Thiotepa msn: detailed information

Package leaflet: Information for the user

Thiotepa MSN, 15 mg, powder for concentrate for solution for infusion
Thiotepa MSN, 100 mg, powder for concentrate for solution for infusion
Thiotepum
Please read all of this leaflet carefully before using this medicine, as it contains
important information for you.

Keep this leaflet, as you may need to read it again.
If you have any further questions, ask your doctor.
If you experience any side effects, including any not listed in this leaflet, tell your doctor. See section 4.

Leaflet contents:

What Thiotepa MSN is and what it is used for
Important information before using Thiotepa MSN
How to use Thiotepa MSN
Possible side effects
How to store Thiotepa MSN
Contents of the pack and other information

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

Thiotepa MSN contains the active substance thiotepa, which belongs to a group of medicines called alkylating agents.
Thiotepa MSN is used to prepare patients for bone marrow transplantation.
The medicine works by destroying bone marrow cells. This allows transplantation of new bone marrow cells (haematopoietic stem cells), enabling the body to produce healthy blood cells.
Thiotepa MSN may be used in adults as well as in children and adolescents.

2. Important information before using Thiotepa MSN

When not to use Thiotepa MSN

if the patient is allergic to thiotepa,
if the patient is pregnant or suspects she may be pregnant,
if the patient is breastfeeding,
during administration of the yellow fever vaccine or vaccines containing live viruses and bacteria.

Warnings and precautions
Tell your doctor if the patient:

has impaired liver or kidney function,
has heart or lung disease,
has seizures (epilepsy) or a history of seizures (especially if treated with phenytoin or fosphenytoin).

Because Thiotepa MSN destroys bone marrow cells responsible for blood cell production, regular blood tests will be performed during treatment to monitor blood cell counts.
Antimicrobial medications will be used to prevent and treat infections.
Thiotepa MSN may cause a different type of cancer in the future. Your doctor will provide information regarding this risk.
Thiotepa MSN and other medicines
Tell your doctor about all medicines the patient is currently taking, has recently taken, or plans to take.
Pregnancy, breastfeeding and effects on fertility
Before starting Thiotepa MSN, inform your doctor if the patient is pregnant or suspects pregnancy. Thiotepa MSN must not be used during pregnancy.
Women receiving Thiotepa MSN must use effective contraception during treatment and for at least 6 months after treatment ends. Men should not father a child during treatment with Thiotepa MSN and for one year after treatment ends.
It is not known whether this medicine passes into human milk. As a precaution, women should not breastfeed during treatment with Thiotepa MSN.
Thiotepa MSN may impair fertility in men and women. Before starting treatment, men should consider sperm preservation.
Driving and operating machinery
Some adverse effects of thiotepa, such as dizziness, headache and blurred vision, may affect the ability to drive or operate machinery. If these symptoms occur, do not drive or operate machinery.

3. How to use Thiotepa MSN

The dose of the medicine will be determined by your doctor according to body surface area or body weight, and depending on the disease.
How Thiotepa MSN is administered
Thiotepa MSN is administered by a qualified healthcare professional as an intravenous infusion (intravenous drip) after dilution of the contents of a single vial. Each infusion lasts 2–4 hours.
Frequency of administration
Infusions will be given every 12 hours or every 24 hours. The duration of treatment is up to 5 days.
The frequency and duration of treatment depend on the type of disease.

4. Possible adverse reactions

Like all medicines, Thiotepa MSN may cause adverse reactions, although not everyone experiences them.

The most serious adverse reactions associated with the use of Thiotepa MSN or the transplant procedure are:

Decreased number of circulating blood cells (an intended effect of the drug to prepare for transplantation)
Infection
Liver disorders, including hepatic vein occlusion
Attack of the body by the transplant (graft-versus-host disease)
Respiratory complications

Your doctor will regularly monitor blood cell counts and liver enzyme activity to detect and treat these adverse reactions.

