Package leaflet: Information for the user

Thiotepa Riemser 15 mg powder for concentrate for solution for infusion, 100 mg powder for concentrate for solution for infusion

tiotepa
Please 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 questions, ask your doctor.
If you experience any side effects, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet

What Thiotepa Riemser is and what it is used for
What you need to know before using Thiotepa Riemser
How to use Thiotepa Riemser
Possible side effects
How to store Thiotepa Riemser
Contents of the pack and other information

1. What Thiotepa Riemser is and what it is used for

Thiotepa Riemser contains the active substance thiotepa, which belongs to a group of medicines
called alkylating agents.
Thiotepa Riemser is used to prepare patients for bone marrow transplantation; it works by destroying
bone marrow cells. This allows for the transplantation of new bone marrow cells (hematopoietic
progenitor cells), which in turn enable the body to produce healthy blood cells.
Thiotepa Riemser can be used in adults, children, and adolescents.

2. What you need to know before using Thiotepa Riemser

Do not use Thiotepa Riemser

if you are allergic to thiotepa,
if you are pregnant or suspect you may be pregnant,
if you are breastfeeding,
if you are receiving the yellow fever vaccine, live virus vaccines or bacterial vaccines.

Warnings and precautions
Tell your doctor if you have:

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

Since Thiotepa Riemser destroys bone marrow cells responsible for blood cell production, you will have regular blood tests during treatment to monitor your blood cell counts.
To prevent and treat infections, you will be given antimicrobial agents.
Thiotepa Riemser may cause another type of tumour in the future. Your doctor will discuss this risk with 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
Before taking Thiotepa Riemser, inform your doctor if you are pregnant or suspect you may be pregnant. Do not use Thiotepa Riemser during pregnancy.
During treatment with Thiotepa Riemser, both men and women must use effective contraception. After stopping treatment, women must continue to use effective contraception for at least 6 months and men for at least 3 months.
It is not known whether this medicine is excreted in human milk. As a precautionary measure, women must not breastfeed during treatment with Thiotepa Riemser.
Thiotepa Riemser may impair male and female fertility. Male patients should seek advice regarding sperm preservation prior to starting therapy.

Driving and using machines
It is likely that certain side effects of thiotepa such as dizziness, headache and blurred vision may affect your ability to drive or operate machinery. If you experience these side effects, do not drive or operate machinery.

3. How to use Thiotepa Riemser

The doctor will calculate the dose according to body surface area, body weight, and the disease.
How Thiotepa Riemser is administered
Thiotepa Riemser is administered by a qualified healthcare professional as an intravenous infusion (into a vein) after dilution of the single vial. Each infusion will last 2–4 hours.
Frequency of administration
Infusions will be given every 12 or 24 hours. The treatment may last up to 5 days. The frequency of administration and duration of treatment depend on the disease.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The most serious side effects of Thiotepa Riemser therapy or the transplant procedure include:

reduction in the number of circulating blood cells (an intended effect of the medicine to prepare you for transplant infusion)
infection
liver disorders, including blockage of a liver vein
the transplanted cells attacking the body (graft-versus-host disease)
respiratory complications

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

Other side effects of Thiotepa Riemser that may occur with various frequencies are listed below:
Very common side effects (may affect more than 1 in 10 people)

increased susceptibility to infections
systemic inflammatory condition (sepsis)
reduced counts of white blood cells, platelets, and red blood cells (anaemia)
transplanted cells attacking the body (graft-versus-host disease)
dizziness, headache, blurred vision
uncontrolled body tremors (seizures)
tingling, prickling, and numbness sensation (paraesthesia)
partial loss of movement
cardiac arrest
nausea, vomiting, diarrhoea
inflammation of the mucous membrane of the mouth (mucositis)
irritation of the stomach, oesophagus, and intestine
inflammation of the colon
anorexia, loss of appetite
high blood glucose levels
skin rash, itching, peeling
change in skin colour (do not confuse with jaundice – see below)
redness of the skin (erythema)
hair loss
abdominal and back pain, pain
muscle and joint pain
abnormal electrical activity of the heart (arrhythmia)
inflammation of lung tissue
enlarged liver
altered organ function
blockage of a hepatic vein (VOD – venous occlusive disease)
yellowing of the skin and eyes (jaundice)
hearing loss
lymphatic obstruction
high blood pressure
increased levels of liver, kidney, and digestive enzymes
abnormal blood electrolytes
weight gain
fever, weakness, chills
bleeding (haemorrhage)
nosebleeds
general swelling due to fluid retention (oedema)
pain or inflammation at the injection site
eye infection (conjunctivitis)
reduced sperm count
vaginal bleeding
absence of menstrual periods (amenorrhoea)
memory loss
delayed weight gain and growth in height
bladder dysfunction
reduced testosterone production
insufficient production of thyroid hormones
reduced pituitary gland activity
confusion

