THIOTEPA RIEMSER 15 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

2. What you need to know before you use Thiotepa Riemser

Do not use Thiotepa Riemser

• if you are allergic to thiotepa,
• if you are pregnant or think you may be pregnant,
• if you are breastfeeding,
• 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 or have had them in the past (if you have been treated with phenytoin or fosphenytoin).

Since Thiotepa Riemser 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.

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

Other medicines and Thiotepa Riemser

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

Pregnancy, breastfeeding, and fertility

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

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

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

Thiotepa Riemser may affect male and female fertility. Male patients must seek advice on sperm preservation before starting treatment.

Driving and using machines

Some side effects of thiotepa, such as dizziness, headache, and blurred vision, may affect your ability to drive and use machines. If you notice these side effects, do not drive or use machines.

3. How to use Thiotepa Riemser

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

How Thiotepa Riemser is administered

Thiotepa Riemser 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 Thiotepa Riemser or the transplant procedure are:

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

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

Other side effects of Thiotepa Riemser, which may occur with certain frequencies, are listed below:

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

• increased risk of infection
• generalized inflammation (septicemia)
• decrease in white blood cell, platelet, and red blood cell count (anemia)
• graft-versus-host disease
• dizziness, headache, blurred vision
• uncontrolled body tremors (seizures)
• tingling, pins and needles, or numbness (paresthesia)
• partial loss of mobility
• cardiac arrest
• nausea, vomiting, diarrhea
• inflammation of the mouth mucosa (mucositis)
• irritation of the stomach, esophagus, intestine
• inflammation of the colon
• loss of appetite, anorexia
• elevated blood glucose
• rash, itching, peeling
• skin color change (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
• elevated liver, kidney, and digestive enzymes
• abnormal blood electrolyte values
• weight gain
• fever, general weakness, chills
• bleeding (hemorrhage)
• nosebleed
• 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 testosterone production
• insufficient thyroid hormone production
• reduced pituitary activity
• state of confusion

Common side 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)
• abnormal heart rhythm
• heart failure
• cardiovascular disability
• oxygen deficiency
• fluid accumulation in the lungs (pulmonary edema)
• pulmonary 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 nitrogen components in the blood
• 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 neoplasms)
• 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 ulcer
• inflammation of the heart muscle (myocarditis)
• abnormal heart disease (myocardial disease)

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, potentially leading to death
• 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 them directly through the national reporting system included in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Thiotepa Riemser

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 vial after "EXP". The expiry date is the last day of the month stated.

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

Do not freeze.

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.

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 Thiotepa Riemser

Thiotepa Riemser 15 mg powder for concentrate for solution for infusion EFG

• The active ingredient is thiotepa. One vial contains 15 mg of thiotepa. After reconstitution, each ml contains 10 mg of thiotepa (10 mg/ml).

Thiotepa Riemser 100 mg powder for concentrate for solution for infusion EFG

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

Appearance of the Product and Container Content

Thiotepa Riemser 15 mg powder for concentrate for solution for infusion EFG

Thiotepa Riemser is a white crystalline powder supplied in a glass vial containing 15 mg of thiotepa.

Thiotepa Riemser 100 mg powder for concentrate for solution for infusion EFG

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

Each box contains 1 vial.

Marketing Authorization Holder

Esteve Pharmaceuticals GmbH

Hohenzollerndamm 150-151

14199 Berlin

Germany

Manufacturer

HWI development GmbH

Straßburger Str. 77

77767 Appenweier

Germany

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

Date of the Last Revision of this Prospectus: {MM/AAAA}.

Other Sources of Information

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

This information is intended only for healthcare professionals:

PREPARATION GUIDE

Thiotepa Riemser 15 mg powder for concentrate for solution for infusion EFG

Thiotepa Riemser 100 mg powder for concentrate for solution for infusion EFG

thiotepa

Read this guide before preparing and administering Thiotepa Riemser.

1. Presentation

Thiotepa Riemser 15 mg powder for concentrate for solution for infusion EFG

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

Thiotepa Riemser 100 mg powder for concentrate for solution for infusion EFG

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

Thiotepa Riemser must be reconstituted and diluted before administration.

1. Special Precautions for Disposal and Other Handling

General Information

Adequate handling and disposal procedures for antineoplastic medications will be taken into account. 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 the handling and preparation of Thiotepa Riemser solutions to avoid accidental contact with the skin or mucous membranes. Topical reactions associated with accidental exposure to thiotepa may occur. Therefore, the use of gloves is recommended during the preparation of the infusion solution. If the thiotepa solution comes into accidental contact with the skin, it should be washed well with water and soap immediately. If thiotepa comes into accidental contact with the mucous membranes, they should be washed well with water.

Calculation of the Dose of Thiotepa Riemser

Thiotepa Riemser 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 Thiotepa Riemser 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) by 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) by 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) by 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) by 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) by 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.

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 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) by 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 varies between 150 mg/m2/day (4.05 mg/kg/day) and 250 mg/m2/day (6.76 mg/kg/day) by 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.

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 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) by 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 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

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) by 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.

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) by 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.

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 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) by 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) by 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

Thiotepa Riemser 15 mg powder for concentrate for solution for infusion EFG

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

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

Thiotepa Riemser 100 mg powder for concentrate for solution for infusion EFG

Thiotepa Riemser must be reconstituted with 10 ml of sterile water for injectable preparations.

With a syringe equipped with a needle, extract 10 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 (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 obtain a final concentration of Thiotepa Riemser between 0.5 and 1 mg/ml.

Administration

Thiotepa Riemser 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.

Thiotepa Riemser 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 sodium chloride 9 mg/ml (0.9%) injectable solution.

Disposal

Thiotepa Riemser 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.