mg/m²/day (8 mg/kg/day) and 250 mg/m²/day (10 mg/kg/day), divided into two daily infusions administered prior to allogeneic HSCT, without exceeding a maximum cumulative total dose of 250 mg/m² (10 mg/kg) throughout the conditioning regimen.

REFRACTORY CYTOPENIA

The recommended dose is 125 mg/m²/day (5 mg/kg/day) given as a single daily infusion administered for 3 consecutive days prior to allogeneic HSCT, without exceeding a maximum cumulative total dose of 375 mg/m² (15 mg/kg) throughout the conditioning regimen.

GENETIC DISORDERS

The recommended dose is 125 mg/m²/day (5 mg/kg/day) given as a single daily infusion administered for 2 consecutive days prior to allogeneic HSCT, without exceeding a maximum cumulative total dose of 250 mg/m² (10 mg/kg) throughout the conditioning regimen.

SICKLE CELL ANEMIA

The recommended dose is 250 mg/m²/day (10 mg/kg/day) divided into two daily infusions administered prior to allogeneic HSCT, without exceeding a maximum cumulative total dose of 250 mg/m² (10 mg/kg) throughout the conditioning regimen.

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 injection.

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, colourless solutions free from particles should 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 9 mg/ml sodium chloride injection solution (0.9%) (1000 ml if the dose exceeds 500 mg), or with an appropriate volume of 9 mg/ml sodium chloride (0.9%) to achieve a final TEPADINA concentration between 0.5 and 1 mg/ml.

Administration

TEPADINA solution for infusion must be visually inspected for particulate matter prior to administration. Solutions containing precipitates must be discarded.

The infusion solution must be administered to patients using an infusion set equipped with an in-line 0.2 µm 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 indwelling catheter should be flushed with approximately 5 ml of 9 mg/ml sodium chloride injection solution (0.9%).

Disposal

TEPADINA is for single use only.

Any unused medicine and all materials that have come into contact with it must be disposed of in accordance with local regulations.