TIOTEPA VIVANTA 15 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

2. What you need to know before you use Tiotepa Vivanta

Do not use Tiotepa Vivanta

• 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 Tiotepa Vivanta 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.

For the prevention and treatment of infections, you will be given anti-infectives.

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

Other medicines and Tiotepa Vivanta

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 Tiotepa Vivanta. You must not use Tiotepa Vivanta during pregnancy.

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

Men must not father a child during treatment with Tiotepa Vivanta or for up to one year after treatment has finished.

It is not known if this medicine is excreted in breast milk. As a precaution, women must not breast-feed during treatment with this medicine.

Tiotepa Vivanta may affect male and female fertility. Male patients should seek advice on sperm conservation before starting 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. Do not drive or use machines if you are affected.

3. How to use Tiotepa Vivanta

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

How Tiotepa Vivanta is administered

Tiotepa Vivanta 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, this medicine can cause side effects, although not everybody gets them.

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

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

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

The side effects of Tiotepa Vivanta 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 (GVHD)
• dizziness, headache, blurred vision
• uncontrolled body tremors (seizures)
• tingling, numbness, or prickling 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
• loss of appetite, anorexia
• elevated blood glucose
• rash, itching, peeling
• skin color changes (not to be confused with jaundice - see below)
• redness of the skin (erythema)
• hair loss
• back and abdominal pain
• muscle and joint pain
• abnormal heart rhythm
• 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)
• nasal bleeding
• 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 blood nitrogen components (elevated BUN)
• cataracts
• liver failure
• cerebral hemorrhage
• cough
• constipation and stomach discomfort
• intestinal obstruction
• stomach perforation
• muscle tone changes
• 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 (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 can affect the entire body surface, which can be fatal
• damage to a component of the brain (the 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 pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaRAM.es By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Tiotepa Vivanta

Keep this medicine out of the sight and reach of children.

Do not use Tiotepa Vivanta after the expiry date which is stated on the carton after "EXP". The expiry date refers to the last day of the month stated.

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 should be done in accordance with local regulations.

6. Container Content and Additional Information

Composition of Tiotepa Vivanta

• The active ingredient is tiotepa. One vial contains 15 mg of tiotepa. After reconstitution with 1.5 ml of water for injectables, each ml contains 10 mg of tiotepa (10 mg/ml).

Tiotepa Vivanta does not contain any other component.

Appearance of the Product and Container Content

Tiotepa Vivanta is a white crystalline powder that is supplied in a 3 ml glass vial containing 15 mg of tiotepa.

Each box contains 1 vial.

Marketing Authorization Holder

Vivanta Generics s.r.o.

Trtinová 260/1, Cakovice

196 00 Prague 9

Czech Republic

Manufacturer

Pharmadox Healthcare Ltd.,

KW20A Corradino Industrial Estate

Paola PLA3000, Malta

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

Local Representative:

Vivanta Generics s.r.o. branch in Spain

C/Guzmán el Bueno, 133, Britannia building

28003 Madrid

Date of the Last Revision of this Prospectus:May 2025

Detailed and updated information about this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es

---------------------------------------------------------------------------------------------------

This information is intended only for healthcare professionals:

PREPARATION GUIDE

Tiotepa Vivanta 15 mg Powder for Concentrate for Solution for Infusion

Tiotepa

Read this guide before preparing and administering Tiotepa Vivanta.

1. PRESENTATION

Tiotepa Vivanta 15 mg powder for concentrate for solution for infusion

Tiotepa Vivanta must be reconstituted and diluted before administration.

1. SPECIAL PRECAUTIONS FOR ELIMINATION AND OTHER HANDLING

Generalities

Proper handling and disposal procedures for antineoplastic medications will be taken into account. All transfer procedures must strictly follow aseptic techniques, preferably using a vertical laminar flow safety cabinet.

As with other cytotoxic compounds, caution will be exercised during handling and preparation of Tiotepa Vivanta solutions to avoid accidental contact with the skin or mucous membranes.

Topical reactions associated with accidental exposure to tiotepa may occur. Therefore, the use of gloves is recommended during the preparation of the infusion solution. If the tiotepa solution comes into accidental contact with the skin, it should be washed well with water and soap immediately. If tiotepa comes into accidental contact with the mucous membranes, they should be washed well with water.

Calculation of the Tiotepa Vivanta Dose

Tiotepa Vivanta is administered in different doses and in combination with other chemotherapeutic medications to patients who are to receive a conventional hematopoietic stem cell transplant (HSCT) for hematological diseases or solid tumors. The recommended tiotepa dosage in adult and pediatric patients depends on the type of HSCT (autologous or allogeneic) and the disease.

Dosage in Adults

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) through a single daily infusion, administered for 2 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic medications, without exceeding the maximum accumulated dose of 900 mg/m2 (24.32 mg/kg) during the entire conditioning treatment.

LYMPHOMA

The recommended dose varies between 125 mg/m2/day (3.38 mg/kg/day) and 300 mg/m2/day (8.10 mg/kg/day) through a single daily infusion, administered for 2 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic medications, 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) through 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) through a single daily infusion, administered for 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic medications, 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 medications, 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) through a single daily infusion, administered for 3 to 5 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic medications, without exceeding the maximum accumulated dose of 800 mg/m2 (21.62 mg/kg) during the entire 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 for 3 to 4 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic medications, 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) through 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) through a single daily infusion, administered for 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic medications, 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 medications, 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) through 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 medications, 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, administered before an allogeneic HSCT, without exceeding the maximum accumulated dose of 370 mg/m2 (10 mg/kg) during the entire conditioning treatment.

Dosage in Pediatric Patients

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) through a single daily infusion, administered for 2 to 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic medications, without exceeding the maximum accumulated dose of 1,050 mg/m2 (42 mg/kg) during the entire 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) through a single daily infusion, administered for 3 consecutive days before an autologous HSCT, depending on the combination with other chemotherapeutic medications, 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 medications, 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, administered 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, administered 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) through 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) through 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, administered before an allogeneic HSCT, without exceeding the maximum accumulated dose of 250 mg/m2 (10 mg/kg) during the entire conditioning treatment.

Reconstitution

Tiotepa Vivanta 15 mg Powder for Concentrate for Solution for Infusion

Tiotepa Vivanta 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 repeatedly inverting the vial.

Only clear, particle-free solutions 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 injectable solution containing 9 mg/ml of sodium chloride (0.9%) for injectables (1,000 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 Tiotepa Vivanta between 0.5 and 1 mg/ml.

Administration

Tiotepa Vivanta infusion solution 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 set equipped with a 0.2 µm in-line filter. Filtration does not alter the potency of the solution.

Tiotepa Vivanta must be administered under aseptic conditions through infusion for 2-4 hours at room temperature (approximately 25 °C) and under normal lighting conditions.

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

Elimination

Tiotepa Vivanta is for single use.

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