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

anxiety, confusion
abnormal outward bulging of one of the brain arteries (intracranial aneurysm)
elevated creatinine
allergic reactions
blockage of a blood vessel (embolism)
disturbances in heart rhythm
altered cardiac function
altered cardiovascular function
oxygen deficiency
fluid accumulation in the lungs (pulmonary oedema)
pulmonary bleeding
respiratory arrest
blood in the urine (haematuria) and moderate renal failure
inflammation of the urinary bladder
difficulty urinating and reduced urine output (dysuria and oliguria)
increased levels of nitrogenous compounds in the blood
cataract
altered liver function
cerebral haemorrhage
cough
constipation and stomach disorders
intestinal obstruction
stomach perforation
altered muscle tone
lack of coordination in muscular movements
bruising due to low platelet count
menopausal symptoms
cancer (secondary primary tumour)
abnormal 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 myocardial tissue (myocarditis)
abnormal heart conditions (cardiomyopathy)

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 and may also be life-threatening.
damage to a component of the brain (so-called white matter) that may also be life-threatening (leukoencephalopathy).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, tell your doctor or nurse.
You can also report side effects directly via the national reporting system listed in Annex V. Reporting side effects helps provide more information on the safety of this medicine.

5. How to store Thiotepa Riemser

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer carton and vial label, following Exp./EXP. The expiry date refers to the last day of that month.
Store and transport in a refrigerator (2 °C-8 °C).
Do not freeze.
After reconstitution, the product is stable for 8 hours if stored at 2 °C-8 °C.
After dilution, the product is stable for 24 hours if stored at 2 °C-8 °C and for 4 hours if stored at 25 °C. From a microbiological standpoint, the product should be used immediately.
Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.

6. Package contents and other information

What Thiotepa Riemser contains
Thiotepa Riemser 15 mg powder for concentrate for solution for infusion

The active substance 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

The active substance 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 ingredients.

Description of the appearance of Thiotepa Riemser and contents of the pack
Thiotepa Riemser 15 mg powder for concentrate for solution for infusion
Thiotepa Riemser is a white crystalline powder contained in a glass vial; each vial contains 15 mg of thiotepa.
Thiotepa Riemser 100 mg powder for concentrate for solution for infusion
Thiotepa Riemser is a white crystalline powder contained in a glass vial; each vial contains 100 mg of thiotepa.
Each carton contains one vial.

Marketing Authorization Holder
Esteve Pharmaceuticals GmbH
Hohenzollerndamm 150-151
14199 Berlin
Germany

Manufacturer
HWI pharma services GmbH
Straßburger Str. 77
77767 Appenweier
Germany

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:

België/Belgique/Belgien Lietuva
Eurocept Pharmaceuticals UAB ARMILA
Pays-Bas/Nederland/Niederlande Lietuva
Tél/Tel: +31 35 528 8377 Tel: +370 (0) 5 2777596
[email protected] [email protected]

България Luxembourg/Luxemburg
Thrive Pharma Ltd. Eurocept Pharmaceuticals
България Pays-Bas/Nederland/Niederlande
Tel: +359 2 878 05 43 Tél/Tel: +31 35 528 8377
[email protected] [email protected]

Česká republika Magyarország
LERAM pharmaceuticals s.r.o. SANATIS Europe Kft.
Česká republika Magyarország
Tel: +420 513 035 442 Tel.: +36 (0) 23 367 673
[email protected] [email protected]

Danmark Malta
Abacus Medicine A/S Esteve Pharmaceuticals GmbH
Danmark Il-Ġermanja
Tlf: +44 (0) 203 630 1244 Tel: +49 (0) 30 338427-0
[email protected] [email protected]

Deutschland Nederland
Esteve Pharmaceuticals GmbH Eurocept Pharmaceuticals
Deutschland Nederland
Tel: +49 (0) 30 338427-0 Tel: +31 35 528 8377
[email protected] [email protected]

Eesti Norge
AUXILIA Pharma OÜ Abacus Medicine A/S
Eesti Danmark
Tel: +372 605 00 05 Tlf: +44 (0) 203 630 1244
[email protected] [email protected]

