Tiotepa Hikma: detailed information

Package leaflet: Information for the user

Tiotepa Hikma 15 mg powder for concentrate for solution for infusion

tiotepa
Equivalent medicine
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 Tiotepa Hikma is and what it is used for
What you need to know before using Tiotepa Hikma
How to use Tiotepa Hikma
Possible side effects
How to store Tiotepa Hikma
Contents of the pack and other information

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

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

2. What you need to know before using Tiotepa Hikma

Do not use Tiotepa Hikma

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

Warnings and precautions
Contact 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 Tiotepa Hikma destroys bone marrow cells responsible for blood cell production, regular blood tests will be performed during treatment to monitor blood cell counts.
To prevent and treat infections, you will be given anti-infective agents.
Tiotepa Hikma may cause another type of tumour in the future. Your doctor will discuss this risk with you.
Other medicines and Tiotepa Hikma
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Pregnancy, breastfeeding and fertility
Before taking Tiotepa Hikma, inform your doctor if you are pregnant or suspect you might be pregnant. Do not use Tiotepa Hikma during pregnancy.
During treatment with Tiotepa Hikma, both men and women must use effective contraception. Men must not father a child during treatment with Tiotepa Hikma and for one year after stopping treatment.
It is not known whether this medicine is excreted in human milk. As a precautionary measure, women must not breastfeed during treatment with Tiotepa Hikma.
Tiotepa Hikma may impair male and female fertility. Male patients are advised to consider sperm preservation before starting therapy.
Driving and using machines
Adverse reactions to thiotepa such as dizziness, headache and blurred vision may affect your ability to drive or operate machinery.

3. How to use Tiotepa Hikma

Your doctor will calculate the dose based on body surface area, or body weight, and the type of disease.
How Tiotepa Hikma is administered
Tiotepa Hikma 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. 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, Tiotepa Hikma can cause side effects, although not everybody will experience them.
The most serious side effects of treatment with Tiotepa Hikma or of the transplant procedure include:

reduction in the number of circulating blood cells (an intended effect of the medicine to prepare 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.

Side effects of Tiotepa Hikma may occur at various frequencies, defined as follows:
Very common side effects (may affect more than 1 in 10 people)

increased susceptibility to infections
systemic inflammatory condition affecting the whole body (sepsis)
reduced count 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, or 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 (not to be confused with jaundice – see below)
redness of the skin (erythema)
hair loss
back pain and abdominal pain
muscle and joint pain
abnormalities in the heart's electrical activity (arrhythmia)
inflammation of lung tissue
enlarged liver
altered organ function
blockage of a hepatic vein (veno-occlusive disease, VOD)
yellowing of the skin and eyes (jaundice)
hearing impairment
lymphatic obstruction
high blood pressure
increased liver, kidney, and digestive enzymes
abnormal blood electrolytes
weight gain
fever, general weakness, chills
bleeding (haemorrhage)
nosebleeds
general swelling due to fluid retention (oedema)
pain or inflammation at the injection site
eye infection (conjunctivitis)
decreased number of spermatozoa
vaginal bleeding
absence of menstruation (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 a brain artery (intracranial aneurysm)
elevated creatinine
allergic reactions
blockage of a blood vessel (embolism)
heart rhythm disturbances
altered cardiac function
altered cardiovascular function
oxygen deficiency
fluid accumulation in the lungs (pulmonary oedema)
pulmonary haemorrhage
respiratory arrest
blood in the urine (haematuria) and moderate kidney failure
inflammation of the urinary bladder
difficulty urinating and reduced urine output (dysuria and oliguria)
increased levels of nitrogen-containing components in the blood (increased BUN)
cataract
altered liver function
cerebral haemorrhage
cough
constipation and stomach disturbances
intestinal obstruction
stomach perforation
changes in muscle tone
lack of coordination in muscle 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 the heart muscle tissue (myocarditis)
abnormal heart condition (cardiomyopathy)

Frequency not known (cannot be estimated from 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 even be life-threatening
damage to a component of the brain (so-called white matter) that may even be fatal (leukoencephalopathy)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse.
You can also report side effects directly via the national reporting system at
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Tiotepa Hikma

Keep this medicine out of the sight and reach of children.
Do not use Tiotepa Hikma after the expiry date which is stated on the label of the carton and
vial after 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.
Keep in the original packaging to protect the medicine from light.
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.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how
to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Tiotepa Hikma contains

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.

