Trecondi

European Union - English - EMA (European Medicines Agency)

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Active ingredient:
Treosulfan
Available from:
medac Gesellschaft für klinische Spezialpräparate mbH
ATC code:
L01AB02
INN (International Name):
treosulfan
Therapeutic group:
Antineoplastic agents,
Therapeutic area:
Hematopoietic Stem Cell Transplantation
Therapeutic indications:
Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients with malignant and non malignant diseases, and in paediatric patients older than one month with malignant diseases.
Product summary:
Revision: 2
Authorization status:
Authorised
Authorization number:
EMEA/H/C/004751
Authorization date:
2019-06-20
EMEA code:
EMEA/H/C/004751

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B. PACKAGE LEAFLET

Package leaflet: Information for the user

Trecondi 1 g powder for solution for infusion

Trecondi 5 g powder for solution for infusion

treosulfan

Read all of this leaflet carefully before you start using this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Trecondi is and what it is used for

What you need to know before you are given Trecondi

How to use Trecondi

Possible side effects

How to store Trecondi

Contents of the pack and other information

1.

What Trecondi is and what it is used for

Trecondi contains the active substance treosulfan, which belongs to a group of medicines called

alkylating agents. Treosulfan is used to prepare patients for bone marrow transplant (haematopoietic

stem cell transplantation). Treosulfan destroys the bone marrow cells and enables the transplant of new

bone marrow cells which leads to the production of healthy blood cells.

Trecondi is used as a

treatment before blood stem cell transplantation

in adults with cancer and

non-cancerous disorders, and in adolescents and children older than one month with cancer.

2.

What you need to know before you are given Trecondi

Do not use Trecondi

if you are allergic to treosulfan,

if you suffer from an active uncontrolled infection,

if you suffer from severe heart, lung, liver or kidney diseases,

if you suffer from hereditary DNA repair disorder, a condition that reduces the ability to repair

DNA (which carries your genetic information),

if you are pregnant, or think you may be pregnant.

Warnings and precautions

Trecondi is a cell-killing (cytotoxic) medicine that is used to decrease the number of blood cells. At

the recommended dose, this is the desired effect. You will have regular blood tests during treatment to

check your blood cell counts do not fall too low.

In order to prevent and treat infections, you will be given medicines, such as antibiotics, antifungals or

antivirals.

Trecondi may increase the risk of having another cancer in the future.

Since inflammation of the oral mucosa is a common side effect of this medicine, you should pay

attention to adequate oral hygiene. Prophylactic use of mouthwashes (e.g. with barrier protectants,

antimicrobials) or application of ice within the oral cavity (lessens blood flow to the oral mucosa and

reduces the amount of treosulfan reaching the cell) is recommended.

You must not receive live vaccines during treatment with treosulfan.

Trecondi may cause symptoms of the menopause (absence of menstrual periods).

Children and adolescents

Fits (seizures) may occur very rarely in infants of less than 4 months of age. Children younger than

1 year may have more severe side effects that affect breathing than older ones. Your child will be

monitored for signs of side effects affecting nerves and breathing problems.

Nappy rash with ulceration of the area around the anus (perianal) may occur in infants, toddlers and

children wearing nappies because treosulfan passed out in the urine can damage the skin. Therefore,

nappies should be changed frequently during 6–8 hours after each dose of this medicine.

There is not sufficient information on the use of treosulfan in children aged less than 1 month.

Other medicines and Trecondi

Tell your doctor if you are taking, have recently taken or might take any other medicines, including

medicines obtained without a prescription.

Pregnancy, breast-feeding and fertility

You must not get pregnant during treatment with this medicine and up to 6 months after treatment.

Use an effective method of contraception when either you or your partner is receiving this medicine.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor for advice before you receive this medicine.

You should stop breast-feeding before starting treatment with this medicine.

If you are a man treated with this medicine, you should not father a child during and up to 6 months

after treatment.

This medicine may make you infertile and it may not be possible for you to get pregnant after

treatment with it. If you are concerned about having children, you should discuss this with your doctor

before treatment. Men should seek advice about the possibility of sperm preservation before starting

therapy.

Driving and using machines

This medicine can cause nausea, vomiting and dizziness which may reduce your ability to drive or use

machines. If you are affected, do not drive or use machines.

3.

How to use Trecondi

Use in adults

This medicine is used in combination with fludarabine.

The recommended dose is 10–14 g/m² body surface area (calculated using your height and weight).

Use in children and adolescents

This medicine is used in combination with fludarabine and in most cases also with thiotepa. The

recommended dose is 10–14 g/m² body surface area.

How Trecondi is given

This medicine will be given to you by your doctor. It is given by drip (infusion) into a vein over

2 hours for 3 days before blood stem cell infusion.

If you were given more Trecondi than you should

Because this medicine is given by a doctor, you will be given the correct dose. However, if you think

you have received more of this medicine than you should, tell your doctor or nurse as soon as possible.