Ελλάδα Österreich
Esteve Pharmaceuticals GmbH AGEA Pharma GmbH
Germany Austria
Tel: +49 (0) 30 338427-0 Tel: +43 (0) 1 336 01 41
[email protected] [email protected]

España Polska
Esteve Pharmaceuticals, S.A. COPHARMA JOSEPH RAKOTO
Spain Poland
Tel: +34 93 446 60 00 Tel.: +48 691 702 426
[email protected]

France Portugal
Esteve Pharmaceuticals S.A.S Esteve Pharmaceuticals – Laboratório
France Farmacêutico, Limitada
Tél: +33 1 42 31 07 10 Portugal
[email protected] Tel: +34 93 446 60 00

Hrvatska România
MEDIS Adria d.o.o. Esteve Pharmaceuticals GmbH
Croatia Germany
Tel: +385 1 2303 446 Tel: +49 (0) 30 338427-0
[email protected] [email protected]

Ireland Slovenija
Esteve Pharmaceuticals GmbH MEDIS d.o.o.
Germany Slovenia
Tel: +49 (0) 30 338427-0 Tel: +386 (0) 1 589 69 00
[email protected] [email protected]

Ísland Slovenská republika
Abacus Medicine A/S LERAM pharmaceuticals s.r.o.
Iceland Czech Republic
Sími: +44 (0) 203 630 1244 Tel: +420 513 035 442
[email protected] [email protected]

Italia Suomi/Finland
Esteve Pharmaceuticals S.r.l. Abacus Medicine A/S
Italy Denmark
[email protected] Tel: +44 (0) 203 630 1244
[email protected]

Κύπρος Sverige
MA Pharmaceuticals Trading Ltd. Abacus Medicine A/S
Cyprus Denmark
Tel: +357 25 587112 Tel: +44 (0) 203 630 1244
[email protected] [email protected]

Latvija United Kingdom (Northern Ireland)
Auxilia Pharma OÜ Esteve Pharmaceuticals GmbH
Estonia Germany
Tel: +372 605 00 05 Tel: +49 (0) 30 338427-0
[email protected] [email protected]

Additional sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

The following information is intended for healthcare professionals only.

INSTRUCTIONS FOR PREPARATION
Thiotepa Riemser 15 mg powder for concentrate for solution for infusion
Thiotepa Riemser 100 mg powder for concentrate for solution for infusion
thiotepa

Read these instructions before preparing and administering Thiotepa Riemser.

1. PRESENTATION

Thiotepa Riemser 15 mg powder for concentrate for solution for infusion
Thiotepa Riemser is available as 15 mg powder for concentrate for solution for infusion.
Thiotepa Riemser 100 mg powder for concentrate for solution for infusion
Thiotepa Riemser is available as 100 mg powder for concentrate for solution for infusion.
Thiotepa Riemser must be reconstituted and diluted prior to administration.

2. SPECIAL PRECAUTIONS FOR DISPOSAL AND HANDLING

General aspects
Appropriate procedures for handling and disposal of antineoplastic medicinal products must be followed. All transfer procedures require strict adherence to aseptic techniques, preferably using a vertical laminar flow safety cabinet.
As with other cytotoxic compounds, extreme care must be taken when handling and preparing Thiotepa Riemser solutions to avoid accidental contact with the skin or mucous membranes. Local reactions may occur following accidental exposure to thiotepa. Therefore, gloves should be worn before preparing the infusion solution. If the thiotepa solution comes into accidental contact with the skin, wash the affected area thoroughly and immediately with water and soap. In case of accidental contact of thiotepa with mucous membranes, copious rinsing with water is recommended.

Dosage calculation of Thiotepa Riemser
Thiotepa Riemser is administered at different doses in combination with other chemotherapeutic agents prior to conventional haematopoietic progenitor cell transplantation (HPCT) in patients with haematological disorders or solid tumours.
The recommended dosage of Thiotepa Riemser in adult and paediatric patients depends on the type of HPCT (autologous or allogeneic) and the underlying disease.

Dosage in adults
AUTologous HPCT
Haematological disorders
The recommended dose in haematological disorders ranges from 125 mg/m²/day (3.38 mg/kg/day) to 300 mg/m²/day (8.10 mg/kg/day) as a single daily infusion administered for 2 to 4 consecutive days before autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 900 mg/m² (24.32 mg/kg) throughout the conditioning regimen.

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) as a single daily infusion administered for 2 to 4 consecutive days before autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative 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) as a single daily infusion administered for 2 consecutive days before autologous HPCT, without exceeding a maximum total cumulative dose of 370 mg/m² (10 mg/kg) throughout the conditioning regimen.