Adverse reactions associated with the use of Thiotepa MSN may occur with a defined frequency as follows:

Very common adverse reactions (may occur in more than 1 in 10 people)

Increased susceptibility to infections
Systemic inflammatory response (sepsis)
Decreased number of white blood cells, platelets, and red blood cells (anaemia)
Attack of the body by transplanted cells (a condition called graft-versus-host disease)
Dizziness, headache, blurred vision
Uncontrolled body shaking (seizures)
Tingling, pricking, or numbness sensation (sensory disturbances)
Partial loss of motor function
Cardiac arrest
Nausea, vomiting, diarrhoea
Inflammation of the mucous membrane of the mouth (mucositis)
Irritation of the stomach, oesophagus, intestines
Inflammation of the large intestine (colitis)
Loss of appetite, decreased appetite
Increased blood glucose concentration
Skin rash, itching, skin eruptions
Skin pigmentation disorders (do not confuse with jaundice – see below)
Redness of the skin (erythema)
Hair loss
Back and abdominal pain, pain
Muscle and joint pain
Disturbances in the electrical activity of the heart (cardiac arrhythmias)
Inflammation of lung tissue (pneumonitis)
Enlargement of the liver
Organ dysfunction
Hepatic vein occlusion (veno-occlusive disease of the liver)
Yellowing of the skin and eyes (jaundice)
Hearing disturbances
Lymphatic vessel obstruction
Hypertension
Increased activity of liver, kidney, and digestive enzymes
Electrolyte imbalances
Weight gain
Fever, general weakness, chills
Bleeding (haemorrhage)
Nosebleeds
Generalized swelling due to fluid retention
Pain or inflammation at the injection site
Eye infection (conjunctivitis)
Decreased sperm count
Vaginal bleeding
Absence of menstrual bleeding
Memory loss
Delayed weight gain and growth disturbances
Bladder dysfunction
Inadequate testosterone production
Inadequate thyroid hormone production
Hypopituitarism
Disorientation

Common adverse reactions (may occur in up to 1 in 10 people)

Anxiety, disorientation
Abnormal dilation of one of the brain arteries (intracranial aneurysm)
Elevated creatinine levels
Allergic reactions
Blockage of blood vessels (embolism)
Heart rhythm disturbances
Heart failure
Cardiovascular insufficiency
Hypoxia
Fluid accumulation in the lungs (pulmonary oedema)
Pulmonary haemorrhage
Respiratory arrest
Presence of blood in urine (haematuria) and moderate kidney failure
Bladder inflammation (cystitis)
Discomfort during urination and reduced urine output (dysuria and oliguria)
Increased nitrogen-containing substances in the blood (elevated BUN)
Cataract
Liver failure
Cerebral haemorrhage
Cough
Constipation and stomach upset
Intestinal obstruction
Gastric perforation
Muscle tone disturbances
Severe motor coordination disturbances
Bruising due to low platelet count
Menopausal symptoms
Malignant tumour (a different, new tumour process)
Brain function disorders
Infertility in men and women

Uncommon adverse reactions (may occur in up to 1 in 100 people)

Skin inflammation and peeling (psoriasiform erythroderma)
Delirium, nervousness, hallucinations, agitation
Gastric and intestinal ulceration
Inflammation of the heart muscle tissue (myocarditis)
Abnormal heart condition (cardiomyopathy)

Frequency not known (cannot be estimated from available data)

Elevated blood pressure in the pulmonary arteries (pulmonary arterial hypertension)
Severe skin damage (e.g. severe lesions, blisters, etc.), potentially affecting the entire body surface and even life-threatening
Damage to part of the brain (so-called white matter), potentially life-threatening (leukoencephalopathy)

Reporting of adverse reactions
If any adverse reactions occur, including those not listed in this leaflet, inform your doctor or nurse. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Reactions of Medicinal Products, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, phone: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Thiotepa MSN

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the cardboard box and on the vial label after EXP. The expiry date refers to the last day of the stated month.
Store and transport in a refrigerated condition (2°C-8°C).
Do not freeze.
After reconstitution, the medicine is stable for 8 hours if stored at 2°C-8°C.
After dilution, the medicine is stable for 24 hours when stored at 2°C-8°C and for 4 hours when stored at 25°C. From a microbiological point of view, the medicine should be used immediately.
Any unused residues or waste of the medicine must be disposed of in accordance with local regulations.

6. Contents of the Package and Other Information

What Thiotepa MSN Contains
Thiotepa MSN, 15 mg, powder for solution for infusion concentrate

The active substance is tiotepa. One vial contains 15 mg of tiotepa. After reconstitution, each mL contains 10 mg of tiotepa (10 mg/mL).

