Tiotepa Seacross

Package leaflet: Information for the user

TIOTEPA SEACROSS 15 mg powder for concentrate for solution for infusion, 100 mg powder for concentrate for solution for infusion

thiotepa
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 get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What TIOTEPA SEACROSS is and what it is used for
2. What you need to know before using TIOTEPA SEACROSS
3. How to use TIOTEPA SEACROSS
4. Possible side effects
5. How to store TIOTEPA SEACROSS
6. Contents of the pack and other information

1. What TIOTEPA SEACROSS is and what it is used for

TIOTEPA SEACROSS contains the active substance tiotepa, which belongs to a group of medicines
called alkylating agents.
TIOTEPA SEACROSS 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 SEACROSS can be used in adults, children, and adolescents.

2. What you need to know before using TIOTEPA SEACROSS

Do not use TIOTEPA SEACROSS

• 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
Inform 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 SEACROSS destroys bone marrow cells responsible for blood cell production,
you will have regular blood tests during treatment to monitor your blood cell counts.
Antimicrobial agents will be administered to prevent and treat infections.
TIOTEPA SEACROSS may cause another type of tumour in the future. Your doctor will discuss this risk with you.

Other medicines and TIOTEPA SEACROSS
Inform your doctor if you are taking, have recently taken or might take any other medicine.

Pregnancy, breastfeeding and fertility
Before taking TIOTEPA SEACROSS, inform your doctor if you are pregnant or suspect you may be pregnant.
Do not use TIOTEPA SEACROSS during pregnancy.
During treatment with TIOTEPA SEACROSS, both men and women must use effective contraception.
Men must not father a child during treatment with TIOTEPA SEACROSS and for one year after stopping treatment.
It is not known whether this medicine is excreted in breast milk. As a precautionary measure, women must not breastfeed during treatment with TIOTEPA SEACROSS.
TIOTEPA SEACROSS may impair male and female fertility. Male patients are advised to 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. If you experience these symptoms, do not drive or operate machinery.

3. How to use TIOTEPA SEACROSS

Your doctor will calculate the dosage according to body surface area or body weight, and depending on the disease.
How TIOTEPA SEACROSS is administered
TIOTEPA SEACROSS is administered by a qualified healthcare professional through intravenous infusion (intravenous drip 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 SEACROSS may cause side effects, although not everybody gets them.
The most serious side effects of therapy with TIOTEPA SEACROSS or of the transplant procedure include:

• reduction in the number of circulating blood cells (an intended effect of the medicine to prepare for the transplant infusion)
• infection
• liver disorders, including blockage of a liver vein
• the transplanted cells attack 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 SEACROSS 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 counts of white blood cells, platelets, and red blood cells (anemia)
• transplanted cells attacking the body (graft-versus-host disease)
• dizziness, headache, blurred vision
• uncontrolled body tremors (seizures)
• tingling, prickling, and numbness sensation (paresthesia)
• partial loss of movement
• cardiac arrest
• nausea, vomiting, diarrhea
• inflammation of the mucous lining of the mouth (mucositis)
• irritation of the stomach, esophagus, and intestine
• inflammation of the colon
• anorexia, loss of appetite
• high blood glucose levels
• skin rash, itching, peeling
• change in skin color (do not confuse 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 - venous occlusive disease)
• yellowing of the skin and eyes (jaundice)
• hearing loss
• lymphatic obstruction
• high blood pressure
• increased 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
• decreased 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)
• 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 urine (haematuria) and moderate kidney failure
• inflammation of the urinary bladder
• difficulty urinating and reduced urine output (dysuria and oliguria)
• increased levels of nitrogenous compounds in the blood (increased BUN)
• cataract
• altered liver function
• cerebral haemorrhage
• cough
• constipation and stomach disturbances
• 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)

• inflammation and peeling of the skin (erythrodermic psoriasis)
• delirium, nervousness, hallucinations, agitation
• gastrointestinal ulcer
• inflammation of myocardial tissue (myocarditis)
• abnormal heart conditions (cardiomyopathy)

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

• increased blood pressure in the arteries (blood vessels) of the lungs (pulmonary arterial hypertension);
• severe skin damage (e.g., severe lesions, blisters, etc.) that 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, talk to your doctor 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 SEACROSS

Keep this medicine out of sight and reach of children.
Do not use TIOTEPA SEACROSS after the expiry date stated on the carton and vial label, 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.
After reconstitution, the product is stable for 72 hours if stored at 2°C-8°C.
After dilution, the product is stable for 36 hours if stored at 2°C-8°C and for 6 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 TIOTEPA SEACROSS 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). One vial contains 100 mg of tiotepa. After reconstitution, each mL contains 10 mg of tiotepa (10 mg/mL).
• TIOTEPA SEACROSS does not contain any other ingredients.

Description of the appearance of TIOTEPA SEACROSS and contents of the pack
TIOTEPA SEACROSS is a white or almost white crystalline powder contained in a glass vial;
each vial contains 15 mg of tiotepa.
TIOTEPA SEACROSS is a white or almost white crystalline powder contained in a glass vial;
each vial contains 100 mg of tiotepa.
Each carton contains one vial.

Marketing Authorisation Holder and Manufacturer
Seacross Pharma (Europe) Limited
POD 13, The Old Station House
15A Main Street, Blackrock
Dublin, A94 T8P8
Ireland

This medicinal product is authorised in the EEA Member States under the following names:

The following information is intended for healthcare professionals only.

INSTRUCTIONS FOR PREPARATION
TIOTEPA SEACROSS 15 mg powder for concentrate for solution for infusion
TIOTEPA SEACROSS 100 mg powder for concentrate for solution for infusion
Thiotepa
Read these instructions before preparing and administering TIOTEPA SEACROSS.

1. PRESENTATION

TIOTEPA SEACROSS is available as 15 mg powder for concentrate for solution for infusion.
TIOTEPA SEACROSS is available as 100 mg powder for concentrate for solution for infusion.
TIOTEPA SEACROSS 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 during the handling and preparation of TIOTEPA SEACROSS 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 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 with mucous membranes, copious rinsing with water is recommended.

Dosage calculation of TIOTEPA SEACROSS
TIOTEPA SEACROSS is administered at varying doses in combination with other chemotherapeutic agents prior to conventional hematopoietic progenitor cell transplantation (HPCT) in patients with hematological disorders or solid tumors.

The recommended dosage of TIOTEPA SEACROSS in adult and pediatric patients depends on the type of HPCT (autologous or allogeneic) and the underlying disease.

Dosage in adults
AUTologous HPCT
Hematological disorders
The recommended dose in hematological 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 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 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 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.

BRAIN 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 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 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) 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
Hematological disorders
The recommended dose in hematological 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 for 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.

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 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 pediatric patients
AUTologous HPCT
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) 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.

BRAIN TUMORS
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
Hematological disorders
The recommended dose in hematological 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.

LEUKEMIA
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 ANEMIA
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 SEACROSS 15 mg powder for concentrate for solution for infusion must be reconstituted with 1.5 mL of water for injections.
Using a syringe with a pre-attached needle, withdraw 1.5 mL of water for injections using aseptic technique.

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

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, particle-free solutions. 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 solution 9 mg/mL (0.9%) for injection (1,000 mL if the dose exceeds 500 mg), or in an appropriate volume of sodium chloride 9 mg/mL (0.9%) for injection to achieve a final concentration of TIOTEPA SEACROSS between 0.5 and 1 mg/mL.

Administration
The infusion solution of TIOTEPA SEACROSS must be visually inspected prior to administration to ensure the absence of particulate matter. 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 TIOTEPA SEACROSS 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 lumen with approximately 5 mL of sodium chloride 9 mg/mL (0.9%) for injection.

Disposal
TIOTEPA SEACROSS 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.