Thiotepa Medac: detailed information

Package leaflet: Information for the user

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

thiotepa
Generic medicine
Please read all of this leaflet carefully before you start using this medicine, as 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 side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

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

Thiotepa medac contains the active substance tiotepa, which belongs to a group of medicines called
alkylating agents.
Thiotepa medac 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 (hematopoietic progenitor cells), which in turn enable the body to produce healthy blood cells.
Thiotepa medac can be used in adults, children, and adolescents.

2. What you need to know before using Thiotepa medac

Do not use Thiotepa medac

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 a history of seizures (if you are being treated with phenytoin or fosphenytoin).

Since Thiotepa medac 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.
Thiotepa medac may cause a different type of cancer in the future. Your doctor will discuss this risk with you.
Other medicines and Thiotepa medac
Inform your doctor if you are taking, have recently taken, or might take any other
medicines.
Pregnancy, breastfeeding and fertility
Before taking Thiotepa medac, inform your doctor if you are pregnant or suspect you may be pregnant. Do not use Thiotepa medac during pregnancy.
During treatment with Thiotepa medac, both men and women must use effective contraception.
It is not known whether this medicine is excreted in human milk. As a precautionary measure, women should not breastfeed during treatment with Thiotepa medac.
Thiotepa medac can impair male and female fertility. Male patients are advised to consider sperm preservation before starting therapy and to avoid fathering children during treatment and for one year after discontinuation of treatment.
Driving and using machines
It is likely that certain side effects of thiotepa, such as dizziness, headache and blurred vision, may affect your ability to drive or operate machinery.

3. How to use Thiotepa medac

The doctor will calculate the dosage according to body surface area, body weight, and the disease.
How Thiotepa medac is administered
Thiotepa medac is administered by a qualified healthcare professional as an 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, this medicine can cause side effects, although not everyone experiences them.
The most serious side effects of treatment with Thiotepa medac or of the transplant procedure include:

reduction in the number of circulating blood cells (an intended effect of the medicine to prepare you for transplant infusion)
infection
liver disorders, including blockage of a liver vein
the transplanted cells 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 Thiotepa medac may occur with varying frequencies, defined as follows:

Very common side effects (may affect more than 1 in 10 patients)

increased susceptibility to infections
systemic inflammatory condition affecting the whole body (sepsis)
reduced counts of white blood cells, platelets, and red blood cells (anaemia)
transplanted cells attacking the body (graft-versus-host disease)
dizziness, headache, blurred vision
uncontrolled body tremors (seizures)
tingling, prickling, and numbness sensation (paraesthesia)
partial loss of movement
cardiac arrest
nausea, vomiting, diarrhoea
inflammation of the mucous membrane of the mouth (mucositis)
irritation of the stomach, oesophagus, and intestine
inflammation of the colon
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
abdominal and back pain, general pain
muscle and joint pain
abnormal electrical activity of the heart (arrhythmia)
inflammation of lung tissue
enlarged liver
impaired 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 growth and weight gain
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 patients)

anxiety, confusion
abnormal outward bulging of a brain artery (intracranial aneurysm)
elevated creatinine
allergic reactions
blockage of a blood vessel (embolism)
heart rhythm disorders
heart failure
cardiovascular failure
oxygen deficiency
fluid accumulation in the lungs (pulmonary oedema)
lung bleeding
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 compounds in the blood (increased BUN)
cataract
liver failure
cerebral haemorrhage
cough
constipation and stomach discomfort
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 patients)

skin inflammation and peeling (erythrodermic psoriasis)
delirium, nervousness, hallucinations, agitation
gastrointestinal ulcer
inflammation of the heart muscle 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, please inform your doctor or nurse. You may 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 Thiotepa medac

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

6. Package contents and other information

What Thiotepa medac contains

The active substance is thiotepa. One vial contains 15 mg of thiotepa. After reconstitution, each mL contains 10 mg of thiotepa (10 mg/mL).
The active substance is thiotepa. One vial contains 100 mg of thiotepa. After reconstitution, each mL contains 10 mg of thiotepa (10 mg/mL).
Thiotepa medac does not contain any other ingredients.

Description of the appearance of Thiotepa medac and contents of the pack
Thiotepa medac is a white powder or white aggregate contained in a glass vial; each vial contains 15 mg of thiotepa.
Thiotepa medac is a white powder or white aggregate contained in a glass vial; each vial contains 100 mg of thiotepa.
Each carton contains 1 vial.

Marketing Authorization Holder
medac
Gesellschaft für klinische
Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
Tel.: +49 4103 8006-0
Fax: +49 4103 8006-100

Manufacturer
ALTERNO AD d.o.o.
Brnčičeva ulica 29
1231 Ljubljana - Črnuče
Slovenia

This medicinal product is authorized in the European Economic Area countries and in the United Kingdom (Northern Ireland) under the following names:
Denmark, France, Germany, Italy, Norway, Netherlands, Sweden, Hungary: Thiotepa medac

The following information is intended exclusively for physicians or healthcare professionals:
Instructions for preparation
Thiotepa medac 15 mg powder for concentrate for solution for infusion
Thiotepa medac 100 mg powder for concentrate for solution for infusion
thiotepa
Read these instructions before preparing and administering Thiotepa medac.

1. PRESENTATION

Thiotepa medac is presented as 15 mg powder for concentrate for solution for infusion.
Thiotepa medac is presented as 100 mg powder for concentrate for solution for infusion.
Thiotepa medac 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 agents, extreme care must be taken during the handling and preparation of Thiotepa medac 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 affected area should be thoroughly and immediately washed with water and soap. In case of accidental contact of thiotepa with mucous membranes, copious washing with water is recommended.

Dosage calculation of Thiotepa medac
Thiotepa medac 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 Thiotepa medac 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 carcinoma
The recommended dose ranges from 120 mg/m²/day (3.24 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day) as a single daily infusion administered for 3 to 5 consecutive days before autologous HPCT, depending on concomitant chemotherapeutic agents, without exceeding a maximum total cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the conditioning regimen.

Central nervous system 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 carcinoma
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 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.

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 1050 mg/m² (42 mg/kg) throughout the conditioning regimen.

Central nervous system 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 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 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
Thiotepa medac must be reconstituted with 1.5 mL of water for injections.
Thiotepa medac must be reconstituted with 10 mL of water for injections.
Using a syringe with a pre-attached needle, withdraw 1.5 mL of water for injections using aseptic technique.
Using a syringe with a pre-attached needle, withdraw 10 mL of water for injections using aseptic technique.
Inject the contents of the syringe 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 before 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 concentration of Thiotepa medac between 0.5 and 1 mg/mL.

Administration
The infusion solution of Thiotepa medac 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 Thiotepa medac aseptically as a 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 9 mg/mL (0.9%) sodium chloride solution for injection.

Disposal
Thiotepa medac 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.