TIOTEPA HIKMA 15 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Tiotepa Hikma 15 mg powder for concentrate for solution for infusion EFG

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

1. What is Tiotepa Hikma and what is it used for

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

Tiotepa Hikma is used to prepare the patient for a bone marrow transplant. It works by destroying the cells of 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. Tiotepa can be used in adults, children, and adolescents.

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

Do not use tiotepa

• 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, 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 (epilepsy) or have had them in the past (if you have been treated with phenytoin or fosphenytoin).

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

Other medicines and Tiotepa Hikma

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

Pregnancy, breast-feeding, and fertility

Tell your doctor if you are pregnant or think you may be pregnant before you start using tiotepa. You must not use tiotepa during pregnancy.

Both women and men using tiotepa must use effective contraceptive methods during treatment. Men must not father a child while receiving treatment and for the 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 tiotepa.

Tiotepa may affect male and female fertility. Male patients should seek advice on sperm conservation before starting treatment.

Driving and using machines

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

3. How to use Tiotepa Hikma

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

How Tiotepa Hikma is administered

Tiotepa 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 most serious side effects of treatment with tiotepa or the transplant procedure are:

• decrease in blood cell counts (expected effect of the medicine as preparation for the transplant infusion)
• 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.

Other side effects of tiotepa that may occur with certain frequencies are listed 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, 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
• 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 (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 loss
• lymphatic obstruction
• high blood pressure
• elevated liver, 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
• confusional state

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

• anxiety, confusion
• abnormal dilation of an artery 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 urea nitrogen (BUN) levels
• cataracts
• liver failure
• brain bleeding
• cough
• constipation and stomach discomfort
• intestinal obstruction
• stomach perforation
• muscle tone changes
• general lack of muscle coordination
• 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)

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

Frequency not known (cannot be estimated from the available data)

• increased blood pressure in the arteries (pulmonary arterial hypertension)
• severe skin damage (e.g., severe lesions, blisters, etc.) that can affect the entire body surface, potentially leading to death
• damage to a component of the brain (white matter) that can be potentially fatal (leukoencephalopathy)

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. You can also report them directly to the Spanish Medicines and Healthcare Products Agency (AEMPS) through the website: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Tiotepa Hikma

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

Do not use this medicine after the expiry date which is stated on the carton and on the label of the vial after "EXP". The expiry date is the last day of the month shown.

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

Store in the original packaging to protect from light.

After reconstitution, the medicine remains stable for 8 hours when stored between 2°C and 8°C.

After dilution, the medicine remains stable for 24 hours when stored between 2°C and 8°C and for 4 hours when stored at 25°C. From a microbiological point of view, the product should be used immediately.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

Tiotepa Hikma 15 mg powder for concentrate for solution for infusion EFG

• The active substance is tiotepa. One vial contains 15 mg of tiotepa. After reconstitution, each ml contains 10 mg of tiotepa (10 mg/ml).
• Tiotepa Hikma does not contain any other ingredients.

Appearance and packaging

Tiotepa Hikma is a white crystalline powder that is supplied in a glass vial containing 15 mg of tiotepa. Each carton contains 1 vial.

Marketing authorization holder and manufacturer

Marketing authorization holder

Hikma Farmacêutica (Portugal), SA

Estrada do Rio da Mó, Nº 8, 8A e 8B

Fervença

2705-906 Terrugem SNT

Portugal

Manufacturer

Thymoorgan Pharmazie GmbH

Schiffgraben 23

38690 Goslar

Germany

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

Hikma España, S.L.U.

Calle Anabel Segura nº11, Edificio A, planta 1ª, oficina 2

28108 - Alcobendas, Madrid

Spain

This medicine is authorized in the Member States of the European Economic Area under the following names:

Date of last revision of this leaflet: 03/2025

Other sources of information

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

This information is intended only for healthcare professionals:

PREPARATION GUIDE

Tiotepa Hikma 15 mg powder for concentrate for solution for infusion EFG

Read this guide before preparing and administering Tiotepa Hikma.

1.

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

Tiotepa Hikma must be reconstituted and diluted before administration.

2.

Generalities

Proper handling and disposal procedures for antineoplastic medications will be taken into account. All transfer procedures must strictly adhere to aseptic techniques, preferably using a vertical laminar flow safety hood. As with other cytotoxic compounds, extreme caution will be exercised during the handling and preparation of Tiotepa Hikma solutions to avoid accidental contact with the skin or mucous membranes. Topical reactions associated with accidental exposure to tiotepa may occur. Consequently, 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 immediately with water and soap. If tiotepa comes into accidental contact with the mucous membranes, they should be washed well with water.

Dosing Calculation of Tiotepa Hikma

Tiotepa Hikma 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 dosage of Tiotepa Hikma in adult and pediatric patients depends on the type of HSCT (autologous or allogeneic) and the disease.

Dosage in Adults

AUTОLOGOUS HSCT

Hematological Diseases

The recommended dose in hematological diseases ranges from 125 mg/m2/day (3.38 mg/kg/day) to 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 ranges from 125 mg/m2/day (3.38 mg/kg/day) to 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 ranges from 150 mg/m2/day (4.05 mg/kg/day) to 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 ranges from 120 mg/m2/day (3.24 mg/kg/day) to 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 ranges from 120 mg/m2/day (3.24 mg/kg/day) to 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 ranges from 125 mg/m2/day (3.38 mg/kg/day) to 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.

GERM CELL TUMORS

The recommended dose ranges from 150 mg/m2/day (4.05 mg/kg/day) to 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 ranges from 185 mg/m2/day (5 mg/kg/day) to 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 ranges from 185 mg/m2/day (5 mg/kg/day) to 481 mg/m2/day (13 mg/kg/day) divided into one or two daily infusions, administered for 1 to 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

AUTОLOGOUS HSCT

Solid Tumors

The recommended dose in solid tumors ranges from 150 mg/m2/day (6 mg/kg/day) to 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 1050 mg/m2 (42 mg/kg) during the entire conditioning treatment.

CNS TUMORS

The recommended dose ranges from 250 mg/m2/day (10 mg/kg/day) to 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 1050 mg/m2 (42 mg/kg) during the entire conditioning treatment.

ALLOGENEIC HSCT

Hematological Diseases

The recommended dose in hematological diseases ranges from 125 mg/m2/day (5 mg/kg/day) to 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 ranges from 200 mg/m2/day (8 mg/kg/day) to 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 Hikma 15 mg powder for concentrate for solution for infusion

Tiotepa Hikma must be reconstituted with 1.5 ml of sterile water for injectable preparations. With a syringe provided 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.

Additional Dilution in the Infusion Bag

The reconstituted solution is hypotonic and must be further diluted before administration with 500 ml of sodium chloride 9 mg/ml (0.9%) injectable solution (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 Tiotepa Hikma between 0.5 and 1 mg/ml.

Administration

Tiotepa Hikma 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 through an infusion set provided with a 0.2 µm in-line filter. Filtration does not alter the potency of the solution.

Tiotepa Hikma 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 sodium chloride 9 mg/ml (0.9%) injectable solution.

Elimination

Tiotepa Hikma 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.