4.

Possible side effects

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

Serious side effects

The most serious side effects of treosulfan therapy or the transplant procedure include:

decrease in blood cell counts which is the intended effect of the medicine to prepare you for

your transplant infusion (all patients: very common)

infections caused by bacteria, viruses and fungi (all patients: very common)

blocking of a vein into the liver (adults: uncommon; children and adolescents: not known)

inflammation of the lung (pneumonitis) (adults: uncommon)

Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage these

events.

Adults

A list of all other side effects is set out below according to how common they are.

Very common

(may affect more than 1 in 10 people)

decreased counts of white blood cells with fever (febrile neutropenia)

inflammation of the lining of various parts of the body, especially in the mouth (which can

cause ulcers), diarrhoea, nausea, vomiting, belly (abdominal) pain

tiredness

increased blood level of bilirubin (a liver pigment, often a sign of liver problems)

Common

(may affect up to 1 in 10 people)

bloodstream infection (sepsis)

allergic reactions

decreased appetite

problems sleeping (insomnia)

headache, dizziness

changes and abnormalities in heart rhythm (heartbeat is irregular, too fast or too slow)

high blood pressure, flushing

difficulty breathing, nosebleeds

mouth pain, inflammation of the stomach, upset stomach, constipation, difficulty in swallowing

a type of rash with flat or raised red bumps on the skin (maculopapular rash), red spots on the

skin (purpura), redness of skin (erythema), hand and foot syndrome (palms of the hands or soles

of the feet tingle, become numb, painfully swollen, or red), itching, hair loss

pain in arms or legs, back pain, bone pain, joint pain, muscle pain

sudden decrease of kidney function, blood in the urine

retention of fluid in the body causing swelling (oedema), fever, chills

increased liver enzymes, increased C-reactive protein (a marker of inflammation in the body),

weight gain, weight loss

Uncommon

(may affect up to 1 in 100 people)

high blood sugar level

confusion

problems in the nerves of the arms or legs with symptoms such as numbness, reduced or

increased sensitivity, tingling, burning pain (peripheral sensory neuropathy)

bruising, low blood pressure

fluid around the lung (pleural effusion), inflammation of throat, inflammation of or pain in voice

box, cough, hiccups

bleeding in the mouth, feeling bloated, gullet or stomach pain, dry mouth

liver damage

a type of rash with red spots and sometimes with purple or blistered areas in the centre

(erythema multiforme), acne, rash, excessive sweating

chest pain, pain

Not known

(frequency cannot be estimated from the available data)

life-threatening condition after bloodstream infection (septic shock)

different cancer caused by chemotherapeutic treatment (second malignancy)

increased acidity in the blood, abnormal control of blood sugar level, abnormal blood level of

electrolytes (salts in the blood)

restlessness

abnormal brain function (encephalopathy), bleeding in the brain, restless, repetitive, or

involuntary movements and rapid speech (extrapyramidal disorder), fainting, sensation of

tingling, pricking or numbness (paraesthesia)

dry eye

heart not pumping enough blood for the body’s needs (heart failure), heart attack, fluid in the

sac around the heart (pericardial effusion)

blockage of a blood vessel (embolism), bleeding

throat pain, decrease in the oxygen supply to a tissue (hypoxia), hoarseness

gastrointestinal bleeding, inflammation of the colon, inflammation of the gullet, inflammation of

the anus, mouth ulcer

liver failure, enlarged liver, liver pain

reddening of the skin(generalised erythema), inflammation of skin (dermatitis), death of skin

tissue, skin ulcer, bronze pigmentation of skin, dry skin

muscle weakness

kidney failure, inflammation of the urinary bladder (cystitis), pain on passing urine (dysuria)

pain or inflammation at the injection site, feeling cold

increased blood level of creatinine (a substance normally removed by the kidneys into the

urine), increased blood level of lactate dehydrogenase (a substance that indicates tissue or

cellular damage)

Children and adolescents

A list of all other side effects is set out below according to how common they are.

Very common

(may affect more than 1 in 10 people)

inflammation of the mucosa especially in the mouth (with ulcers), diarrhoea, nausea, vomiting,

abdominal pain

itching

fever

Common

(may affect up to 1 in 10 people)

throat pain, nosebleeds

difficulty in swallowing, mouth pain

reddening and flaking of most of the skin of the body (dermatitis exfoliative), a type of rash

with flat or raised red bumps on the skin (maculopapular rash), rash, redness of skin (erythema),

skin pain, bronze pigmentation of skin, hair loss

increased liver enzymes, increased blood level of bilirubin (a liver pigment, often a sign of liver

problems)

Not known

(frequency cannot be estimated from the available data)

different cancer caused by chemotherapeutic treatment (second malignancy)

decreased counts of white blood cells with fever (febrile neutropenia)

less acid than normal in the blood (alkalosis), abnormal blood level of electrolytes, decreased

blood level of magnesium

headache, sensation of tingling, pricking or numbness (paraesthesia), seizure

bleeding in the eye, dry eye

leakage of fluid from the capillaries (small blood vessels), high blood pressure, low blood

pressure

decrease in the oxygen supply to parts of the body (hypoxia)

inflammation of the colon, inflammation of anus, upset stomach, inflammation of the lining of

the rectum, gastrointestinal pain, constipation

enlarged liver, liver damage

skin ulcer, a type of rash with red spots and sometimes with purple or blistered areas in the

centre (erythema multiforme), hives, skin condition with fluid-filled blisters (dermatitis

bullous), acne, hand and foot syndrome (palms of the hands or soles of the feet tingle, become

numb, painfully swollen, or red), nappy rash with ulceration in the area surrounding the anus

pain in arms or legs

decrease of kidney function, kidney failure, inflammation of the urinary bladder (cystitis)

redness of scrotal skin

chills, tiredness, pain

increased blood level of a liver enzyme (gamma-glutamyl transferase)

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the national reporting

system listed in Appendix V. By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store Trecondi

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after “EXP”. The

expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

For storage conditions after reconstitution of the medicine, see the information below for healthcare

professionals.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Trecondi contains

The active substance is treosulfan. This medicine contains no other ingredients.

Trecondi 1 g powder for solution for infusion

1 vial contains 1 g of treosulfan.

Trecondi 5 g powder for solution for infusion

1 vial contains 5 g of treosulfan.

After reconstitution 1 mL of the solution contains 50 mg treosulfan.

What Trecondi looks like and contents of the pack

White crystalline powder in a glass vial with a rubber stopper and aluminium cap.

Trecondi is available in packs containing 1 or 5 vials (type I glass).

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

medac

Gesellschaft für klinische Spezialpräparate mbH

Theaterstr. 6

22880 Wedel

Germany

Tel.:

+49 4103 8006-0

Fax:

+49 4103 8006-100

E-mail:

contact@medac.de

This leaflet was last revised in <{MM/YYYY}><{month YYYY}>.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.

------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

As with all cytotoxic substances, appropriate precautions should be taken when handling treosulfan.

Trained personnel should reconstitute the medicinal product. When handling treosulfan, inhalation,

skin contact or contact with mucous membranes should be avoided (the use of adequate protective

disposable gloves, goggles, gown and mask is recommended). Contaminated body parts should be

carefully rinsed with water and soap, the eyes should be rinsed with sodium chloride 9 mg/mL (0.9%)

solution. If possible it is recommended to work on a special safety workbench, equipped with laminar

flow, with liquid-impermeable, absorbent disposable foil. Adequate care and precautions should be

taken in the disposal of items (syringes, needles, etc.) used to reconstitute cytotoxic medicinal

products. Use Luer-lock fittings on all syringes and sets. Large bore needles are recommended to

minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of

a venting needle.

Pregnant personnel should be excluded from handling cytotoxics.

Instructions for reconstitution of treosulfan:

Treosulfan is reconstituted in its original glass container. Reconstituted solutions of treosulfan

may be combined into a larger glass vial, PVC bag or PE bag.

To avoid solubility problems, warm the solvent, sodium chloride 4.5 mg/mL (0.45%) solution,

to 25 °C - 30 °C (not higher), for example by using a water bath.

Remove the treosulfan powder carefully from the inner surface of the vial by shaking. This

procedure is very important, because moistening of powder that sticks to the surface results in

caking. If this happens, vigorously shake the vial to redissolve the cake.

Reconstitute each vial of Trecondi containing 1 g treosulfan in 20 mL of pre-warmed

(maximum 30 °C) sodium chloride 4.5 mg/mL (0.45%) solution by shaking.

Reconstitute each vial of Trecondi containing 5 g treosulfan in 100 mL of pre-warmed

(maximum 30 °C) sodium chloride 4.5 mg/mL (0.45%) solution by shaking.

For preparation of sodium chloride 4.5 mg/mL (0.45%) solution equivalent volumes of sodium

chloride 9 mg/mL (0.9%) solution and water for injections can be mixed.

Reconstituted solution for infusion

The reconstituted solution contains 50 mg treosulfan per mL and appears as a clear colourless solution.

Solutions showing any sign of precipitation should not be used.

After reconstitution with sodium chloride 4.5 mg/mL (0.45%) solution, chemical and physical stability

has been demonstrated for 3 days at 25 °C.

From a microbiological point of view, unless the method of reconstitution precludes the risk of

microbial contamination, the product should be used immediately. If not used immediately, in-use

storage times and conditions are the responsibility of the user.

Do not store the reconstituted solution in a refrigerator (2 °C - 8 °C) as this might cause precipitation.

Treosulfan has mutagenic and carcinogenic potential. Remnants of the medicinal product as well as all

materials that have been used for reconstitution and administration must be destroyed according to

standard procedures applicable to antineoplastic agents, with due regard to current laws related to the

disposal of hazardous waste.

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Trecondi 1 g powder for solution for infusion

Trecondi 5 g powder for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Trecondi 1 g powder for solution for infusion

One vial contains 1 g of treosulfan.

Trecondi 5 g powder for solution for infusion

One vial contains 5 g of treosulfan.

When reconstituted according to section 6.6, 1 mL of the solution for infusion contains 50 mg

treosulfan.

3.

PHARMACEUTICAL FORM

Powder for solution for infusion.

White crystalline powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to

allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients with malignant and

non-malignant diseases, and in paediatric patients older than one month with malignant diseases.

4.2

Posology and method of administration

Administration of treosulfan should be supervised by a physician experienced in conditioning

treatment followed by alloHSCT.

Posology

Adults with malignant disease

Treosulfan is given in combination with fludarabine.

The recommended dose and schedule of administration is:

Treosulfan 10 g/m² body surface area (BSA) per day as a two-hour intravenous infusion, given

on three consecutive days (day -4, -3, -2) before stem cell infusion (day 0). The total treosulfan

dose is 30 g/m²;

Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on five

consecutive days (day -6, -5, -4, -3, -2) before stem cell infusion (day 0). The total fludarabine

dose is 150 mg/m²;

Treosulfan should be administered before fludarabine on days -4, -3, -2 (FT

regimen).

Adults with non-malignant disease

Treosulfan is given in combination with fludarabine with or without thiotepa.

The recommended dose and schedule of administration is:

Treosulfan 14 g/m² body surface area (BSA) per day as a two-hour intravenous infusion, given

on three consecutive days (day -6, -5, -4) before stem cell infusion (day 0). The total treosulfan

dose is 42 g/m²;

Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on five

consecutive days (day -7, -6, -5, -4, -3) before stem cell infusion (day 0). The total fludarabine

dose is 150 mg/m²;

Treosulfan should be administered before fludarabine on days -6, -5, -4 (FT

regimen).

Thiotepa 5 mg/kg twice a day, given as two intravenous infusions over 2–4 hours on day -2

before stem cell infusion (day 0).

Elderly

No dose adjustment is necessary in any subset of the elderly population.

Renal and hepatic impairment

No dose adjustment is necessary for mild or moderate impairment, but treosulfan is contraindicated in

patients with severe impairment (see section 4.3).

Paediatric population

Treosulfan is given in combination with fludarabine, with thiotepa (intensified regimen;

10-14

TT regimen) or without thiotepa (FT

10-14

regimen).

The recommended dose and schedule of administration is:

Treosulfan 10-14 g/m² body surface area (BSA) per day as a two-hour intravenous infusion,

given on three consecutive days (day -6, -5, -4) before stem cell infusion (day 0). The total

treosulfan dose is 30-42 g/m²;

The dose of treosulfan should be adapted to the patient’s BSA as follows (see section 5.2):

Body surface area (m²)

Treosulfan dose (g/m²)

≤ 0.5

10.0

> 0.5 – 1.0

12.0

> 1.0

14.0

Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on five

consecutive days (day -7, -6, -5, -4, -3) before stem cell infusion (day 0). The total fludarabine

dose is 150 mg/m²;

Treosulfan should be administered before fludarabine;

Thiotepa (intensified regimen 5 mg/kg twice a day), given as two intravenous infusions over 2–

4 hours on day -2 before stem cell infusion (day 0).

The safety and efficacy of treosulfan in children less than 1 month of age has not yet been established.

Method of administration

Treosulfan is for intravenous use as a two-hour infusion.

Precautions to be taken before handling or administering the medicinal product

When handling treosulfan, inhalation, skin contact or contact with mucous membranes should be

avoided. Pregnant personnel should be excluded from handling cytotoxics.

Intravenous administration should be performed using a safe technique to avoid extravasation (see

section 4.4).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3

Contraindications

Hypersensitivity to the active substance

Active non-controlled infectious disease

Severe concomitant cardiac, lung, liver, and renal impairment

Fanconi anaemia and other DNA breakage repair disorders

Pregnancy (see section 4.6)

Administration of live vaccine

4.4

Special warnings and precautions for use

Myelosuppression

Profound myelosuppression with pancytopenia is the desired therapeutic effect of treosulfan-based

conditioning treatment, occurring in all patients. It is therefore recommended to monitor blood cell

counts frequently until recovery of the haematopoietic system.

During phases of severe neutropenia (median duration of neutropenic period is 14-17.5 days in adults

and 21-24 days in paediatric patients) the risk of infection is increased. Prophylactic or empiric

anti-infective treatment (bacterial, viral, fungal) should therefore be considered. Growth factors

(G-CSF, GM-CSF), platelet and/or red blood cell support should be given as indicated.

Secondary malignancies

Secondary malignancies are well-established complications in long-term survivors after alloHSCT.

How much treosulfan contributes to their occurrence is unknown. The possible risk of a second

malignancy should be explained to the patient. On the basis of human data, treosulfan has been

classified by the International Agency for Research on Cancer (IARC) as a human carcinogen.

Mucositis

Oral mucositis (including high-grade severity) is a very common undesirable effect of

treosulfan-based conditioning followed by alloHSCT (see section 4.8). Use of mucositis prophylaxis

(e.g. topical antimicrobials, barrier protectants, ice and adequate oral hygiene) is recommended.

Vaccines

Concomitant use of live attenuated vaccines is not recommended.

Fertility

Treosulfan can impair fertility. Therefore, men treated with treosulfan are advised not to father a child

during and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to

treatment because of the possibility of irreversible infertility due to therapy with treosulfan.

Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in

pre-menopausal patients (see section 4.6).

Paediatric population

Seizures

There have been isolated reports of seizures in infants (≤ 4 months of age) with primary

immunodeficiencies after conditioning treatment with treosulfan in combination with fludarabine or

cyclophosphamide. Therefore, infants ≤ 4 months of age should be monitored for signs of neurological

adverse reactions. Although it cannot be proved that treosulfan was the cause, the use of clonazepam

prophylaxis for children younger than 1 year might be considered.

Respiratory, thoracic and mediastinal disorders

There was a significant association between age and respiratory toxicity in paediatric patients treated

with treosulfan-based conditioning.

Children younger than one year (mainly non-malignant diseases, especially immunodeficiencies)

experienced more respiratory grade III/IV toxicity, possibly due to pulmonary infections already

existing before the start of conditioning treatment.

Dermatitis diaper

Dermatitis diaper may occur in small children because of excretion of treosulfan in the urine.

Therefore, nappies should be changed frequently up to 6–8 hours after each infusion of treosulfan.

Extravasation

Treosulfan is considered an irritant. Intravenous application should be performed using a safe

technique. If extravasation is suspected, general safety measures should be implemented. No specific

measure has been proven to be recommendable.

4.5

Interaction with other medicinal products and other forms of interaction

No interaction of treosulfan was observed in high-dose chemotherapy.

Detailed

in vitro

studies did not completely exclude potential interactions between high plasma

concentrations of treosulfan and CYP3A4, CYP2C19, or P-gp substrates. Therefore, medicinal

products with a narrow therapeutic index (e.g. digoxin) that are substrates for CYP3A4, CYP2C19 or

P-gp should not be given during treatment with treosulfan.

The effect of treosulfan on the pharmacokinetics of fludarabine is not known.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Both sexually active men and women of childbearing potential have to use effective contraception

during and up to 6 months after treatment.

Pregnancy

There are no data from the use of treosulfan in pregnant women. Animal studies are insufficient with

respect to reproductive toxicity (see section 5.3). Treosulfan is contraindicated during pregnancy (see

section 4.3).

Breast-feeding

It is unknown whether treosulfan is excreted in human milk. Breast-feeding should be discontinued

during treatment with treosulfan.

Fertility

Treosulfan might impair fertility in men and women. Men should seek advice on cryo-conservation of

sperm prior to treatment because of the possibility of irreversible infertility.

As known for other alkylating conditioning agents treosulfan can cause ovarian suppression and

amenorrhoea with menopausal symptoms in pre-menopausal women.

4.7

Effects on ability to drive and use machines

Treosulfan has moderate influence on the ability to drive and use machines. It is likely that certain

adverse reactions of treosulfan like nausea, vomiting or dizziness could affect these functions.

4.8

Undesirable effects

Summary of the safety profile

Profound myelosuppression/pancytopenia is the desired therapeutic effect of conditioning therapy and

occurs in all patients. Blood cell counts usually recover after HSCT.

The most commonly observed adverse reactions (adults/paediatric patients) after treosulfan-based

conditioning followed by alloHSCT include infections (13.1% /11.4%), gastrointestinal disorders

(nausea [39.5%/30.7%], stomatitis [36.0%/69.3%], vomiting [22.5%/43.2%], diarrhoea

[15.6%/33.0%], abdominal pain [10.4%/17%]), fatigue (15.1%/2.3%), febrile neutropenia

(11.3%/1.1%), oedema (7.8%/0%), rash (7.2%/12.5%), and increases of alanine transaminase (ALT

[5.1%/9.1%]), aspartate transaminase (AST [4.4%/8.0%]), gamma-glutamyl transferase (γGT

[3.7%/2.3%]), and bilirubin (18.8%/5.7%).

Adults

Tabulated list of adverse reactions

The frequencies of adverse reactions reported in the table below are derived from 5 clinical trials

(including a total of 564 patients) where treosulfan combined with fludarabine was investigated as

conditioning treatment prior to alloHSCT in adult patients. Treosulfan was administered in a dose

range of 10-14 g/m² BSA on 3 consecutive days.

Adverse reactions are listed below, by system organ class and by frequency: 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) and not known (cannot be estimated from the available data). Within each frequency

group, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

(SOC)

All Adverse Reactions / Frequency

Grade 3-4 Adverse Reactions /

Frequency

Infections and

infestations*

Very common

Infections (bacterial, viral, fungal)

Common

Sepsis

Not known

Septic shock

Common

Infections (bacterial, viral, fungal),

sepsis

Not known

Septic shock

Neoplasms benign,

malignant and

unspecified

(including cysts and

polyps)*

Not known

Treatment-related second malignancy

Not known

Treatment-related second malignancy

Blood and lymphatic

system disorders*

Very common

Myelosuppression, pancytopenia,

febrile neutropenia

Very common

Myelosuppression, pancytopenia,

febrile neutropenia

Immune system

disorders*

Common

Hypersensitivity

System Organ Class

(SOC)

All Adverse Reactions / Frequency

Grade 3-4 Adverse Reactions /

Frequency

Metabolism and

nutrition disorders

Common

Decreased appetite

Uncommon

Hyperglycaemia

Not known

Acidosis

, glucose tolerance

impaired, electrolyte imbalance

Common

Decreased appetite

Uncommon

Hyperglycaemia

Not known

Acidosis

, glucose tolerance

impaired, electrolyte imbalance

Psychiatric disorders

Common

Insomnia

Uncommon

Confusional state

Not known

Agitation

Rare

Confusional state

Nervous system

disorders

Common

Headache, dizziness

Uncommon

Peripheral sensory neuropathy

Not known

Encephalopathy, intracranial

haemorrhage, extrapyramidal

disorder, syncope, paraesthesia

Rare

Headache, peripheral sensory

neuropathy

Not known

Encephalopathy, intracranial

haemorrhage, syncope

Eye disorders

Not known

Dry eye

Cardiac disorders*

Common

Cardiac arrhythmias (e.g. atrial

fibrillation, sinus arrhythmia)

Not known

Cardiac arrest, cardiac failure,

myocardial infarction, pericardial

effusion

Uncommon

Cardiac arrhythmias (e.g. atrial

fibrillation, sinus arrhythmia)

Not known

Cardiac arrest, myocardial infarction

Vascular disorders

Common

Hypertension, flushing

Uncommon

Haematoma, hypotension

Not known

Embolism, haemorrhage

Uncommon

Hypertension

Not known

Embolism, haemorrhage

System Organ Class

(SOC)

All Adverse Reactions / Frequency

Grade 3-4 Adverse Reactions /

Frequency

Respiratory, thoracic

and mediastinal

disorders

Common

Dyspnoea, epistaxis

Uncommon

Pneumonitis, pleural effusion,

pharyngeal or laryngeal

inflammation, cough, laryngeal pain,

hiccups

Not known

Oropharyngeal pain, hypoxia,

dysphonia

Uncommon

Dyspnoea, pleural effusion,

pharyngeal or laryngeal

inflammation

Rare

Epistaxis, pneumonitis

Not known

Hypoxia

Gastrointestinal

disorders*

Very common

Stomatitis/mucositis, diarrhoea,

nausea, vomiting, abdominal pain

Common

Oral pain, gastritis, dyspepsia,

constipation, dysphagia

Uncommon

Mouth haemorrhage, abdominal

distension, oesophageal or

gastrointestinal pain, dry mouth

Not known

Gastrointestinal haemorrhage,

neutropenic colitis, oesophagitis, anal

inflammation, mouth ulceration

Common

Stomatitis/mucositis, diarrhoea,

nausea, abdominal pain

Uncommon

Vomiting, oral pain, dysphagia,

mouth haemorrhage, oesophageal or

gastrointestinal pain

Not known

Gastrointestinal haemorrhage,

neutropenic colitis

Hepatobiliary

disorders*

Uncommon

Veno-occlusive liver disease,

hepatotoxicity

Not known

Hepatic failure, hepatomegaly,

hepatic pain

Rare

Veno-occlusive liver disease,

hepatotoxicity

Not known

Hepatic failure

Skin and

subcutaneous tissue

disorders

Common

Maculo-papular rash, purpura,

erythema, palmar-plantar

erythrodysaesthesia syndrome,

pruritus, alopecia

Uncommon

Erythema multiforme, dermatitis

acneiform, rash, hyperhidrosis

Not known

Generalised erythema, dermatitis,

skin necrosis or ulcer, skin

hyperpigmentation

, dry skin

Uncommon

Maculo-papular rash, purpura,

erythema

Not known

Skin necrosis

System Organ Class

(SOC)

All Adverse Reactions / Frequency

Grade 3-4 Adverse Reactions /

Frequency

Musculoskeletal and

connective tissue

disorders

Common

Pain in extremities, back pain, bone

pain, arthralgia, myalgia

Not known

Muscular weakness

Rare

Pain in extremities, bone pain

Renal and urinary

disorders

Common

Acute kidney injury, haematuria

Not known

Renal failure, cystitis

, dysuria

Uncommon

Acute kidney injury, haematuria

General disorders

and administration

site conditions

Very common

Asthenic conditions (fatigue,

asthenia, lethargy)

Common

Oedema, pyrexia

chills

Uncommon

Non-cardiac chest pain, pain

Not known

Injection site reaction, feeling cold

Common

Fatigue

Rare

Non-cardiac chest pain, oedema

pyrexia

Investigations

Very common

Bilirubin increased

Common

Transaminases (ALT/AST)

increased, γGT increased, blood

alkaline phosphatase increased,

C-reactive protein increased, weight

decreased, weight increased

Not known

Blood creatinine increased, blood

lactate dehydrogenase (LDH)

increased

Common

Bilirubin increased, transaminases

(ALT/AST) increased, γGT increased

Uncommon

Blood alkaline phosphatase

increased, C-reactive protein

increased

Not known

Blood LDH increased

See detailed sections below

Clinically or microbiologically documented infection with grade 3 or 4 neutropenia (absolute

neutrophil count [ANC] < 1.0 x 10

/L) and sepsis

Acidosis might be a consequence of the release of methanesulfonic acid through treosulfan

activation/cleavage in the plasma

Case reports (> 2) after treosulfan-based conditioning obtained from other sources

Bronze pigmentation

Fever in the absence of neutropenia where neutropenia is defined as ANC < 1.0 x 10

Description of selected adverse reactions

Infections

The overall incidence of infections was 13.1% (74/564). The most frequent type was lung infection

(12/74 [16.2%]). Pathogens included bacteria (e.g.

Staphylococcus

Enterococcus

Corynebacterium

viruses (e.g. cytomegalovirus [CMV], Epstein-Barr virus [EBV], herpes) as well as fungi (e.g.

candida). The infection rate was lowest in patients treated with the dose regimen of 10 g/m² of

treosulfan per day, from day -4 to -2 (7.7%).

Neoplasms benign, malignant and unspecified (including cysts and polyps)

One of 564 adult patients (0.2%) developed a second malignancy (breast cancer). A few further cases

of second malignancies after treosulfan-based conditioning have been reported by other investigators.

After long-term therapy with conventional doses of oral treosulfan in patients with solid tumours acute

myeloid leukaemia was observed in 1.4% of 553 patients.

Blood and lymphatic system disorders

Blood disorders were observed in 67 of 564 adult patients (11.9%). The most frequent adverse reaction

was febrile neutropenia (11.3%). The lowest incidence was noted with the dose regimen of

10 g/m²/day, day -4 to -2 (4.1%).

The median (25%/75% percentiles) duration of neutropenia was 14 (12, 20) days with the 10 g/m²

treosulfan dose and 17.5 (14, 21) days with the 14 g/m² treosulfan dose.

Cardiac disorders

Cardiac disorders were observed in 25 patients (4.4%). The most frequent adverse reactions were

cardiac arrhythmias, e.g. atrial fibrillation (1.2%), sinus tachycardia (0.9%), supraventricular

tachycardia (0.4%), and ventricular extrasystole (0.4%). Isolated cases of cardiac arrest, cardiac

failure, and myocardial infarction occurred. The lowest frequency of cardiac disorders was seen with

the dose regimen of 10 g/m²/day, day -4 to -2 (2.7%).

Gastrointestinal disorders

Gastrointestinal disorders were observed in 357 patients (63.3%). The most frequent adverse reactions

reported were nausea (39.5%), stomatitis (36%), vomiting (22.5%), diarrhoea (15.6%), and abdominal

pain (10.4%). The lowest frequencies of these adverse reactions were seen with the dose regimen of

10 g/m² per day, day -4 to -2 (20.4%, 30.3%, 13.1%, 5.0%, and 5.5% respectively).

Hepatobiliary disorders

The overall incidence of veno-occlusive liver disease (VOD) was 0.9% (5/564). VOD occurred only

with the dose regimen of 14 g/m²/day treosulfan. None of these cases were fatal or life-threatening.

Paediatric population

Tabulated list of adverse reactions

The adverse reactions reported in the table below are derived from two clinical trials (including a total

of 88 patients; median age 8 years [range 0–17 years]) where treosulfan combined with fludarabine

(and mostly with additional thiotepa) was administered as conditioning treatment prior to alloHSCT in

paediatric patients with malignant or non-malignant diseases. Treosulfan was administered in a dose

range of 10-14 g/m² BSA on three consecutive days.

Adverse reactions are listed below, by system organ class and by frequency: 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

Official address

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© European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged.

EMA/887197/2018

EMEA/H/C/004751

Trecondi (treosulfan)

An overview of Trecondi and why it is authorised in the EU

What is Trecondi and what is it used for?

Trecondi is a medicine given to patients before they have a bone marrow transplant from a donor

known as ‘allogeneic haematopoietic stem cell transplantation’. It is used as a ‘conditioning’ treatment

to clear the patient’s bone marrow and make room for the transplanted bone marrow cells, which can

then produce healthy blood cells.

Trecondi is used together with another medicine called fludarabine in adults and children from 1 month

of age with blood cancers as well as in adults with other severe disorders requiring a bone marrow

transplant.

The active substance in Trecondi is treosulfan.

Haematopoietic stem cell transplantation is rare, and Trecondi was designated an ‘orphan medicine’ (a

medicine used in rare diseases) on 23 February 2004. Further information on the orphan designation

can be found here: ema.europa.eu/medicines/human/orphan-designations/eu304186

How is Trecondi used?

Trecondi is given as a two-hour infusion (drip) into a vein. The patient receives Trecondi once a day for

3 days before the transplantation. Fludarabine is given once a day for 5 days before transplantation.

The dose of Trecondi depends on the condition for which transplantation is needed, whether the

patient is an adult or a child and on the patient’s weight and height.

The medicine can only be obtained with a prescription and use of Trecondi must be supervised by a

doctor experienced in conditioning treatment before allogeneic haematopoietic stem cell

transplantation.

For more information about using Trecondi, see the package leaflet or contact your doctor or

pharmacist.

How does Trecondi work?

The active substance in Trecondi, treosulfan, belongs to a group of medicines called alkylating agents.

In the body, treosulfan is converted into other compounds called epoxides which kill cells, especially

Trecondi (treosulfan)

EMA/887197/2018

Page 2/3

cells that develop rapidly such as bone marrow cells, by attaching to their DNA while they are dividing.

Trecondi can therefore kill cells in the patient’s bone marrow and make room for the new cells from a

donor.

What benefits of Trecondi have been shown in studies?

Two main studies showed that Trecondi is at least as effective as busulfan, another medicine used to

prepare patients for haematopoietic stem cell transplantation.

In one of the studies, involving 570 adults with acute myeloid leukaemia (a blood cancer) or

myelodysplastic syndromes (conditions in which large numbers of abnormal blood cells are produced),

64% of patients given Trecondi (with fludarabine) had a successful transplant and were alive and

disease-free after 2 years, compared with 51% of patients given busulfan (with fludarabine).

In an additional study in 70 children with blood cancers, 99% of children given Trecondi (with

fludarabine) were alive 3 months after their transplant.

What are the risks associated with Trecondi?

The most common side effects in adults and children with Trecondi (which may affect more than 1 in

10 people) are infections, nausea (feeling sick), stomatitis (inflammation of the lining of the mouth),

vomiting, diarrhoea and abdominal pain (belly ache). Tiredness, febrile neutropenia (low white blood

cell counts with fever) and high blood levels of bilirubin (a breakdown product of red blood cells) are

also seen in more than 1 in 10 adults, and rash also affects more than 1 in 10 children.

Trecondi must not be used in patients with an active, uncontrolled infection, with severe heart, lung,

liver or kidney problems, and in patients with Fanconi anaemia and other DNA repair disorders.

Pregnant women must not use Trecondi and live vaccines must not be given to patients receiving

Trecondi.

For the full list of side effects and restrictions, see the package leaflet.

Why is Trecondi authorised in the EU?

Trecondi is effective at preparing adults and children with blood cancers for haematopoietic stem cell

transplantation. There is also sufficient data to show that Trecondi is effective in adults (but not

enough data are available in children) with non-cancerous blood disorders.

Side effects with Trecondi are manageable and comparable to those seen with busulfan. Like busulfan,

Trecondi is considered as a conditioning treatment of ‘reduced-intensity’: this means that it is less toxic

than standard conditioning treatments which are based on chemotherapy with or without radiation.

The European Medicines Agency therefore decided that Trecondi’s benefits are greater than its risks

and it can be authorised for use in the EU.

What measures are being taken to ensure the safe and effective use of

Trecondi?

Recommendations and precautions to be followed by healthcare professionals and patients for the safe

and effective use of Trecondi have been included in the summary of product characteristics and the

package leaflet.

As for all medicines, data on the use of Trecondi are continuously monitored. Side effects reported with

Trecondi are carefully evaluated and any necessary action taken to protect patients.

Trecondi (treosulfan)

EMA/887197/2018

Page 3/3

Other information about Trecondi

Trecondi received a marketing authorisation valid throughout the EU on 20 June 2019.

Further information on Trecondi can be found on the Agency’s website:

ema.europa.eu/medicines/human/EPAR/trecondi

This overview was last updated in 03-2019.

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