Consumer medicine information

Thiotepa-Reach

Thiotepa

BRAND INFORMATION

Brand name

Thiotepa-Reach

Active ingredient

Thiotepa

Schedule

SUMMARY CMI

THIOTEPA-REACH

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using THIOTEPA-REACH?

THIOTEPA-REACH contains the active ingredient thiotepa. THIOTEPA-REACH is used to prepare patients for bone marrow transplantation. It works by destroying bone marrow cells. This enables the transplantation of new bone marrow cells (haematopoietic progenitor cells), which in turn enable the body to produce healthy blood cells.

THIOTEPA-REACH can be used in adults and children and adolescents.

For more information, see Section 1. Why am I using THIOTEPA-REACH? in the full CMI.

2. What should I know before I use THIOTEPA-REACH?

Do not use if you have ever had an allergic reaction to thiotepa or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use THIOTEPA-REACH? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with THIOTEPA-REACH and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use THIOTEPA-REACH?

Your healthcare Professional will decide what dose you will receive. This depends on your condition and other factors such as your weight, kidney function and other chemotherapy medicines you are being given.

More instructions can be found in Section 4. How do I use THIOTEPA-REACH? in the full CMI.

5. What should I know while using THIOTEPA-REACH?

Things you should do	Tell your doctor if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. Undertake regular blood tests during treatment to check your blood cell counts. Treatment with THIOTEPA-REACH reduces the ability of men and women to have children. You should consider discussing ways to preserve your fertility with your doctor before you start treatment. THIOTEPA-REACH is excreted from your skin and can cause irritation. You should wash four times each day while receiving treatment and for 2 days after completion of treatment.
Things you should not do	You must not get pregnant during treatment with this medicine. Female patients should not breast-feed during treatment. Both men and women should use an effective method of contraception during treatment with THIOTEPA-REACH. Male patients should not father a child during and up to 1 year after treatment.
Drinking alcohol	Tell your doctor if you drink alcohol. Drinking alcohol may make some side effects such as dizziness worse.
Looking after your medicine	This medication is cytotoxic and appropriate precautions must be taken when handling thiotepa. For this reason, your medicine will be handled and stored by trained personnel at the hospital

For more information, see Section 5. What should I know while using THIOTEPA-REACH? in the full CMI.

6. Are there any side effects?

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of the common side effects

are: decrease in circulating blood cell counts; infection; liver disorders including blocking of a liver vein; bleeding; the transplanted stem cells attack your body cells (graft versus host disease); kidney problems; lung and airway complications; headache; seizures; sore, red mouth; mouth ulcers; nausea; diarrhoea; vomiting; fatigue; pain at injection site; skin rash; hair loss.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

THIOTEPA-REACH

Active ingredient(s): thiotepa

Consumer Medicine Information (CMI)

This leaflet provides important information about using THIOTEPA-REACH. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using THIOTEPA-REACH.

Where to find information in this leaflet:

1. Why am I using THIOTEPA-REACH?
2. What should I know before I use THIOTEPA-REACH?
3. What if I am taking other medicines?
4. How do I use THIOTEPA-REACH?
5. What should I know while using THIOTEPA-REACH?
6. Are there any side effects?
7. Product details

1. Why am I using THIOTEPA-REACH?

THIOTEPA-REACH contains the active ingredient THIOTEPA. THIOTEPA-REACH contains the active substance thiotepa, which belongs to a group of medicines called alkylating agents.

THIOTEPA-REACH is used to prepare patients for bone marrow transplantation. It works by destroying bone marrow cells. This enables the transplantation of new bone marrow cells (haematopoietic progenitor cells), which in turn enable the body to produce healthy blood cells.

THIOTEPA-REACH can be used in adults and children and adolescents.

2. What should I know before I use THIOTEPA-REACH?

Warnings

Do not use THIOTEPA-REACH if:

you are allergic to thiotepa, or any of the ingredients listed at the end of this leaflet.
if you are pregnant or think you may be pregnant,
if you are breast-feeding.

Check with your doctor if you:

have liver or kidney problems,
have heart or lung problems,
have seizures/fits (epilepsy) or have had them in the past (if treated with phenytoin or fosphenytoin).
Are hypersensitive to thiotepa or to any of other ingredients in THIOTEPA-REACH
take any medicines for any other condition
THIOTEPA-REACH may increase the risk of having another cancer in the future. You will have regular follow up with your doctor after treatment with THIOTEPA-REACH is completed.
Because THIOTEPA-REACH destroys bone marrow cells responsible for producing blood cells, regular blood tests will be taken during treatment to check your blood cell counts.
In order to prevent and manage infections, you will be given medicines to treat infection.
THIOTEPA-REACH impairs male and female fertility. Patients or their carers should discuss fertility preservation before therapy is started.
Men should not father a child while treated and during the year after cessation of treatment.
Both women and men using THIOTEPA-REACH must use effective contraceptive methods during treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect THIOTEPA-REACH.

4. How do I use THIOTEPA-REACH?

How much to take / use

Your Healthcare Professional will decide what dose you will receive. This depends on your condition and other factors such as your weight, kidney function and other chemotherapy medicines you are being given.
THIOTEPA-REACH will be given in combination with other drugs or with radiation treatment.
Several courses of therapy may be needed depending on your response to treatment.
Additional treatment may not be repeated until your blood cell numbers have returned to acceptable levels and any unwanted effects have been controlled.
Ask your Healthcare Professional if you want to know more about the dose of THIOTEPA-REACH you receive.

When to take / use THIOTEPA-REACH

THIOTEPA-REACH should be administered by a Healthcare Professional. You may receive medication to reduce nausea before you are given THIOTEPA-REACH.

How to use THIOTEPA-REACH

THIOTEPA-REACH is administered by a qualified Healthcare Professional as an intravenous infusion (drip in a vein) after dilution of the individual vial. Each infusion will last 2-4 hours.

If you use too much THIOTEPA-REACH

THIOTEPA-REACH is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any side-effects after being given THIOTEPA-REACH, you may need urgent medical attention.

You should immediately:

contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using THIOTEPA-REACH?

Things you should do

Keep all follow up appointments with your doctor.

It is important to have your follow-up injections of THIOTEPA-REACH at the appropriate times to get the best effects from your treatment. Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Tell any other doctors, dentists and pharmacists who are treating you that you are having THIOTEPA-REACH.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are having THIOTEPA-REACH.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are having THIOTEPA-REACH.

If you become pregnant while having THIOTEPA-REACH, tell your doctor.

THIOTEPA-REACH can lower the number of white blood cells and platelets in your blood. This means that you have an increased change of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate.
Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having ay dental work.
Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.
Avoid contact sports or other situations you may bruise or get injured.

Your body breaks down THIOTEPA-REACH. The breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomit and semen.

It is important to wash four times daily when receiving THIOTEPA-REACH and for 2 days after completion of treatment so that skin irritation caused by thiotepa is reduced. Only one wash should be with soap and the other washes with water only.

In general, precautions to protect other people should be taken while you are receiving chemotherapy and for one week after the treatment period by:

Flushing the toilet twice to dispose of any body fluids and waste
Wearing gloves to clean any spill of blood fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet.
Wash linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Using a strong solution of non-bleaching detergent and large amounts of water.
Place soiled disposable nappies and other pads in a plastic, seal and dispose into the garage.
For sexual intercourse, use a barrier method such as a condom.

Call your doctor straight away if you:

Notice any sign of bleeding or infection. Signs of bleeding may include bruising easily, change in the colour of your urine, black stools or bleeding nose.

Remind any doctor, dentist or pharmacist visit that you are using THIOTEPA-REACH.

Things you should not do

Do not use THIOTEPA to treat any complaint other than that directed by your doctor. It may not be safe to use THIOTEPA-REACH for another complaint.
Do not have any immunisations while you are having THIOTEPA-REACH or for some time after you have stopped treatment.
Ask your doctor when you can have immunisations.
Do not drink alcohol while taking THIOTEPA-REACH Drinking alcohol may make some side effects such as dizziness worse.
Do not take more than your doctor has prescribed.
High doses of THIOTEPA-REACH may be associated with a serious blood disorder.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how THIOTEPA-REACH affects you.

As with other cytotoxic medicines, THIOTEPA-REACH may cause dizziness, tiredness, headache and blurred vision in some people. Make sure you know how to react to it before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

Drinking alcohol

Tell your doctor if you drink alcohol.

Drinking alcohol may make some side effects such as dizziness worse.

Looking after your medicine

Keep out of the sight and reach of children.

Store and transport refrigerated (2°C-8°C). Do not freeze.

After reconstitution the product is stable for 8 hours when stored at 2°C -8°C.

After dilution the product 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 product should be used immediately.

When to discard your medicine (as relevant)

Any unused product or waste material should be disposed of in accordance with state requirements.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

The most serious side effects of THIOTEPA-REACH therapy or the transplant procedure

may include decrease in circulating blood cell counts (intended effect of the medicine to prepare you for your transplant infusion)
infection
bleeding including into the brain, gut and lungs
severe skin rash which may be life-threatening
heart disorders including inflammation and blockage of blood vessels in the heart
damage to kidneys
liver disorders including blocking of a liver vein
the graft attacks your body (graft versus host disease)
respiratory complications
male and female infertility
delirium, seizures
reduced appetite
delay in height and body weight increase in children and adolescents

Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage some of these events.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What THIOTEPA-REACH contains

Active ingredient (main ingredient)	thiotepa
Other ingredients (inactive ingredients)	Nil
Potential allergens	Nil

Do not take this medicine if you are allergic to any of these ingredients.

What THIOTEPA-REACH looks like

THIOTEPA-REACH is a freeze-dried powder. The powder is first mixed with sterile water and then may be further diluted with sterile water, saline or glucose before it is given to you. The mixed solution is clear to slightly cloudy.

THIOTEPA-REACH 15 mg AUST R 364527

THIOTEPA-REACH 100 mg AUST R 364570

Who distributes THIOTEPA-REACH

THIOTEPA-REACH are supplied in Australia by:

Reach Pharmaceuticals Pty Ltd
Ground Floor, Corporate One,
84 Hotham Street,
Preston VIC 3072

This leaflet was prepared in June 2022.

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Thiotepa-Reach

Active ingredient

Thiotepa

Schedule

1 Name of Medicine

Thiotepa.

2 Qualitative and Quantitative Composition

Thiotepa-Reach 15 mg.

Each vial contains 15 mg thiotepa powder.

Thiotepa-Reach 100 mg.

Each vial contains 100 mg thiotepa powder.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White crystalline powder for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Thiotepa-Reach is indicated, in combination with other chemotherapy medicinal products:
with or without total body irradiation (TBI), as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients;
when high dose chemotherapy with HPCT support is appropriate for the treatment of solid tumours in adult and paediatric patients. (See Section 5.1, Clinical trials).

4.2 Dose and Method of Administration

Thiotepa-Reach administration must be supervised by a physician experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation.
Consideration should be given to administering an antiemetic prior to commencing administration of Thiotepa-Reach.

Posology.

Thiotepa-Reach is administered at different doses, in combination with other chemotherapeutic medicinal products, in patients with haematological diseases or solid tumours prior to HPCT.
Thiotepa-Reach posology is reported, in adult and paediatric patients, according to the type of HPCT (autologous or allogeneic) and disease.

Adults.

Autologous HPCT. Haematological diseases. 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 from 2 up to 4 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 900 mg/m² (24.32 mg/kg), during the time of the entire conditioning treatment.

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 from 2 up to 4 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 900 mg/m² (24.32 mg/kg), during the time of the entire conditioning treatment.

Central nervous system (CNS) 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 the total maximum cumulative dose of 370 mg/m² (10 mg/kg), during the time of the entire conditioning treatment.

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 the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 750 mg/m² (20.27 mg/kg), during the time of the entire conditioning treatment.
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 in one or two daily infusions, administered from 2 up to 5 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 800 mg/m² (21.62 mg/kg), during the time of the entire conditioning treatment.

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 from 3 up to 5 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 800 mg/m² (21.62 mg/kg), during the time of the entire conditioning treatment.

CNS 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 in one or two daily infusions, administered from 3 up to 4 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 750 mg/m² (20.27 mg/kg), during the time of the entire conditioning treatment.

Ovarian cancer.

The recommended dose is 250 mg/m²/day (6.76 mg/kg/day) as a single daily infusion, administered in 2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative dose of 500 mg/m² (13.51 mg/kg), during the time of the entire conditioning treatment.

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 the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 750 mg/m² (20.27 mg/kg), during the time of the entire conditioning treatment.
Allogeneic HPCT. Haematological diseases. 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 in one or two daily infusions, administered from 1 up to 3 consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 555 mg/m² (15 mg/kg), during the time of the entire conditioning treatment.

Lymphoma.

The recommended dose in lymphoma is 370 mg/m²/day (10 mg/kg/day) divided in two daily infusions before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m² (10 mg/kg), during the time of the entire conditioning treatment.

Multiple myeloma.

The recommended dose is 185 mg/m²/day (5 mg/kg/day) as a single daily infusion before allogeneic HPCT, without exceeding the total maximum cumulative dose of 185 mg/m² (5 mg/kg), during the time of the entire conditioning treatment.

Leukaemia.

The recommended dose ranges from 185 mg/m²/day (5 mg/kg/day) to 481 mg/m²/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 2 consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 555 mg/m² (15 mg/kg), during the time of the entire conditioning treatment.

Thalassemia.

The recommended dose is 370 mg/m²/day (10 mg/kg/day) divided in two daily infusions, administered before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m² (10 mg/kg), during the time of the entire conditioning treatment.

Paediatric population.

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 from 2 up to 3 consecutive days before autologous HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 1050 mg/m² (42 mg/kg), during the time of the entire conditioning treatment.

CNS 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 the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 1050 mg/m² (42 mg/kg), during the time of the entire conditioning treatment.
Allogeneic HPCT. Haematological diseases. 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 in one or two daily infusions, administered from 1 up to 3 consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic medicinal products, without exceeding the total maximum cumulative dose of 375 mg/m² (15 mg/kg), during the time of the entire conditioning treatment.

Leukaemia.

The recommended dose is 250 mg/m²/day (10 mg/kg/day) divided in two daily infusions, administered before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m² (10 mg/kg), during the time of the entire conditioning treatment.

Thalassemia.

The recommended dose ranges from 200 mg/m²/day (8 mg/kg/day) to 250 mg/m²/day (10 mg/kg/day) divided in two daily infusions, administered before allogeneic HPCT without exceeding the total maximum cumulative dose of 250 mg/m² (10 mg/kg), during the time of the entire conditioning treatment.

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 the total maximum cumulative dose of 375 mg/m² (15 mg/kg), during the time of the entire conditioning treatment.

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 the total maximum cumulative dose of 250 mg/m² (10 mg/kg), during the time of the entire conditioning treatment.

Sickle cell anaemia.

Special populations.

Renal impairment.

Studies in renally impaired patients have not been conducted. As thiotepa and its metabolites are poorly excreted in the urine, dose modification is not recommended in patients with mild or moderate renal insufficiency. However, caution is recommended.

Hepatic impairment.

Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly metabolized through the liver, caution needs to be exercised when thiotepa is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. Dose modification is not recommended for transient alterations of hepatic parameters.

Elderly.

The administration of thiotepa has not been specifically investigated in elderly patients. However, in clinical studies, a proportion of patients over the age of 65 received the same cumulative dose as the other patients. No dose adjustment was deemed necessary.

Method of administration.

Thiotepa-Reach must be administered by a qualified healthcare professional as a 2-4 hours intravenous infusion via a central venous catheter.
Thiotepa-Reach 15 mg vial must be reconstituted with 1.5 mL of sterile water for injection. Thiotepa-Reach 100 mg vial must be reconstituted with 10 mL of sterile water for injection. The total volume of reconstituted vials to be administered should be further diluted in 500 mL of sodium chloride 9 mg/mL (0.9%) solution for injection prior to administration (1,000 mL if the dose is higher than 500 mg). In children, if the dose is lower than 250 mg, an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection may be used in order to obtain a final Thiotepa-Reach concentration between 0.5 and 1 mg/mL. For instructions on reconstitution and further dilution prior to administration, see Reconstitution section below.

Precautions to be taken before handling or administering the medicinal product.

Topical reactions associated with accidental exposure to thiotepa may occur. Therefore, the use of gloves is recommended in preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, the skin must be immediately thoroughly washed with soap and water. If thiotepa accidentally contacts mucous membranes, they must be flushed thoroughly with water (see Section 6.6 Special Precautions for Disposal).

Preparation of Thiotepa-Reach.

Procedures for proper handling and disposal of anticancer medicinal products must be considered. All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood.
As with other cytotoxic compounds, caution needs to be exercised in handling and preparation of Thiotepa-Reach solutions to avoid accidental contact with skin or mucous membranes. Topical reactions associated with accidental exposure to thiotepa may occur. In fact, the use of gloves is recommended in preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, the skin must be immediately and thoroughly washed with soap and water. If thiotepa accidentally contacts mucous membranes, they must be flushed thoroughly with water.

Reconstitution.

Thiotepa-Reach 15 mg must be reconstituted with 1.5 mL of sterile water for injection.
Thiotepa-Reach 100 mg must be reconstituted with 10 mL of sterile water for injection.
Using a syringe fitted with a needle, aseptically withdraw the required amount of sterile water (1.5 mL for 15 mg vial and 10 mL for 100 mg vial). Inject the content of the syringe into the vial through the rubber stopper.
Remove the syringe and the needle and mix manually by repeated inversions.
Only colourless solutions, without any particulate matter, must be used. Reconstituted solutions may occasionally show opalescence; such solutions can 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 sodium chloride 9 mg/mL (0.9%) solution for injection (1000 mL if the dose is higher than 500 mg) or with an appropriate volume of sodium chloride 9 mg/mL (0.9%) in order to obtain a final Thiotepa-Reach concentration between 0.5 and 1 mg/mL.

Administration.

Thiotepa-Reach infusion solution should be inspected visually for particulate matter prior to administration. Solutions containing a precipitate should be discarded.
Prior to and following each infusion, the indwelling catheter line should be flushed with approximately 5 mL sodium chloride 9 mg/mL (0.9%) solution for injection.
The infusion solution must be administered to patients using an infusion set equipped with a 0.2 micron-line filter. Filtering does not alter solution potency.

Disposal.

Product is for single use in one patient only. Discard any residue.

4.3 Contraindications

Hypersensitivity to the active substance.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines.

4.4 Special Warnings and Precautions for Use

The consequence of treatment with thiotepa at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts need to be performed during the treatment and until recovery is achieved. Platelet and red blood cell support, as well as the use of growth factors such as Granulocyte-colony stimulating factor (G-CSF), should be employed as medically indicated. Daily white blood cell counts and platelet counts are recommended during therapy with thiotepa and after transplant for at least 30 days.
Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period.
Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly metabolized through the liver, caution needs to be observed when thiotepa is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. When treating such patients it is recommended that serum transaminase, alkaline phosphatase and bilirubin are monitored regularly following transplant, for early detection of hepatotoxicity.
Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk of hepatic veno-occlusive disease (see Section 4.8 Adverse Effects (Undesirable Effects)).
Caution must be used in patients with history of cardiac diseases, and cardiac function must be monitored regularly in patients receiving thiotepa.
Caution must be used in patients with history of renal diseases and periodic monitoring of renal function should be considered during therapy with thiotepa.
Thiotepa might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic agents (busulfan, fludarabine and cyclophosphamide) (see Section 4.8 Adverse Effects (Undesirable Effects)).
Previous brain irradiation or craniospinal irradiation may contribute to severe toxic reactions (e.g. encephalopathy).
The increased risk of a secondary malignancy with thiotepa, a known carcinogen in humans, must be explained to the patient.
Concomitant use with live attenuated vaccines (except yellow fever vaccines), phenytoin and fosphenytoin is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal products are present in the same conditioning treatment. Thiotepa-Reach must be delivered after the completion of any cyclophosphamide infusion (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
During the concomitant use of thiotepa and inhibitors of CYP2B6 or CYP3A4, patients should be carefully monitored clinically (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
As most alkylating agents, thiotepa might impair male or female fertility. Male patients should not father a child while treated and during the year after cessation of treatment. An evidence based guideline should be followed when discussing fertility preservation, including with paediatric patients and their carers (see Section 4.6 Fertility, Pregnancy and Lactation).
Thiotepa-Reach is excreted through the skin and is a skin irritant. Patients should be advised to wash four times a day, with one wash using soap and the remaining three washes with water only. Showering is preferred. Four times a day washing should continue until 48 hours after the last dose.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Specific interactions with thiotepa.

Live virus and bacterial vaccines must not be administered to a patient receiving an immunosuppressive chemotherapeutic agent and at least three months must elapse between discontinuation of therapy and vaccination.
Thiotepa appears to be metabolised via CYP2B6 and CYP3A4. Co-administration with inhibitors of CYP2B6 (for example clopidogrel and ticlopidine) or CYP3A4 (for example azole antifungals, macrolides like erythromycin, clarithromycin, telithromycin, and protease inhibitors) may increase the plasma concentrations of thiotepa and potentially decrease the concentrations of the active metabolite TEPA. Co-administration of inducers of cytochrome P450 (such as rifampicin, carbamazepine, phenobarbital) may increase the metabolism of thiotepa leading to increased plasma concentrations of the active metabolite. Therefore, during the concomitant use of thiotepa and these medicinal products, patients should be carefully monitored clinically.
Thiotepa is a weak inhibitor for CYP2B6, and may thereby potentially increase plasma concentrations of substances metabolised via CYP2B6, such as ifosfamide, tamoxifen, bupropion, efavirenz and cyclophosphamide. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide to its active form 4-hydroxycyclophosphamide (4-OHCP) and coadministration of thiotepa may therefore lead to decreased concentrations of the active 4-OHCP. Therefore, a clinical monitoring should be exercised during the concomitant use of thiotepa and these medicinal products.

Contraindications of concomitant use.

Yellow fever vaccine: risk of fatal generalized vaccine-induced disease.
More generally, live virus and bacterial vaccines must not be administered to a patient receiving an immunosuppressive chemotherapeutic agent and at least three months must elapse between discontinuation of therapy and vaccination.

Concomitant use not recommended.

Live attenuated vaccines (except yellow fever): risk of systemic, possibly fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease.
An inactivated virus vaccine should be used instead, whenever possible (poliomyelitis).
Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicinal product or risk of toxicity enhancement and loss of efficacy of the cytotoxic medicinal product due to increased hepatic metabolism by phenytoin.

Concomitant use to take into consideration.

Ciclosporine, tacrolimus: excessive immunosuppression with risk of lymphoproliferation.
Alkylating chemotherapeutic agents, including thiotepa, inhibit plasma pseudocholinesterase by 35% to 70%. The action of succinyl-choline can be prolonged by 5 to 15 minutes.
Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal products are present in the same conditioning treatment. Thiotepa-Reach must be delivered after the completion of any cyclophosphamide infusion.
The concomitant use of thiotepa and other myelosuppressive or myelotoxic agents (i.e. cyclophosphamide, melphalan, busulfan, fludarabine, treosulfan) may potentiate the risk of haematologic adverse reactions due to overlapping toxicity profiles of these medicinal products.

Interaction common to all cytotoxics.

Due to the increase of thrombotic risk in case of malignancy, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulation state during malignancy, and the potential interaction between oral anticoagulants and anticancer chemotherapy require, if it is decided to treat the patient with oral anticoagulants, to increase the frequency of the INR (International Normalised Ratio) monitoring.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

As most alkylating agents, thiotepa might impair male and female fertility.
Thiotepa impaired fertility in male mice at oral or intraperitoneal (IP) doses ≥ 0.7 mg/kg (2.24 mg/m²), significantly less than the maximum recommended human dose (MRHD, 13 mg/kg, 481 mg/m² in adults) based on body surface area. Thiotepa interfered with spermatogenesis in mice and hamsters at doses less than the MRHD.
Male patients should seek for sperm cryopreservation before therapy is started and should not father a child while treated and during the year after cessation of treatment.
Women of childbearing potential have to use effective contraception during treatment and a pregnancy test should be performed before treatment is started.
(Category D)
Based on the mechanism of action and findings in animals, thiotepa can cause fetal harm when administered to a pregnant woman.
There are no data on the use of thiotepa during pregnancy.
In pre-clinical studies thiotepa, as most alkylating agents, has been shown to cause embryofoetal lethality and teratogenicity. Thiotepa was teratogenic in mice and rats and lethal to rabbit fetuses at doses less than the MRHD.
Therefore, thiotepa is contraindicated during pregnancy.
It is unknown whether thiotepa is excreted in human milk. Due to its pharmacological properties and its potential toxicity for breast-fed newborns/infants, breast-feeding is contraindicated during treatment with thiotepa.

4.7 Effects on Ability to Drive and Use Machines

Thiotepa-Reach may have major influence on the ability to drive and use machines. It is likely that certain adverse reactions of thiotepa like dizziness, headache and blurred vision could affect these functions.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety of thiotepa has been examined through a review of adverse events reported in published data from clinical trials. In these studies, a total of 6,588 adult patients and 902 paediatric patients received thiotepa for conditioning treatment prior to haematopoietic progenitor cell transplantation.
Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process. These include infection and Graft-versus host disease (GvHD) which, although not directly related, were the major causes of morbidity and mortality, especially in allogeneic HPCT.
The most frequently adverse reactions reported in the different conditioning treatments including thiotepa are: infections, cytopenia, acute GvHD and chronic GvHD, gastrointestinal disorders, haemorrhagic cystitis, mucosal inflammation.

Leukoencephalopathy.

Cases of leukoencephalopathy have been observed following treatment with thiotepa in adult and paediatric patients with multiple previous chemotherapies, including methotrexate and radiotherapy. Some cases had a fatal outcome.

Tabulated list of adverse reactions.

Adults.

The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, reported in adult patients as more than an isolated case, are listed below by system organ class and by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) very rare (< 1/10,000), not known (cannot be estimated from the available data). See Table 1.

Paediatric population.

The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, reported in paediatric patients as more than an isolated case, are listed below by system organ class and by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). See Table 2.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no experience with overdoses of thiotepa. The most important adverse reactions expected in case of overdose is myeloablation and pancytopenia.
There is no known antidote for thiotepa.
The haematological status needs to be closely monitored and vigorous supportive measures instituted as medically indicated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, Alkylating Agents, ATC code: L01AC01.

Mechanism of action.

Thiotepa is a polyfunctional cytotoxic agent related chemically and pharmacologically to the nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylene imine radicals that, as in the case of irradiation therapy, disrupt the bonds of DNA, e.g. by alkylation of guanine at the N-7, breaking the linkage between the purine base and the sugar and liberating alkylated guanine.

Clinical trials.

The efficacy of thiotepa as a component of conditioning regimens prior to allogeneic and autologous HPCT for haematological conditions and solid tumours has been reported in published studies. The following paragraphs describe results from a selected group of published papers that generally provide low level evidence of efficacy.
The results of published clinical studies supporting the efficacy of thiotepa are summarised.

Adult population.

Autologous HPCT. Haematological diseases. Engraftment: Conditioning treatments including thiotepa have proved to be myeloablative.
Disease Free Survival (DFS): An estimated 43% at five years has been reported, confirming that conditioning treatments containing thiotepa following autologous HPCT are effective therapeutic strategies for treating patients with haematological diseases.
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been reported as being 60% or lower, which was considered by the physicians as the threshold to prove efficacy. In some of the conditioning treatments evaluated, relapse rates lower than 60% have also been reported at 5 years.
Overall Survival (OS): OS ranged from 29% to 87% with a follow-up ranging from 22 up to 63 months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging from 2.5% to 29% have been reported. TRM values ranged from 0% to 21% at 1 year, confirming the safety of the conditioning treatment including thiotepa for autologous HPCT in adult patients with haematological diseases.

Lymphoma.

Thiotepa in combination with busulfan and melphalan showed engraftment at 92%, OS at 42-52%, EFS at 34-45% and 5-year relapse at 32-42%. Most patients were at high risk because of their very advanced disease or prior dose-limiting radiation therapy.
Thiotepa in combination with melphalan and carboplatin showed OS, EFS, relapse estimated at 2 years of 65%, 60% and 21%, respectively.
Thiotepa in combination with mitoxantrone and carboplatin resulted in a 5-year DFS of 43% in high risk patients.
Thiotepa in combination with cyclophosphamide and etoposide regimen showed DFS at 66% and OS at 76%.
Thiotepa in combination with etoposide in high risk patients was accompanied at 3 years by an OS of 40% and an EFS of 32%.
Thiotepa in combination with carmustine resulted in a survival rate at 5 years of 87% and it was associated with a relapse mortality rate of 8.7%.
Solid tumours. Engraftment: Conditioning treatments including thiotepa have proved to be myeloablative.
Disease Free Survival (DFS): Percentages reported with follow-up periods of more than 1 year confirm that conditioning treatments containing thiotepa following autologous HPCT are effective choices for treating patients with solid tumours.
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been reported as being lower than 60%, which was considered by the physicians as the threshold to prove efficacy. In some cases, relapse rates of 35% and of 45% have been reported at 5 years and 6 years respectively.
Overall Survival: OS ranged from 30% to 87% with a follow-up ranging from 11.7 up to 87 months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging from 0% to 2% have been reported. TRM values ranged from 0% to 7.4% confirming the safety of the conditioning treatment including thiotepa for autologous HPCT in adult patients with solid tumours.

Breast cancer.

Thiotepa in combination with cyclophosphamide lead to a Disease Free Survival (DFS) of 49% and Overall Survival (OS) of 58% at 6 year.
Thiotepa in combination with cyclophosphamide and carboplatin showed engraftment at 98%. OS was 66-81% and RFS was 59-65%. DFS with a median follow up of 51 months was 72%.
Thiotepa in combination with cyclophosphamide and carmustine showed an OS of 68-74.7% and RFS was 59.3-62%.
Thiotepa in combination with cyclophosphamide and epirubicine showed a mean number of positive nodes at 17.6, and median follow-up was 48.6 months. In high dose group OS was 87%, 78% and 73% at 2, 3 and 4 years, respectively. EFS was 71%, 60% and 52% at 2, 3 and 4 years, respectively. 4 year event-free survival was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% in the control group (p=0.00069). The corresponding overall survival was 75% vs 70% (p=0.02).
Thiotepa in combination with cyclophosphamide and mitoxantrone OS and EFS at 4 years were 70% and 52%, respectively. There was a trend in favor of high-dose chemotherapy with respect to EFS.

Ovarian cancer.

Thiotepa in combination with busulfan and melphalan showed actuarial survival, EFS and relapse probability at 18 months of 57%, 30% and 63%, respectively.
Allogeneic HPCT. Haematological diseases. Engraftment: Engraftment has been achieved (92%-100%) in all reported conditioning treatments and it was considered to occur at the expected time. Therefore it can be concluded that conditioning treatments including thiotepa are myeloablative.
GvHD (graft versus host disease): all conditioning treatments evaluated assured a low incidence of acute GvHD grade III-IV (from 4% to 24%).
Disease Free Survival (DFS): Percentages reported with follow-up periods of more than 1 year and up to 5 years confirm that conditioning treatments containing thiotepa following allogeneic HPCT are effective choices for treating patients with haematological diseases.
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been reported as being lower than 40% (which was considered by the physicians as the threshold to prove efficacy). In some cases, relapse rates lower than 40% have also been reported at 5 years and 10 years.
Overall Survival: OS ranged from 31% to 81% with a follow-up ranging from 7.3 up to 120 months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): low values have been reported, confirming the safety of the conditioning treatments including thiotepa for allogeneic HPCT in adult patients with haematological diseases.

Lymphoma.

Thiotepa in combination with fludarabine and cyclophosphamide had engraftment of 100%, estimated OS at 3 year was 62 - 81% and relapse was 12 - 41% with estimated PFS at 3 year of 64%.

Thalassemia.

Thiotepa in combination with cyclophosphamide and busulfan showed engraftment at 96%. Thalassemia-free survival and OS was 70%.

Paediatric population.

Autologous HPCT. Solid tumours. Engraftment: It has been achieved with all reported conditioning regimens including thiotepa.
Disease Free Survival (DFS): With a follow-up of 36 to 57 months, DFS ranged from 46% to 70% in the reported studies. Considering that all patients were treated for high risk solid tumours, DFS results confirm that conditioning treatments containing thiotepa following autologous HPCT are effective therapeutic strategies for treating paediatric patients with solid tumours.
Relapse: In all the reported conditioning regimens containing thiotepa, relapse rates at 12 to 57 months ranged from 33% to 57%. Considering that all patients suffer of recurrence or poor prognosis solid tumours, these rates support the efficacy of conditioning regimens based on thiotepa.
Overall Survival (OS): OS ranged from 17% to 84% with a follow-up ranging from 12.3 up to 99.6 months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging from 0% to 26.7% have been reported. TRM values ranged from 0% to 18% confirming the safety of the conditioning treatments including thiotepa for autologous HPCT in paediatric patients with solid tumours.
Allogeneic HPCT. Haematological diseases. Engraftment: It has been achieved with all evaluated conditioning regimens including thiotepa with a success rate of 96% -100%. The haematological recovery is in the expected time.
Disease Free Survival (DFS): Percentages of 40% - 75% with follow-up of more than 1 year have been reported. DFS results confirm that conditioning treatment containing thiotepa following allogeneic HPCT are effective therapeutic strategies for treating paediatric patients with haematological diseases.
Relapse: In all the reported conditioning regimens containing thiotepa, the relapse rate was in the range of 15% - 44%. These data support the efficacy of conditioning regimens based on thiotepa in all haematological diseases.
Overall Survival (OS): OS ranged from 50% to 100% with a follow-up ranging from 9.4 up to 121 months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging from 0% to 2.5% have been reported. TRM values ranged from 0% to 30% confirming the safety of the conditioning treatment including thiotepa for allogeneic HPCT in paediatric patients with haematological diseases.

Thalassemia.

Thiotepa in combination with busulfan and cyclophosphamide: In this cohort, rejection and mortality rates were 12.5% and 19%, respectively. 69% of the patients were alive with sustained engraftment of donor hematopoiesis, this leading to a projected thalassemia-free survival of 66%. Thiotepa added to BU/CY decreased rejection to 7% (2/28). The OS rate was 93% in class III pts and 69% in the cumulative population.
Thiotepa in combination with treosulfan and fludarabine: all patients engrafted. The overall cumulative incidence of graft failure was 11%. 17 patients were transfusion independent. 2 year estimated transfusion-free survival (TFS) was 85% and OS at 2 years was 95%.

5.2 Pharmacokinetic Properties

Absorption.

Thiotepa is unreliably absorbed from the gastrointestinal tract: acid instability prevents thiotepa from being administered orally.

Distribution.

Thiotepa is a highly lipophilic compound. After intravenous administration, plasma concentrations of the active substance fit a two compartment model with a rapid distribution phase. The volume of distribution of thiotepa is large and it has been reported as ranging from 40.8 L/m² to 75 L/m², indicating distribution to total body water. The apparent volume of distribution of thiotepa appears independent of the administered dose. The fraction unbound to proteins in plasma is 70-90%; insignificant binding of thiotepa to gamma globulin and minimal albumin binding (10-30%) has been reported.
After intravenous administration, CSF medicinal product exposure is nearly equivalent to that achieved in plasma; the mean ratio of AUC in CSF to plasma for thiotepa is 0.93. CSF and plasma concentrations of TEPA, the first reported active metabolite of thiotepa, exceed the concentrations of the parent compound.

Biotransformation.

Thiotepa undergoes rapid and extensive hepatic metabolism and metabolites could be detected in urine within 1 hour after infusion. The metabolites are active alkylating agents but the role they play in the antitumor activity of thiotepa remains to be elucidated. Thiotepa undergoes oxidative desulphuration via the cytochrome P450 CYP2B and CYP3A isoenzyme families to the major and active metabolite TEPA (triethylenephosphoramide). The total excreted amount of thiotepa and its identified metabolites accounts for 54-100% of the total alkylating activity, indicating the presence of other alkylating metabolites. During conversion of GSH conjugates to N-acetylcysteine conjugates, GSH, cysteinylglycine, and cysteine conjugates are formed. These metabolites are not found in urine, and, if formed, are probably excreted in bile or as intermediate metabolites rapidly converted into thiotepa-mercapturate.

Elimination.

The total clearance of thiotepa ranged from 11.4 to 23.2 L/h/m². The elimination half-life varied from 1.5 to 4.1 hours. The identified metabolites TEPA, monochlorotepa and thiotepamercapturate are all excreted in the urine. Urinary excretion of thiotepa and TEPA is nearly complete after 6 and 8 hours respectively. The mean urinary recovery of thiotepa and its metabolites is 0.5% for the unchanged medicinal product and monochlorotepa, and 11% for TEPA and thiotepa-mercapturate.

Linearity/non-linearity.

There is no clear evidence of saturation of metabolic clearance mechanisms at high doses of thiotepa.

Special populations.

Paediatric population.

The pharmacokinetics of high dose thiotepa in children between 2 and 12 years of age do not appear to vary from those reported in children receiving 75 mg/m² or adults receiving similar doses.

Renal impairment.

The effects of renal impairment on thiotepa elimination have not been assessed.

Hepatic impairment.

The effects of hepatic impairment on thiotepa metabolism and elimination have not been assessed.

5.3 Preclinical Safety Data

Genotoxicity.

Thiotepa was shown to be genotoxic. It induced gene mutation, DNA damage and chromosome aberration in multiple in vitro and in vivo assays.

Carcinogenicity.

Thiotepa was carcinogenic in mice and rats. When thiotepa was administered intermittently for a year, it caused multiple tumours (including leukeamia) in mice and rats at doses significantly less than the MRHD. Thiotepa is expected to be carcinogenic in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

None.

6.2 Incompatibilities

Thiotepa-Reach is unstable in acid medium.
This medicinal product must not be mixed with other medicinal products except those mentioned in Section 4.2.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

Unopened vial.

24 months.

After reconstitution.

Chemical and physical in-use stability after reconstitution has been demonstrated for 8 hours when stored at 2°C-8°C.

After dilution.

Chemical and physical in-use stability after dilution has been demonstrated for 24 hours when stored at 2°C-8°C and for 4 hours when stored below 25°C.
The prepared infusion solution should be used immediately. If not used immediately, to prevent microbiological hazard, the infusion should not be stored for longer than 24 hours at 2°C-8°C.

6.4 Special Precautions for Storage

Unopened vial.

Store and transport refrigerated (2°C-8°C). Do not freeze.

After reconstitution and dilution.

For storage conditions of the reconstituted and diluted medicinal product, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Type I clear glass vial with a rubber stopper (Bromo Butyl), containing 15 mg thiotepa.
Pack size of 1 vial.
Type I clear glass vial with a rubber stopper (Bromo Butyl), containing 100 mg thiotepa.
Pack size of 1 vial.

6.6 Special Precautions for Disposal

All materials used for dilution and administration should be disposed of according to local procedures applicable to the discarding of antineoplastic agents. Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.

6.7 Physicochemical Properties

Thiotepa is a polyfunctional alkylating agent for use in the chemotherapy of certain neoplastic diseases.
Thiotepa is an ethylenimine-type compound, 1,1',1"-Phosphino-thioylidynetrisaziridine.
Thiotepa has also been known as TESPA and TSPA and is not the same as TEPA. The empirical formula is C₆H₁₂N₃PS which corresponds to a molecular weight of 189.21.

Chemical structure.

CAS number.

52-24-4.
Thiotepa is stable in alkaline medium and unstable in acid medium. It has a solubility of 19 g/100 mL in water and is soluble in ethanol, ether, benzene and chloroform. The pka is low (unspecified). When reconstituted with sterile water for injection, the resulting solution has a pH of approximately 5.5-7.5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

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