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) as a single daily infusion administered for 3 consecutive days before autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 750 mg/m² (20.27 mg/kg) throughout the conditioning regimen.

Solid tumours
The recommended dose in solid tumours 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 autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning regimen.

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) as a single daily infusion administered for 3 to 5 consecutive days before autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning regimen.

CENTRAL NERVOUS SYSTEM (CNS) TUMOURS
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 autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative 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) as a single daily infusion administered for 2 consecutive days before autologous HPCT, without exceeding a maximum total cumulative dose of 500 mg/m² (13.51 mg/kg) throughout the conditioning regimen.

GERM CELL TUMOURS
The recommended dose ranges from 150 mg/m²/day (4.05 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day) as a single daily infusion administered for 3 consecutive days before autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 750 mg/m² (20.27 mg/kg) throughout the conditioning regimen.

ALLOGENEIC HPCT
Haematological disorders
The recommended dose in haematological disorders 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 allogeneic HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 555 mg/m² (15 mg/kg) throughout the conditioning regimen.

LYMPHOMA
The recommended dose in lymphoma is 370 mg/m²/day (10 mg/kg/day), divided into two daily infusions before allogeneic HPCT, without exceeding a maximum total cumulative 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) as a single daily infusion before allogeneic HPCT, without exceeding a maximum total cumulative dose of 185 mg/m² (5 mg/kg) throughout the conditioning regimen.

LEUKAEMIA
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 allogeneic HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative 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 before allogeneic HPCT, without exceeding a maximum total cumulative dose of 370 mg/m² (10 mg/kg) throughout the conditioning regimen.

Dosage in paediatric patients
AUTologous HPCT
Solid tumours
The recommended dose in solid tumours ranges from 150 mg/m²/day (6 mg/kg/day) to 350 mg/m²/day (14 mg/kg/day) as a single daily infusion administered for 2 to 3 consecutive days before autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 1,050 mg/m² (42 mg/kg) throughout the conditioning regimen.

CNS TUMOURS
The recommended dose ranges from 250 mg/m²/day (10 mg/kg/day) to 350 mg/m²/day (14 mg/kg/day) as a single daily infusion administered for 3 consecutive days before autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 1,050 mg/m² (42 mg/kg) throughout the conditioning regimen.

ALLOGENEIC HPCT
Haematological disorders
The recommended dose in haematological disorders 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 allogeneic HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 375 mg/m² (15 mg/kg) throughout the conditioning regimen.

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

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 allogeneic HPCT, without exceeding a maximum total cumulative 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) as a single daily infusion administered for 3 consecutive days before allogeneic HPCT, without exceeding a maximum total cumulative 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) as a single daily infusion administered for 2 consecutive days before allogeneic HPCT, without exceeding a maximum total cumulative dose of 250 mg/m² (10 mg/kg) throughout the conditioning regimen.

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

Reconstitution
Thiotepa Riemser 15 mg powder for concentrate for solution for infusion
Thiotepa Riemser must be reconstituted with 1.5 mL of sterile water for injections. Using a syringe with a pre-attached needle, withdraw 1.5 mL of sterile water for injections using aseptic techniques.

Thiotepa Riemser 100 mg powder for concentrate for solution for infusion
Thiotepa Riemser must be reconstituted with 10 mL of sterile water for injections. Using a syringe with a pre-attached needle, withdraw 10 mL of sterile water for injections using aseptic techniques.

Inject the syringe contents into the vial through the rubber stopper.
Remove the syringe and needle and mix manually by repeated inversions.
Use only clear solutions free from particulate matter. Reconstituted solutions may occasionally appear opalescent; such solutions may still be administered.

Further dilution in the infusion bag
The reconstituted solution is hypotonic and must be further diluted prior to administration in 500 mL of sodium chloride 9 mg/mL (0.9%) solution for injection (1,000 mL if the dose exceeds 500 mg), or in an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection to achieve a final concentration of Thiotepa Riemser between 0.5 and 1 mg/mL.

Administration
The infusion solution of Thiotepa Riemser must be visually inspected to exclude the presence of particulate matter before administration. Discard solutions containing precipitate.
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.
Administer Thiotepa Riemser aseptically as a 2- to 4-hour infusion at room temperature (approximately 25 °C) under normal light conditions.
Before and after each infusion, thoroughly flush the indwelling catheter line with approximately 5 mL of 9 mg/mL (0.9%) sodium chloride injection solution.

Disposal
Thiotepa Riemser is for single use only.
Any unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations.