Thiotepa Vivanta

Package leaflet: Information for the user

Thionovia 15 mg powder for concentrate for solution for infusion
Thionovia 100 mg powder for concentrate for solution for infusion
tiotepa
Equivalent medicine
Please read all of this leaflet carefully before taking 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.
• This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet:

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

1. What Thionovia is and what it is used for

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

2. What you need to know before using Thionovia

Do not use Thionovia

• 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
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 Thionovia 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.
Thionovia may cause another type of cancer in the future. Your doctor will discuss this risk with you.

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

Pregnancy, breastfeeding and fertility
Before taking Thionovia, inform your doctor if you are pregnant or suspect you might be pregnant. Do not use Thionovia during pregnancy.
During treatment with Thionovia, both men and women must use effective contraception.
Men must not father a child during treatment with thiotepa and for one year after stopping treatment.
It is not known whether this medicine is excreted in human milk. As a precautionary measure, women should not breastfeed during treatment with thiotepa.
Thionovia can 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 and avoid operating machinery.

3. How to use Thionovia

The doctor will calculate the dosage according to body surface area or body weight, and depending on the disease.
How Thionovia is administered
Thionovia is administered by a qualified healthcare professional as an intravenous infusion (a 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, this medicine can cause side effects, although not everybody will experience them.
The most serious side effects of Thionovia therapy or of the transplant procedure include:

• reduction in circulating blood cell counts (an intended effect of the medicine to prepare the patient for 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 with Thionovia 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 (sepsis)
• reduced counts of white blood cells, platelets, and red blood cells (anaemia)
• transplanted cells attack the body (graft-versus-host disease)
• dizziness, headache, blurred vision
• uncontrolled body tremors (convulsions)
• 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, desquamation
• change in skin colour (not to be confused 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 liver vein (VOD – veno-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
• 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 swelling of a cerebral artery (intracranial aneurysm)
• elevated creatinine
• allergic reactions
• blockage of a blood vessel (embolism)
• heart rhythm disorders
• 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 nitrogenous compounds in the blood (increased BUN)
• cataract
• altered liver function
• brain 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)

• skin inflammation and peeling (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 Thionovia

Keep this medicine out of the sight and reach of children.
Do not use Thionovia 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 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.
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 Thionovia contains
Thionovia 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).
Thionovia 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).
Thionovia contains no other components.

Description of the appearance of Thionovia and contents of the pack
Thionovia 15 mg powder for concentrate for solution for infusion
Thionovia is a white crystalline powder contained in a 3 ml glass vial containing 15 mg of thiotepa.
Thionovia 100 mg powder for concentrate for solution for infusion
Thionovia is a white crystalline powder contained in a 10 ml glass vial containing 100 mg of thiotepa.
Each carton contains one vial.

Marketing Authorization Holder
Atnahs Pharma Netherlands B.V.
Copenhagen Towers, Ørestads Boulevard 108, 5.tv
DK-2300 Copenhagen S., Denmark

Manufacturer
Pharmadox Healthcare Ltd.,
KW20A Corradino Industrial Estate
Paola PLA3000, Malta

The following information is intended for healthcare professionals only:
INSTRUCTIONS FOR PREPARATION
Thionovia 15 mg powder for concentrate for solution for infusion
Thionovia 100 mg powder for concentrate for solution for infusion
Thiotepa
Read these instructions before preparing and administering Thionovia.

1. PRESENTATION

Thionovia 15 mg powder for concentrate for solution for infusion
Thionovia 100 mg powder for concentrate for solution for infusion
Thionovia must be reconstituted and diluted before 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 Thionovia solutions to avoid accidental contact with the skin or mucous membranes. Local reactions may occur following accidental exposure to Thionovia. Therefore, gloves should be worn before preparing the infusion solution. If the Thionovia solution comes into accidental contact with the skin, wash the affected area thoroughly and immediately with soap and water. In case of accidental contact with mucous membranes, rinse abundantly with water.

Dosage calculation of Thionovia
Thionovia is administered at different 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 Thionovia 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to autologous HPCT, without exceeding a maximum total cumulative dose of 500 mg/m² (13.51 mg/kg) throughout the conditioning regimen.

GERMINAL 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 1050 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 prior to autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 1050 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to 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 prior to allogeneic HPCT, without exceeding a maximum total cumulative dose of 250 mg/m² (10 mg/kg) throughout the conditioning regimen.

Reconstitution
Thionovia 15 mg powder for concentrate for infusion solution
Thionovia must be reconstituted with 1.5 mL of water for injections.
Using a syringe with a pre-attached needle, aseptically aspirate 1.5 mL of water for injections.
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.

Thionovia 100 mg powder for concentrate for infusion solution
Thionovia must be reconstituted with 10 mL of water for injections.
Using a syringe with a pre-attached needle, aseptically aspirate 10 mL of water for injections.
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 9 mg/mL (0.9%) sodium chloride solution for injection (1000 mL if the dose exceeds 500 mg), or in an appropriate volume of 9 mg/mL (0.9%) sodium chloride solution for injection to achieve a final Thionovia concentration between 0.5 and 1 mg/mL.

Administration
The infusion solution of Thionovia must be visually inspected prior to administration to exclude the presence 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 Thionovia 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 solution for injection.

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