Description of the appearance of Tiotepa Hikma and contents of the pack
Tiotepa Hikma is a white crystalline powder supplied in a glass vial containing 15 mg of tiotepa. Each pack contains 1 vial.
Marketing Authorisation Holder
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó, nº8, 8A/8B, Fervença
2705-906 Terrugem SNT
Portugal
Manufacturer
Thymoorgan Pharmazie GmbH
Schiffgraben 23
38690 Goslar
Germany
This medicinal product is authorised in the European Economic Area Member States and in
the United Kingdom (Northern Ireland) under the following names:
Austria: Thiotepa Hikma 15 mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
France: Thiotepa Hikma 15 mg, poudre pour solution à diluer pour perfusion
Germany: Thiotepa Hikma 15 mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
Italy: Tiotepa Hikma
Portugal: Tiotepa Hikma
Spain: Tiotepa Hikma 15 mg polvo para concentrado para solución para perfusión EFG
United Kingdom: Thiotepa 15 mg powder for concentrate for solution for infusion
This leaflet was last reviewed on {MM/YYYY}.
The following information is intended for healthcare professionals only:
INSTRUCTIONS FOR PREPARATION
Tiotepa Hikma 15 mg powder for concentrate for solution for infusion
Tiotepa
Read this guide before preparing and administering Tiotepa Hikma.

1. PRESENTATION

Tiotepa Hikma is supplied as 15 mg powder for concentrate for solution for infusion.
Tiotepa Hikma must be reconstituted and diluted prior to administration.

2. SPECIAL PRECAUTIONS FOR DISPOSAL AND

HANDLING
General aspects
Appropriate procedures must be followed for the handling and disposal of antineoplastic medicinal products. 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 Tiotepa Hikma solutions to avoid accidental contact with the skin or mucous membranes. Local reactions may occur following accidental exposure to thiopeta. Therefore, the use of gloves is recommended during the preparation of the infusion solution. If the thiopeta solution accidentally comes into contact with the skin, the exposed area should be thoroughly and immediately washed with soap and water.
In case of accidental contact of thiopeta with mucous membranes, abundant washing with water is recommended.

Dosage calculation of Tiotepa Hikma
Tiotepa Hikma 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 Tiotepa Hikma 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 combination with other 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 900 mg/m² (24.32 mg/kg) throughout the conditioning regimen.

CENTRAL NERVOUS SYSTEM 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 combination with other 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 combination with other 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning regimen.

BRAIN 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 combination with other 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 combination with other 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 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 allogeneic HPCT, depending on combination with other 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 combination with other 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 1,050 mg/m² (42 mg/kg) throughout the conditioning regimen.

BRAIN 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 combination with other 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 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 allogeneic HPCT, depending on combination with other 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 DISEASES
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
Tiotepa Hikma must be reconstituted with 1.5 mL of water for injections.
Using a syringe equipped with a needle, withdraw 1.5 mL of water for injections under aseptic conditions.
Inject the syringe contents through the rubber stopper into the vial.
Remove the syringe and needle and mix manually by repeated inversions.
Only clear, particle-free solutions should be used. 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 with 500 mL of sodium chloride 9 mg/mL (0.9%) injection solution (1,000 mL if the dose exceeds 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/L.

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

Disposal
Tiotepa Hikma is for single use only.
Unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.

Package leaflet: Information for the user

Tiotepa Hikma 100mg powder for concentrate for solution for infusion

tiotepa
Equivalent medicine
Please read this leaflet carefully before 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, consult your doctor.
If you experience any side effects, including those not listed in this leaflet, consult your doctor. See section 4.

