Label: Information for the User

TEPADINA 100 mg powder for concentrate for solution for infusion

tiotepa

Read the entire label carefully before starting to use the medication because it contains important information for you.

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

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

TEPADINA is used to prepare the patient for a bone marrow transplant. It works by destroying bone marrow cells. In this way, the patient can 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.

Do not use TEPADINA

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

Warnings and precautions

Inform your doctor if you have:

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

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

Antibiotics will be provided to prevent and treat infections.

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

Use of TEPADINA with other medications

Inform your doctor if you are using, have used recently, or may need to use any other medication.

Pregnancy, breastfeeding, and fertility

Inform your doctor if you are pregnant or think you may be pregnant before receiving TEPADINA. Do not use TEPADINA during pregnancy.

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

It is unknown if this medication is excreted in breast milk. As a precaution, women should not breastfeed during TEPADINA treatment.

TEPADINA may affect male and female fertility. Male patients should consider sperm preservation before starting treatment and not father any children while receiving treatment and during the year following its completion.

Driving and operating machinery

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

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

How TEPADINA is administered

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

Administration frequency

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

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

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

• Decrease in circulating blood cell counts (expected effect of the medicine as a preparation for its transplant)
• Infection
• Liver problems, such as occlusion of a hepatic vein
• Attack of the graft against the 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.

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 susceptibility to infections
• Generalized inflammation (septicemia)
• Decrease in white blood cell, platelet, and red blood cell counts (anemia)
• Attack of the transplanted cells against the body (graft-versus-host disease)
• Dizziness, headache, blurred vision
• Uncontrolled body tremors (convulsions)
• Feeling of 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, and intestine
• Inflammation of the colon
• Loss of appetite, weight loss
• Elevated blood glucose
• Rash, itching, peeling
• Alteration of 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 electrical activity (arrhythmia)
• Inflammation of lung tissue
• Enlargement of the liver
• Alteration of function of some organs
• Occlusion of a hepatic vein (veno-occlusive disease, VOD)
• Yellowing of the skin and eyes (jaundice)
• Impairment of hearing
• Lymphatic occlusion
• High blood pressure
• Enlargement of the liver, elevation of renal and digestive enzymes
• Abnormal values of electrolytes in the blood
• Weight gain
• Fever, general weakness, chills
• Bleeding (hemorrhage)
• Nasal bleeding
• General swelling due to fluid retention (edema)
• Pain or inflammation at the injection site
• Infection of the eye (conjunctivitis)
• Decrease in sperm count
• Vaginal bleeding
• Absence of menstrual periods (amenorrhea)
• Memory loss
• Delay in weight and height gain
• Urinary problems
• Inadequate production of testosterone
• Inadequate production of thyroid hormones
• Decreased 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)
• Elevation of creatinine
• Allergic reactions
• Occlusion of a blood vessel (embolism)
• Alteration of heart rhythm
• Heart failure
• Cardiovascular incapacity
• Oxygen deficiency
• Accumulation of fluid in the lungs (pulmonary edema)
• Pulmonary hemorrhage
• Respiratory arrest
• Blood in the urine (hematuria) and moderate renal insufficiency
• Inflammation of the urinary bladder
• Difficulty urinating and decrease in urine production (dysuria and oliguria)
• Increase in the amount of nitrogen components in the blood (elevation of BUN)
• Cataracts
• Liver insufficiency
• Cerebral hemorrhage
• Cough
• Constipation and gastrointestinal discomfort
• Intestinal obstruction
• Perforation of the stomach
• Changes in muscle tone
• General lack of coordination of muscle movements
• Hematomas associated with low platelet count
• Menopausal symptoms
• Cancer (main secondary neoplasms)
• Alteration of brain function
• Male and female infertility

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

• Inflammation and peeling of the skin (psoriasis eritrodérmica)
• Delirium, nervousness, hallucinations, agitation
• Gastrointestinal ulcer
• Inflammation of the cardiac muscle tissue (myocarditis)
• Abnormal heart disease (myocardialopathy)

Unknown frequency: the frequency cannot be estimated from the available data

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

Reporting of side effects

If you experience any type of side effect, consult your doctor or nurse, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through thenational notification system included in theAppendix V. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep out of sight and reach of children.

Do not use TEPADINA after the expiration date that appears on the packaging after "CAD". The expiration date is the last day of the month indicated.

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

Do not freeze.

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

After dilution, the medication 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.

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

Composition of TEPADINA

• The active ingredient is tiotepa. A vial contains 100 mg of tiotepa. After reconstitution, each ml contains 10 mg of tiotepa (10 mg/ml).
• TEPADINA does not contain any other component.

Appearance of the product and contents of the pack

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

Each box contains 1 vial.

Marketing authorization holder and responsible manufacturer

ADIENNE S.r.l. S.U.

Via Galileo Galilei, 19

20867 Caponago (MB) Italy

Tel: +39 02 40700445

[email protected]

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Last update of this leaflet:

Other sources of information

The detailed information on this medicinal product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu/.

This information is intended solely for healthcare professionals:

PREPARATION GUIDE

TEPADINA 100 mg powder for concentrate for solution for infusionTiotepa

Read this guide before 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 PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING

General

Proper procedures for handling and disposal of anticancer drugs will be taken into account. All transfer procedures will have to comply strictly with aseptic techniques, preferably using a vertical laminar flow safety cabinet. As with other cytotoxic compounds, extreme caution will be exercised during the handling and preparation of TEPADINA solutions to avoid accidental contact with the skin or mucous membranes. Accidental exposure to tiotepa may cause topical reactions. Therefore, the use of gloves during the preparation of the infusion solution is recommended. If the tiotepa solution accidentally comes into contact with the skin, it should be washed immediately with water and soap. If the tiotepa solution accidentally comes into contact with mucous membranes, they should be washed immediately with water.

Calculation of the TEPADINA dose

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

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

Adult dose

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 over 2 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 900 mg/m2(24.32 mg/kg), throughout the 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 over 2 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 900 mg/m2(24.32 mg/kg), throughout the 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 over 2 consecutive days before an autologous HSCT, without exceeding the maximum cumulative total dose of 370 mg/m2(10 mg/kg), throughout the 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 over 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 750 mg/m2(20.27 mg/kg), throughout the 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 over 2 to 5 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 800 mg/m2(21.62 mg/kg), throughout the 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 over 3 to 5 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 800 mg/m2(21.62 mg/kg), throughout the conditioning treatment.

CNS tumors

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 over 3 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 750 mg/m2(20.27 mg/kg), throughout the conditioning treatment.

Ovarian cancer

The recommended dose is 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered over 2 consecutive days before an autologous HSCT, without exceeding the maximum cumulative total dose of 500 mg/m2(13.51 mg/kg), throughout the 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 over 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 750 mg/m2(20.27 mg/kg), throughout the conditioning treatment.

Allogenic 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 over 1 to 3 consecutive days before an allogenic HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 555 mg/m2(15 mg/kg), throughout the conditioning treatment.

Lymphoma

The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided into two daily infusions before an allogenic HSCT, without exceeding the maximum cumulative total dose of 370 mg/m2(10 mg/kg), throughout the conditioning treatment.

Multiple Myeloma

The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion before an allogenic HSCT, without exceeding the maximum cumulative total dose of 185 mg/m2(5 mg/kg), throughout the 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 over 1 or 2 consecutive days before an allogenic HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 555 mg/m2(15 mg/kg), throughout the conditioning treatment.

Talassemia

The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided into two daily infusions, administered before an allogenic HSCT, without exceeding the maximum cumulative total dose of 370 mg/m2(10 mg/kg), throughout the conditioning treatment.

Pediatric dose

Autologous HSCT

Solid tumors

The recommended dose in solid tumors 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 over 2 to 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 1,050 mg/m2(42 mg/kg), throughout the conditioning treatment.

CNS tumors

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 over 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 1,050 mg/m2(42 mg/kg), throughout the conditioning treatment.

Allogenic 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 over 1 to 3 consecutive days before an allogenic HSCT, depending on the combination with other chemotherapy drugs, without exceeding the maximum cumulative total dose of 375 mg/m2(15 mg/kg), throughout the conditioning treatment.

Leukemia

The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided into two daily infusions, administered before an allogenic HSCT, without exceeding the maximum cumulative total dose of 250 mg/m2(10 mg/kg), throughout the conditioning treatment.

Talassemia

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, administered before an allogenic HSCT, without exceeding the maximum cumulative total dose of 250 mg/m2(10 mg/kg), throughout the conditioning treatment.

Citopenia refractoria

The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered over 3 consecutive days before an allogenic HSCT, without exceeding the maximum cumulative total dose of 375 mg/m2(15 mg/kg), throughout the conditioning treatment.

Genetic diseases

The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered over 2 consecutive days before an allogenic HSCT, without exceeding the maximum cumulative total dose of 250 mg/m2(10 mg/kg), throughout the conditioning treatment.

Falciform anemia

The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided into two daily infusions, administered before an allogenic HSCT, without exceeding the maximum cumulative total dose of 250 mg/m2(10 mg/kg), throughout the conditioning treatment.

Reconstitution

TEPADINA must be reconstituted with 10 ml of sterile water for injection.

Using a syringe provided with a needle, withdraw 10 ml of sterile water for injection in aseptic conditions.

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

Remove the syringe and needle and mix the solution manually by repeatedly inverting the vial.

Only colorless, transparent solutions without particles will be used. Reconstituted solutions may occasionally show opalescence; such solutions can still be administered.

Additional dilution in the infusion bag

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

Administration

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

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

TEPADINA must be administered in aseptic conditions using 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 washed with approximately 5 ml of injection solution with 9 mg/ml of sodium chloride (0.9%).

Disposal

TEPADINA is for single use only.

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