Thiotepa MSN, 100 mg, powder for solution for infusion concentrate

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

What Thiotepa MSN Looks Like and Contents of the Pack
Thiotepa MSN, 15 mg, powder for solution for infusion concentrate
Thiotepa MSN is a white lyophilised powder supplied in a glass vial containing 15 mg of tiotepa.
Thiotepa MSN, 100 mg, powder for solution for infusion concentrate
Thiotepa MSN is a white lyophilised powder supplied in a glass vial containing 100 mg of tiotepa.
Each carton contains 1 vial.

Marketing Authorisation Holder and Manufacturer/Importer
Marketing Authorisation Holder:
MSN Labs Europe Limited
KW20A Corradino Park
Paola, PLA 3000
Malta
tel.: (+48) 699 711 147
{logo of the marketing authorisation holder}

Manufacturer/Importer:
Pharmadox Healthcare Limited
KW20A Kordin Industrial Park
Paola, PLA 3000
Malta
MSN Labs Europe Limited
KW20A Corradino Park
Paola, PLA 3000
Malta

This medicinal product is authorised in the European Economic Area member states under the following names:
Germany: Thiotepa Vivanta Generics 15 mg Powder for a Concentrate for Solution for Infusion ENR: 7012513
Thiotepa Vivanta Generics 100 mg Powder for a Concentrate for Solution for Infusion ENR: 7012514
Czech Republic: Thiotepa MSN
Poland: Thiotepa MSN
Bulgaria: Thiotepa MSN 15 mg powder for concentrate for solution for infusion
Thiotepa MSN 100 mg powder for concentrate for solution for infusion
Croatia: Tiotepa MSN 15 mg prašak za koncentrat za otopinu za infuziju
Tiotepa MSN 100 mg prašak za koncentrat za otopinu za infuziju
Hungary: Thiotepa MSN 15 mg por oldatos infúzióhoz való koncentrátumhoz
Thiotepa MSN 100 mg por oldatos infúzióhoz való koncentrátumhoz
Lithuania: Thiotepa MSN 15 mg milteliai infuzinio tirpalo koncentratui
Thiotepa MSN 100 mg milteliai infuzinio tirpalo koncentratui
Latvia: Thiotepa MSN 15 mg pulveris infūziju šķīduma koncentrāta pagatavošanai
Thiotepa MSN 100 mg pulveris infūziju šķīduma koncentrāta pagatavošanai
Estonia: Thiotepa MSN
Romania: Thiotepa MSN 15 mg pulbere pentru concentrat pentru soluție perfuzabilă
Thiotepa MSN 100 mg pulbere pentru concentrat pentru soluție perfuzabilă
Slovakia: Thiotepa MSN 15 mg
Thiotepa MSN 100 mg
Slovenia: Tiotepa MSN 15 mg prašek za koncentrat za raztopino za infundiranje
Tiotepa MSN 100 mg prašek za koncentrat za raztopino za infundiranje

Information intended for healthcare professionals only.

PREPARATION GUIDELINES
Thiotepa MSN, 15 mg, powder for solution for infusion concentrate
Thiotepa MSN, 100 mg, powder for solution for infusion concentrate
Thiotepum
Please read the guidelines before preparing and administering Thiotepa MSN.

1. PRESENTATION
Thiotepa MSN, 15 mg, powder for solution for infusion concentrate
Thiotepa MSN is supplied as a 15 mg powder for solution for infusion concentrate.
Thiotepa MSN, 100 mg, powder for solution for infusion concentrate
Thiotepa MSN is supplied as a 100 mg powder for solution for infusion concentrate.
Thiotepa MSN must be reconstituted and diluted before administration.

2. SPECIAL PRECAUTIONS FOR DISPOSAL AND PREPARATION OF THE MEDICINAL PRODUCT FOR ADMINISTRATION
General Information
Appropriate procedures for the safe preparation and disposal of cytotoxic medicinal products must be followed. All transfer procedures must strictly adhere to aseptic techniques, preferably using a laminar airflow cabinet and fume hood.
As with other cytotoxic drugs, caution must be exercised during administration and preparation of the Thiotepa MSN solution to avoid accidental contact with skin or mucous membranes. Accidental contact with tiotepa may cause local reactions. Use of protective gloves is recommended when preparing the infusion solution.
If accidental contact with the tiotepa solution occurs on the skin, wash the skin immediately and thoroughly with water and soap. If accidental contact with the tiotepa solution occurs on mucous membranes, rinse immediately and thoroughly with large amounts of water.

Dosing of Thiotepa MSN
Thiotepa MSN is administered at various doses in combination with other chemotherapeutic medicinal products in patients prior to conventional haematopoietic progenitor cell transplantation (HPCT) for haematological disorders or solid tumours.
Dosing of Thiotepa MSN has been established in adult, adolescent, and paediatric patients depending on the type of HPCT (autologous or allogeneic) and the disease.

Dosing in Adults
AUTOLOGOUS HPCT
Haematological Disorders
The recommended dose in haematological disorders is 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 over 2 to 4 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 900 mg/m² (24.32 mg/kg) throughout the conditioning treatment period.

Lymphoma
The recommended dose is 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 over 2 to 4 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 900 mg/m² (24.32 mg/kg) throughout the conditioning treatment period.

CENTRAL NERVOUS SYSTEM LYMPHOMA (CNS)
The recommended dose is 185 mg/m²/day (5 mg/kg/day) as a single daily infusion administered over 2 consecutive days prior to autologous HPCT, without exceeding a total maximum cumulative dose of 370 mg/m² (10 mg/kg) throughout the conditioning treatment period.

MULTIPLE MYELOMA
The recommended dose is 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 over 3 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 750 mg/m² (20.27 mg/kg) throughout the conditioning treatment period.

Solid Tumours
The recommended dose for the treatment of solid tumours is 120 mg/m²/day (3.24 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day) as one or two daily infusions administered over 2 to 5 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning treatment period.

BREAST CANCER
The recommended dose is 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 over 3 to 5 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning treatment period.

CNS TUMOURS
The recommended dose is 125 mg/m²/day (3.38 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day) as one or two daily infusions administered over 3 to 4 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 750 mg/m² (20.27 mg/kg) throughout the conditioning treatment period.

OVARIAN CANCER
The recommended dose is 250 mg/m²/day (6.76 mg/kg/day) as a single daily infusion administered over 2 consecutive days prior to autologous HPCT, without exceeding a total maximum cumulative dose of 500 mg/m² (13.51 mg/kg) throughout the conditioning treatment period.

GERM CELL TUMOURS
The recommended dose is 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 over 3 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 750 mg/m² (20.27 mg/kg) throughout the conditioning treatment period.

ALLOGENEIC HPCT
Haematological Disorders
The recommended dose in haematological disorders is 185 mg/m²/day (5 mg/kg/day) to 481 mg/m²/day (13 mg/kg/day) as one or two daily infusions administered over 1 to 3 consecutive days prior to allogeneic HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 555 mg/m² (15 mg/kg) throughout the conditioning treatment period.

Lymphoma
The recommended dose in lymphoma is 370 mg/m²/day (10 mg/kg/day) as two daily infusions administered prior to allogeneic HPCT, without exceeding a total maximum cumulative dose of 370 mg/m² (10 mg/kg) throughout the conditioning treatment period.

MULTIPLE MYELOMA
The recommended dose is 185 mg/m²/day (5 mg/kg/day) as a single infusion administered prior to allogeneic HPCT, without exceeding a total maximum cumulative dose of 185 mg/m² (5 mg/kg) throughout the conditioning treatment period.

LEUKAEMIA
The recommended dose is 185 mg/m²/day (5 mg/kg/day) to 481 mg/m²/day (13 mg/kg/day) as one or two daily infusions administered over 1 to 2 consecutive days prior to allogeneic HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 555 mg/m² (15 mg/kg) throughout the conditioning treatment period.

THALASSEMIA
The recommended dose is 370 mg/m²/day (10 mg/kg/day) as two daily infusions administered prior to allogeneic HPCT, without exceeding a total maximum cumulative dose of 370 mg/m² (10 mg/kg) throughout the conditioning treatment period.

Dosing in Children and Adolescents
AUTOLOGOUS HPCT
Solid Tumours
The recommended dose for the treatment of solid tumours is 150 mg/m²/day (6 mg/kg/day) to 350 mg/m²/day (14 mg/kg/day) as a single daily infusion administered over 2 to 3 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 1050 mg/m² (42 mg/kg) throughout the conditioning treatment period.

CNS TUMOURS
The recommended dose is 250 mg/m²/day (10 mg/kg/day) to 350 mg/m²/day (14 mg/kg/day) as a single daily infusion administered over 3 consecutive days prior to autologous HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 1050 mg/m² (42 mg/kg) throughout the conditioning treatment period.

ALLOGENEIC HPCT
Haematological Disorders
The recommended dose in haematological disorders is 125 mg/m²/day (5 mg/kg/day) to 250 mg/m²/day (10 mg/kg/day) as one or two daily infusions administered over 1 to 3 consecutive days prior to allogeneic HPCT, depending on the treatment regimen combined with other chemotherapeutic medicinal products, without exceeding a total maximum cumulative dose of 375 mg/m² (15 mg/kg) throughout the conditioning treatment period.

LEUKAEMIA
The recommended dose is 250 mg/m²/day (10 mg/kg/day) as two daily infusions administered prior to allogeneic HPCT, without exceeding a total maximum cumulative dose of 250 mg/m² (10 mg/kg) throughout the conditioning treatment period.

THALASSEMIA
The recommended dose is 200 mg/m²/day (8 mg/kg/day) to 250 mg/m²/day (10 mg/kg/day) as two daily infusions administered prior to allogeneic HPCT, without exceeding a total maximum cumulative dose of 250 mg/m² (10 mg/kg) throughout the conditioning treatment period.

REFRACTORY CYTOPENIA
The recommended dose is 125 mg/m²/day (5 mg/kg/day) as a single daily infusion administered over 3 consecutive days prior to allogeneic HPCT, without exceeding a total maximum cumulative dose of 375 mg/m² (15 mg/kg) throughout the conditioning treatment period.

GENETIC DISORDERS
The recommended dose is 125 mg/m²/day (5 mg/kg/day) as a single daily infusion administered over 2 consecutive days prior to allogeneic HPCT, without exceeding a total maximum cumulative dose of 250 mg/m² (10 mg/kg) throughout the conditioning treatment period.

SICKLE CELL DISEASE
The recommended dose is 250 mg/m²/day (10 mg/kg/day) as two daily infusions administered prior to allogeneic HPCT, without exceeding a total maximum cumulative dose of 250 mg/m² (10 mg/kg) throughout the conditioning treatment period.

Reconstitution
Thiotepa MSN, 15 mg, powder for solution for infusion concentrate
Thiotepa MSN must be reconstituted with 1.5 mL of sterile water for injections.
Using a syringe with a needle, withdraw 1.5 mL of sterile water for injections under aseptic conditions.

Thiotepa MSN, 100 mg, powder for solution for infusion concentrate
Thiotepa MSN must be reconstituted with 10 mL of sterile water for injections.
Using a syringe with a needle, withdraw 10 mL of sterile water for injections under aseptic conditions.

Inject the syringe contents into the vial through the rubber stopper.
Remove the syringe and needle and mix by repeated inversion.
Reconstituted solutions may occasionally exhibit opalescence or small aggregated polymerised particles due to polymerisation of tiotepa, which is an inherent property of this medicinal product; such solutions may still be used for further dilution in an infusion bag.

Further Dilution in an Infusion Bag
The prepared solution is hypotonic and must be further diluted before administration in 500 mL of sodium chloride 9 mg/mL (0.9%) for injection (1000 mL if the dose exceeds 500 mg), or in an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution, to achieve a final concentration of Thiotepa MSN between 0.5 and 1 mg/mL.

Method of Administration
Before administration, visually inspect the Thiotepa MSN infusion solution for particulate matter. The intensity of opalescence will drastically decrease and disappear during further dilution in the infusion bag, indicating that these are not foreign particles. If any particles are observed in the diluted solution, the diluted solution must be discarded.

The infusion solution must be administered to patients using an infusion set equipped with a 0.2 μm in-line filter. Filtration does not affect the potency of the solution.

Thiotepa MSN must be administered under sterile conditions as an infusion lasting 2–4 hours at room temperature (approximately 25°C) and under normal lighting conditions.

Before each infusion and after completion of the infusion, the indwelling catheter should be flushed with approximately 5 mL of 0.9% sodium chloride solution (9 mg/mL) for injection.

Disposal
Thiotepa MSN is intended for single use only.
Any unused medicinal product or waste material must be disposed of in accordance with local regulations.