Contents of this leaflet:

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

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

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

2. What you need to know before using Tiotepa Hikma

Do not use Tiotepa Hikma

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

Warnings and precautions
Please consult 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 Tiotepa Hikma destroys bone marrow cells responsible for blood cell production, regular blood tests will be performed during treatment to monitor your blood cell counts.
To prevent and treat infections, you will be given anti-infective agents.
Tiotepa Hikma may cause a different type of cancer in the future. Your doctor will discuss this risk with you.
Other medicines and Tiotepa Hikma
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Pregnancy, breastfeeding and fertility
Before taking Tiotepa Hikma, inform your doctor if you are pregnant or suspect you may be pregnant. Do not use Tiotepa Hikma during pregnancy.
During treatment with Tiotepa Hikma, both men and women must use effective contraception. Men must not father a child during treatment with Tiotepa Hikma and for one year after stopping treatment.
It is not known whether this medicine is excreted in human milk. Male patients are advised to consider sperm preservation before starting therapy.
Tiotepa Hikma may impair male and female fertility. If desired, male patients should consider sperm preservation before starting therapy.
Driving and using machines
Some adverse reactions of thiotepa such as dizziness, headache and blurred vision may affect your ability to drive or operate machinery.

3. How to use Tiotepa Hikma

The doctor will calculate the dosage according to body surface area, or body weight, and the disease.
How Tiotepa Hikma is administered
Tiotepa Hikma is administered by a qualified healthcare professional through intravenous infusion (intravenous drip into a vein) after dilution of the single vial. Each infusion lasts 2–4 hours.
Frequency of administration
Infusions will be given every 12 or 24 hours. 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, Tiotepa Hikma can cause side effects, although not everyone experiences them.
The most serious side effects of therapy with Tiotepa Hikma or of the transplant procedure include:

reduction in the number of circulating blood cells (an intended effect of the medicine to prepare for transplant infusion)
infection
liver disorders, including blockage of a liver vein
the transplant 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.

Side effects of Tiotepa Hikma may occur at certain frequencies defined as follows:
Very common side effects (may affect more than 1 in 10 people)

increased susceptibility to infections
systemic inflammatory condition affecting the whole body (sepsis)
reduction in white blood cells, platelets and red blood cells (anaemia)
attack by transplanted cells against the body (graft-versus-host disease)
dizziness, headache, blurred vision
uncontrolled body tremors (seizures)
tingling, prickling or numbness sensation (paraesthesia)
partial loss of movement
cardiac arrest
nausea, vomiting, diarrhoea
inflammation of the mucous membrane of the mouth (mucositis)
irritation of stomach, oesophagus and intestine
inflammation of the colon
anorexia, decreased appetite
high blood glucose levels
rash, itching, skin peeling
change in skin colour (not to be confused with jaundice – see below)
redness of the skin (erythema)
hair loss
abdominal and back pain, general 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 – veno-occlusive disease)
yellowing of the skin and eyes (jaundice)
hearing impairment
lymphatic obstruction
high blood pressure
increased liver, kidney and digestive enzymes
abnormal blood electrolytes
weight gain
fever, general weakness, chills
bleeding (haemorrhage)
nosebleeds
general swelling due to fluid retention (oedema)
pain or inflammation at the injection site
eye infection (conjunctivitis)
decreased number of spermatozoa
vaginal bleeding
absence of menstruation (amenorrhoea)
memory loss
delayed weight gain and height growth
bladder dysfunction
reduced testosterone production
insufficient production of thyroid hormones
inadequate pituitary gland function
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)
disturbance in heart rhythm
altered cardiac function
altered cardiovascular function
oxygen deficiency
fluid accumulation in the lungs (pulmonary oedema)
pulmonary haemorrhage
respiratory arrest
blood in the urine (haematuria) and moderate kidney failure
inflammation of the urinary bladder
discomfort during urination and reduced urine output (dysuria and oliguria)
increased levels of nitrogen-containing components in the blood (increased BUN)
cataract
altered liver function
cerebral haemorrhage
cough
constipation and stomach ache
intestinal obstruction
stomach perforation
changes in 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)

inflammation and peeling of the skin (erythrodermic psoriasis)
delirium, nervousness, hallucinations, agitation
gastrointestinal ulcer
inflammation of the heart muscle 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.), which may involve the entire body surface and may even be fatal
damage to a component of the brain (so-called white matter) which may even be fatal (leukoencephalopathy).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system at the website https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Tiotepa Hikma

Keep this medicine out of the sight and reach of children.
Do not use Tiotepa Hikma after the expiry date stated on the carton and vial label after EXP. The expiry date refers to the last day of the month.
Store and transport in a refrigerator (2 °C - 8 °C). Do not freeze.
Keep in the original packaging to protect the medicine from light.
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.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Tiotepa Hikma contains

The active substance is tiotepa. One vial contains 100 mg of tiotepa. After reconstitution, each mL contains 10 mg of tiotepa (10 mg/mL).
Tiotepa Hikma does not contain any other ingredients.

Description of the appearance of Tiotepa Hikma and contents of the pack
Tiotepa Hikma is a white crystalline powder supplied in a glass vial containing 100 mg of tiotepa. Each pack contains 1 vial.
Marketing Authorisation Holder
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó, nº8, 8A/8B, Fervença
2705-906 Terrugem SNT
Portugal
Manufacturer
Thymoorgan Pharmazie GmbH
Schiffgraben 23
38690 Goslar
Germany
This medicinal product is authorised in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
Austria: Thiotepa Hikma 100 mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
France: Thiotepa Hikma 100 mg, poudre pour solution à diluer pour perfusion
Germany: Thiotepa Hikma 100 mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
Italy: Tiotepa Hikma
Portugal: Tiotepa Hikma
Spain: Tiotepa Hikma 100 mg polvo para concentrado para solución para perfusión EFG
United Kingdom: Thiotepa 100 mg powder for concentrate for solution for infusion
This Patient Information Leaflet was last reviewed on {MM/YYYY}.
The following information is intended for healthcare professionals only:
INSTRUCTIONS FOR PREPARATION
Tiotepa Hikma 100 mg powder for concentrate for solution for infusion
Tiotepa
Read this guide before preparing and administering Tiotepa Hikma.

1. PRESENTATION

Tiotepa Hikma is supplied as a powder for concentrate for solution for infusion containing 100 mg.
Tiotepa Hikma must be reconstituted and diluted prior to administration.

2. SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER

HANDLING
General aspects
Appropriate procedures must be followed for the handling and disposal of antineoplastic medicinal products. 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 during handling and preparation of Tiotepa Hikma solutions to avoid accidental contact with skin or mucous membranes. Local reactions may occur following accidental exposure to tiotepa. Therefore, the use of gloves is recommended during the preparation of the infusion solution. If tiotepa 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 tiotepa with mucous membranes, abundant rinsing with water is recommended.

Dosage calculation of Tiotepa Hikma
Tiotepa Hikma 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 Tiotepa Hikma 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 diseases 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 combination with other 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 900 mg/m² (24.32 mg/kg) throughout the conditioning regimen.

CENTRAL NERVOUS SYSTEM 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 750 mg/m² (20.27 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning regimen.

BRAIN 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 combination with other 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 750 mg/m² (20.27 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 combination with other 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 1050 mg/m² (42 mg/kg) throughout the conditioning regimen.

BRAIN 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 combination with other chemotherapeutic agents, without exceeding a maximum total cumulative dose of 1050 mg/m² (42 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 DISEASES
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
Tiotepa Hikma must be reconstituted with 10 mL of solvent for injectable preparations.
Using a syringe equipped with a needle, withdraw 10 mL of solvent for injectable preparations 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.
Only colourless solutions free from particulate matter should be used. 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 before administration with 500 mL of 9 mg/mL (0.9%) sodium chloride injectable solution (1000 mL if the dose exceeds 500 mg) or with an appropriate volume of 9 mg/mL (0.9%) sodium chloride solution to achieve a final concentration of Tiotepa Hikma between 0.5 and 1 mg/mL.

Administration
The Tiotepa Hikma infusion solution 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.
Tiotepa Hikma must be administered under aseptic conditions as a 2- to 4-hour infusion at room temperature (approximately 25°C) and under normal light conditions.
Before and after each infusion, the indwelling catheter line must be flushed with approximately 5 mL of 9 mg/mL (0.9%) sodium chloride injectable solution.

Disposal
Tiotepa Hikma is for single use only.
Unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations.