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MITOXANTRONE 2 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): MITOXANTRONE HYDROCHLORIDE / MITOXANTRONE HYDROCHLORIDE

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Package leaflet: Information for the patient
Mitoxantrone 2mg/ml
Concentrate for solution for infusion
Mitoxantrone hydrochloride
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
1.
What Mitoxantrone is and what it is used for
2.
What you need to know before you use Mitoxantrone
3.
How to use Mitoxantrone
4.
Possible side effects
5.
How to store Mitoxantrone
6.
Contents of the pack and other information

1.

What Mitoxantrone is and what it is used for

Mitoxantrone contains the active substance mitoxantrone. Mitoxantrone belongs to the group of medicines
known as antineoplastic or anti-cancer medicines. It also belongs to the subgroup of anti-cancer medicines
called anthracyclines. Mitoxantrone prevents cancer cells from growing, as a result of which they
eventually die. The medicine also suppresses the immune system and is used because of this effect to treat a
specific form of multiple sclerosis when there are no alternative treatment options.
Mitoxantrone is used in the treatment of:
advanced stage (metastatic form) of breast cancer;
a form of lymph node cancer (non-Hodgkin’s lymphoma);
a cancer of the blood in which the bone marrow (the spongy tissue inside the large bones) makes too
many white blood cells (acute myeloid leukaemia);
a cancer of the white blood cells (chronic myeloid leukaemia) at a stage where it is difficult to control
the number of white blood cells (blast crisis). Mitoxantrone is used in combination with other
medicinal products in this indication;
pain caused by prostate cancer at an advanced stage of prostate cancer in combination with
corticosteroids;
highly active relapsing multiple sclerosis associated with rapidly evolving disability where no
alternative therapeutic options exist (see sections 2 and 3).

2.

What you need to know before you use Mitoxantrone

Do not use Mitoxantrone:
if you are allergic to mitoxantrone or any of the other ingredients of this medicine (see section 6);
if you are allergic to sulphite;
if you have a form of asthma (bronchial asthma) with sulphite allergy;
if you are breast-feeding (see section “pregnancy and breast-feeding”).

-

For use as treatment of multiple sclerosis:
if you are pregnant.

Warnings and precautions

Mitoxantrone should be administered under the supervision of a doctor experienced in the use of
cancer medicines that are toxic to your cells (cytotoxic chemotherapy agents).
Mitoxantrone should be given by slow and freely flowing infusion into the vein.
Mitoxantrone must not be administered under the skin (subcutaneous), in a muscle (intramuscular), or into
the artery (intra-arterial). Severe local tissue damage may occur if Mitoxantrone leaks in surrounding tissue
(extravasation) during administration.
Mitoxantrone must also not be injected into the space under the brain or spinal cord (intrathecal injection)
as this can result in severe injury with permanent impairment.
Talk to your doctor or, pharmacist or nurse before using Mitoxantrone:
-

if you have liver problems;
if you have kidney problems;
if you have used Mitoxantrone before;
if your heart is not working well;
if you had prior radiotherapy of the chest;
if you already use other medicines that affect your heart;
if you had previous therapies with anthracyclines or anthracenediones, such as
daunorubicin or doxorubicin;
if your bone marrow is not working well (is depressed) or if you are in generally poor health;
if you have an infection. This infection should be treated before using Mitoxantrone;
if you plan a vaccination or immunisation during treatment. Vaccinations and immunisations may not
work during treatment with Mitoxantrone and for 3 months after the end of treatment;
if you are pregnant or if you and your partner are trying to become pregnant;
if you are breast-feeding. You should stop breast-feeding before using Mitoxantrone.

Tell your doctor or pharmacist or nurse immediately if you get any of the following signs or symptoms
during treatment with Mitoxantrone:
- fever, infections, unexplained bleeding or bruising, weakness and easy fatigability;
- breathlessness (including breathlessness at night), cough, fluid retention (swelling), in the ankles or legs,
heart fluttering (irregular heart beat). This may occur either during or months to years after therapy with
Mitoxantrone.
Your doctor may need to adjust your treatment or stop Mitoxantrone temporarily or permanently.
Blood tests prior and during treatment with Mitoxantrone
Mitoxantrone may affect your blood cell counts. Before you start Mitoxantrone and during treatment, your
doctor will do a blood test to count the number of your blood cells. Your doctor will carry out blood tests
more often, in which he will in particular monitor the number of white blood cells (neutrophilic leucocytes)
in the blood:
• if you have a low count of a specific type of white blood cells (neutrophils) (less than
1,500 cells/mm3);
• if you use Mitoxantrone in high doses (>14 mg/m2 per day x 3 days).

Heart function tests prior and during treatment with Mitoxantrone
Mitoxantrone may damage your heart and cause a deterioration of your heart function or in more severe
cases heart failure. You are more prone to these side effects if you use higher doses of Mitoxantrone or:
• if your heart is not working well;
• if you had prior treatment of the chest with radiation;
• if you already use other medicines that affect your heart;
• if you had previous therapies with anthracyclines or anthracenediones, such as daunorubicin or
doxorubicin.

Your doctor will do heart function tests before you start Mitoxantrone and at regular intervals during therapy.
If you receive Mitoxantrone to treat multiple sclerosis your doctor will test your heart function before the
start of therapy, prior to each subsequent dose and yearly for up to 5 years after the end of therapy.
Acute myeloid leukemia (AML) and Myelodysplastic syndrome
A group of anticancer medicines (topoisomerase II inhibitors), including Mitoxantrone, may cause
the following diseases when used alone but especially in combination with other chemotherapy
and/or radiotherapy:
• cancer of white blood cells (acute myeloid leukaemia, AML)
• a bone marrow disorder that causes abnormally shaped blood cells and leads to leukaemia
(myelodysplastic syndrome)
Discolouration of urine and other tissues
Mitoxantrone may cause a blue-green colouration to the urine for 24 hours after administration. A bluish
disolouration of the whites of your eyes, skin and nails may also occur.
Contraception in men and women
Men must not father a child and should use contraceptive measures during and at least 6 months after therapy.
Women of childbearing potential should have a negative pregnancy test prior to each dose, and use effective
contraception during therapy and for at least 4 months after cessation of therapy. If this medicine is used
during pregnancy or if you become pregnant while using this medicine, inform your doctor as there may be
risks to the foetus.
Fertility
This medicine might increase the risk for transitory or persistent absence of menstruation (amenorrhoea) in
women of childbearing age.
Children and adolescents
There is little experience in children and adolescents.
Do not give this medicine to children and adolescents from birth up to age of 18 years as safety and efficacy
in children and adolescents have not been established.
Other medicines and Mitoxantrone
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. It is
particularly important that you mention any of the following medicines.
Medicines which may increase the risk of side effects with Mitoxantrone:
Medicines that can damage your heart (e.g. anthracyclines).
Medicines that suppress the bone marrow's production of blood cells and platelets (myelosuppressive
agents).
Medicines that suppress your immune system (immunosuppressive agents).
Antivitamin K, in particular if you are using Mitoxantrone because you have cancer.
Topoisomerase II inhibitors (a groups of anticancer medicines including mitoxantrone) in combination
with other chemotherapy and/or radiotherapy. These can cause:
o cancer of white blood cells (acute myeloid leukaemia, AML);
o a bone marrow disorder that causes abnormally shaped blood cells and leads to leukaemia
(myelodysplastic syndrome).
Ask your doctor or pharmacist if you are not sure whether your medicine is one of the medicines listed
above.
These medicines should be used with care or may need to be avoided during your treatment with
Mitoxantrone. If you are using any of these, your doctor might need to prescribe an alternative medicine for
you.
You should also tell your doctor if you are already using Mitoxantrone and you are prescribed a new medicine
that you have not already taken at the same time as Mitoxantrone.

Vaccinations and immunisation (protection against the vaccination substances) may not work during
treatment with Mitoxantrone and for three months after the end of treatment.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your
doctor or pharmacist for advice before you are given this medicine.
Pregnancy
Mitoxantrone may cause damage to your unborn child. Therefore you should avoid becoming pregnant.
Mitoxantrone must not be used during pregnancy for treatment of multiple sclerosis (specifically in the
first three months of the pregnancy).
If you become pregnant during the treatment with Mitoxantrone, you must tell your doctor immediately and
stop treatment with Mitoxantrone.
You should avoid becoming pregnant. Men must use an effective method of contraception during the
treatment and for at least 6 months after discontinuing the treatment. Women of child-bearing potential should
have a negative pregnancy test prior to each dose and must practise effective contraception for at least
4 months after stopping the treatment with Mitoxantrone.
Breast-feeding
Mitoxantrone is secreted into breast milk and may cause serious adverse reactions in your baby. You must
not breast-feed while using mitoxantrone and for up to one month after the last administration.
Fertility
Mitoxantrone might increase the risk for transient or persistent absence of menstruation (amenorrhoea) in
women of childbearing age. Therefore you should talk to your doctor if you are planning to become pregnant
in the future; your eggs may need to be frozen. In men, no data are available. However, in male animals,
damage to the testes and decreased sperm counts were observed.
Driving and using machines
Mitoxantrone has a minor effect on your ability to drive and use machines. This is caused by possible
side effects, such as confusion or feeling tired (see section 4).
If you suffer from these side effects, do not drive any vehicles and/or use any machines.

3.

How to use Mitoxantrone

Posology and method of administration
Mitoxantrone will be given to you under supervision of a doctor experienced in the use of cytotoxic
chemotherapy agents. It must always be administered as an intravenous infusion (in a vein) and must always
be diluted before. The infusion liquid can leak out of the vein into the tissue (extravasation). If this happens,
the infusion must be stopped and restarted in another vein. You should avoid contact with Mitoxantrone,
especially with the skin, mucous membranes (moist body surfaces, such as the lining of the mouth) and eyes.
The individual dose of Mitoxantrone is calculated by your doctor. The recommended dose is based on your
body surface area, which is calculated in square metres (m2) using your height and weight. In addition your
blood will be tested regularly during the treatment. The dosage of the medicine will be adjusted in
accordance with the results of these tests.
The usual dose is:
Metastatic breast cancer, non-Hodgkin’s lymphoma
If Mitoxantrone is used alone:
The recommended initial dosage of Mitoxantrone is 14 mg/m2 of body surface area, given as a
single intravenous dose, which may be repeated at 21-day intervals, if your blood values have
returned to acceptable levels.
A lower initial dosage (12 mg/m2 or less) is recommended in patients with low bone marrow reserves e.g.

due to prior chemotherapy or poor general condition.
Your doctor will decide precisely which subsequent dosage you need.
For subsequent courses, the prior dose can usually be repeated if white blood cell and platelet counts have
returned to normal levels after 21 days.
Combination therapy (if used with other agents)
Mitoxantrone has been given as part of combination therapy. In metastatic breast cancer, combinations of
Mitoxantrone with other cytotoxic agents including cyclophosphamide and 5-fluorouracil or methotrexate
and mitomycin C have been shown to be effective.
Mitoxantrone has also been used in various combinations for non-Hodgkin’s lymphoma; however, data
are presently limited and specific regimens cannot be recommended.
As a guide, when Mitoxantrone is used in combination chemotherapy, the initial dose of Mitoxantrone should
be reduced by 2-4 mg/m2 below the doses recommended when Mitoxantrone is used alone.
Acute myeloid leukaemia:
If used alone for recurrence (return of the cancer)
The recommended dosage for remission induction is 12 mg/m2 of body surface area, given as a single
intravenous dose daily for five consecutive days (total of 60 mg/m2 per 5 days).
If used with other agents against cancer:
Your doctor will decide exactly what dosage you need. This dose might be adjusted if:
- The combination of medicines reduces the production of white and red blood cells as well as platelets in
your bone marrow more than Mitoxantrone used alone;
- If you have serious liver or kidney problems.
Treatment of blast crisis in (chronic) myeloid leukaemia
Used alone for recurrence
The recommended dosage in relapse is 10 to 12 mg/m2 body surface area given as a single intravenous dose
daily over 5 consecutive days (total of 50 to 60 mg/m2).
Advanced castrate-resistant prostate cancer
The recommended dosage of Mitoxantrone is 12 to 14 mg/m2 given as a short intravenous infusion every
21 days, in combination with low oral doses of corticosteroids (hormonal medicines that suppress the
immune system).
Multiple Sclerosis
Mitoxantrone will be given to you under the supervision of a doctor experienced in the use of
cytotoxic chemotherapeutic agents for the treatment of multiple sclerosis.
The recommended dosage of mitoxantrone is usually 12 mg/m2 body surface area given as a short
(approximately 5 to 15 minutes) intravenous infusion that may be repeated every 1 to 3 months. The
maximum lifetime cumulative dose should not exceed 72 mg/m2.
If mitoxantrone is administered repeatedly, dosing adjustments should be guided by extent and duration of
the reduction in the number of white and red blood cells as well as platelets in your blood.
Elderly patients
Elderly patient should receive doses at the low end of the dosing range due to possible reduced liver, kidney
or heart function and of possible illness or treatment with other medicines.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The most serious
side effects are damage to the heart (myocardial toxicity) and myelosuppression (reduced activity of the bone
marrow).
Some side effects could be serious
If any of the following happen, tell the doctor immediately:
- If your skin becomes pale and you feel weak or experience sudden shortness of breath, this can be sign
of a reduction in red blood cells.
- Unsual bruising or bleeding, such as coughing up blood, blood in your vomit or urine, or black stools
(potential sign of platelet reduction).
- New or worsening breathing difficulties.
- Chest pain, breathlessness, changes in your heartbeat (fast or slow), fluid retention (swelling) in the
ankles or legs (potential signs or symptoms of heart problems).
- Severe itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may
cause difficulty in swallowing or breathing), or if you feel you like you are going to faint, these may be
signs of severe allergic reaction.
- Fever or infections.
For patients being treated for cancer:
Very Common (may affect more than 1 in 10 people)
- Infections.
- Low number of red blood cells which can cause a feeling of tiredness and shortness of breath (anaemia).
You may require a blood transfusion.
- Low number of special white blood cells (neutrophils and leukocytes)
- Nausea (feeling sick).
- Vomiting (being sick).
- Hair loss.
Common (may affect up to 1 in 10 people)
- Low level of platelets – which may cause bleeding or bruising.
- Low number of special white blood cells (granulocytes).
- Loss of appetite.
- Tiredness, weakness and lack of energy.
- Congestive heart failure (severe condition where the heart cannot anymore pump enough blood).
- Heart attack.
- Shortness of breath.
- Constipation.
- Diarrhoea.
- Inflammation of the mouth and lips.
- Fever.
Uncommon (may affect up to 1 in 100 people)
- Reduced activity of the bone marrow. Your bone marrow can be more depressed or be depressed for a
longer period if you have had chemotherapy or radiotherapy.
- Insufficient production of bloods cells in the bone marrow (bone marrow failure).
- Abnormal number of white blood cells.
- Severe allergic reaction (anaphylactic reaction including anaphylactic shock) – you may experience a
sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat, which may
cause difficulty in swallowing or breathing, and you may feel you are going to faint).
- Infections of the upper airways.
- Infections of the urinary tract.
- Blood poisoning (sepsis).

-

-

Infections caused by microorganisms which do not normally cause diseases with a healthy immune
system (opportunistic infections).
Cancer of the white blood cells (acute myeloid leukemia (AML)).
Bone marrow abnormality which causes the formation of abnormal blood cells which leads to leukaemia
(myelodisplastic syndrome (MDS)).
Changes in weight.
Metabolic disturbances (tumour lysis syndrome).
Anxiety.
Confusion.
Headache.
Tingling sensation.
Irregular heart beat or slowed heart beat.
Abnormal electrocardiogram.
Reduction of the volume of blood that the left ventrical can pump, with no symptoms.
Bruising.
Heavy bleeding.
Low blood pressure.
Abdominal pain.
Bleeding in your stomach or bowels, this may include blood in vomit, bleeding when emptying the
bowels or black tarry stool.
Mucosal inflammation.
Inflammation of the pancreas.
Liver abnormalities.
Skin inflammations (erythema).
Nail abnormalities (e.g. detachment of the nail from the nail bed, changes in nail texture and structure).
Rash.
Changes to the colour of the whites of the eyes.
Skin discolouration.
Leakage of fluid into surrounding tissue (extravasation):
o Reddening (erythema).
o Swelling.
o Pain.
o Burning feeling and/or discolouration of the skin.
o Death of tissue cells which can lead to the need to remove dead cells and skin
transplantation.
Abnormal results of blood tests to check liver and kidney functions (raised aspartate aminotransferase
levels, elevated creatinine and urea nitrogen concentration in the blood).
Damage to the kidneys, causing swelling and weakness (nephropathy).
Urine discolouration.
Abnormal absence of menstruation (amenorrhoea).
Swelling (oedema).
Taste disturbances.

Rare (may affect up to 1 in 1,000 people)
- Lung inflammation (pneumonia).
- Damages to the heart muscle preventing it from pumping properly (cardiomyopathy).

For patients being treated for Multiple Sclerosis:
Very Common (may affect more than 1 in 10 people)
-

Infections, including infections of the upper airways and urinary tract.
Nausea (feeling sick).
Hair loss.
Abnomal absence of menstruation (amenorrhea).

Common (may affect up to 1 in 10 people)
- Low number of red blood cells which can cause a feeling of tiredness and shortness of breath (anaemia).
You may require a blood transfusion.
- Low number of special white blood cells (granulocytes and leukocytes).
- Constipation.
- Vomiting (being sick).
- Diarrhoea.
- Inflammation of the mouth and lips.
- Abnormal number of white blood cells.
- Headache.
- Irregular heart beat.
- Abnormal electrocardiogram.
- Reduction of the volume of blood that the left ventrical can pump, with no symptoms.
- Abnormal results of blood tests to check liver function (raised aspartate aminotransferase levels).
Uncommon (may affect up to 1 in 100 people)
- Lung inflammation (pneumonia).
- Blood poisoning (sepsis).
- Infections caused by microorganisms which do not normally cause diseases with a healthy immune
system (opportunistic infections).
- Cancer of the white blood cells (acute myeloid leukemia (AML)).
- A bone marrow abnormality which causes the formation of abnormal blood cells which leads to
leukaemia (myelodisplastic syndrome (MDS)).
- Insufficient production of blood cells in the bone marrow (bone marrow failure).
- Reduced activity of the bone marrow. Your bone marrow can be more depressed or be depressed for a
longer period if you have had chemotherapy or radiotherapy.
- Low level of platelets – which may cause bleeding or bruising.
- Low number of special white blood cells (neutrophils).
- Severe allergic reaction (anaphylactic reaction including anyphylactic shock) – you may experience a
sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat, which may
cause difficulty in swallowing or breathing, and you may feel you are going to faint).
- Loss of appetite.
- Changes in weight.
- Anxiety.
- Confusion.
- Tingling sensation.
- Tiredness, feeling weak and having no energy.
- Severe condition where the heart cannot anymore pump enough blood (congestive heart failure).
- Damages to the heart muscle preventing it from pumping properly (cardiomyopathy).
- Slowed heart beat.
- Heart attack.
- Unusual bruising.
- Heavy bleeding.
- Low blood pressure.
- Shortness of breath.
- Abdominal pain.
- Bleeding in your stomach or bowels, this may include blood in vomit, bleeding when emptying the
bowels or black tarry stool.
- Mucosal inflammation.
- Inflammation of the pancreas.
- Liver abnormalities.
- Nail abnormalities (e.g. detachment of the nail from the nail bed, changes in nail texture and structure).
- Rash.
- Changes to the colour of the whites of the eyes.
- Skin discolouration.

-

-

Leakage of fluid into surrounding tissue (extravasation):
o Reddening (erythema).
o Swelling.
o Pain.
o Burning feeling and/or discolouration of the skin.
o Death of tissue cells which can lead to the need to remove dead cells and skin
transplantation.
Abnormal results of blood tests to check liver and kidney functions (elevated creatinine and
urea nitrogen concentration in the blood).
Damage to the kidneys, causing swelling and weakness (nephropathy).
Urine discolouration.
Swelling (oedema).
Fever.
Sudden death.

Rare (may affect up to 1 in 1,000 people)
None.
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 Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide more information on the safety of this medicine.
5.

How to store Mitoxantrone

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. The expiry date refers to the last
day of that month.
Chemical and physical stability of the diluted product has been demonstrated for 24 hours when stored at
room temperature. From a microbiological point of view, the diluted product should be used immediately.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user
and would normally not be longer than 24 hours at 2 to 8º C, unless dilution has taken place in controlled
and validated aseptic conditions.

6.






Contents of the pack and other information
The name of your medicine is Mitoxantrone 2 mg/ml concentrate for solution for infusion.
The active ingredient is mitoxantrone hydrochloride.
The other ingredients are sodium chloride, anhydrous sodium acetate, glacial acetic acid and water for
injections.
Each vial contains 2 mg/ml of mitoxantrone (as hydrochloride).
The product is available in pack sizes of 1 vial. Each vial contains 5, 10, 12.5 or 15 ml of solution.

Marketing Authorisation Holder and Manufacturer
The Marketing Authorisation holder is TEVA UK Limited, Brampton Road, Hampden Park, Eastbourne,
East Sussex, BN22 9AG, UK
The company responsible for manufacture is Pharmachemie BV, Swensweg 5-2031, GA Haarlem, The
Netherlands
This leaflet was last revised: October 2016

PRESCRIBER INFORMATION LEAFLET

1.

NAME OF THE MEDICINAL PRODUCT
Mitoxantrone 2 mg/ml concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 2 mg mitoxantrone (as hydrochloride).
Excipient(s) with known effect:
For the full list of excipients, see sectin 6.1.

3.

PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Mitoxantrone 2 mg/ml Infusion is a dark blue aqueous concentrate for solution for infusion,
packaged in type 1 glass vials.

4.

CLINICAL PARTICULARS

4.1

Therapeutic Indications
Mitoxantrone is indicated in the treatment of metastatic breast cancer.
Mitoxantrone is indicated in the treatment of non-Hodgkin’s lymphoma.
Mitoxantrone is indicated for the treatment of acute myeloid leukaemia (AML) in adults.
Mitoxantrone in combination regimens is indicated in the remission-induction treatment of blast
crisis in chronic myeloid leukaemia.
Mitoxantrone is indicated in combination with corticosteroids for palliation (e.g. pain relief)
related to advanced castrate resistant prostate cancer.
Mitoxantrone is indicated for treatment of patients with highly active relapsing multiple sclerosis
associated with rapidly evolving disability where no alternative therapeutic options exist (see
sections 4.2, 4.4 and 5.1).

4.2

Posology and Method of Administration
Posology
Mitoxantrone should be administered under the supervision of a physician experienced in the use
of cytotoxic chemotherapy agents.
Metastatic breast cancer, non-Hodgkin’s lymphoma
Single agent therapy
The recommended initial dosage of mitoxantrone used as a single agent is 14 mg/m2 of body
surface area, given as a single intravenous dose, which may be repeated at 21-day intervals. A
lower initial dosage (12 mg/m2 or less) is recommended in patients with inadequate bone marrow
reserves e.g. due to prior chemotherapy or poor general condition.
Dosage modification and the timing of subsequent dosing should be determined by clinical
judgment depending on the degree and duration of myelosuppression. For subsequent courses, the

prior dose can usually be repeated if white blood cell and platelet counts have returned to normal
levels after 21 days.
The following table is suggested as a guide to dosage adjustment, in the treatment of metastatic
breast cancer and non-Hodgkin’s lymphoma according to haematological nadir (which usually
occurs about 10 days after dosing).

WBC and platelet nadir
If WBC nadir > 1,500 μl
and platelet nadir > 50,000
μl
If WBC nadir > 1,500 μl
and platelet nadir > 50,000
μl
If WBC nadir < 1,500 μl or
platelet nadir < 50,000 μl
If WBC nadir < 1,000 μl or
platelet nadir < 25,000 μl

Time to
Recovery
Recovery<
21 days

Subsequent dosing

Recovery>21
days

Withhold until recovery then repeat
prior dose.

Any duration

Decrease by 2 mg/m2 from prior
dose after recovery.
Decrease by 4 mg/m2 from prior
dose after recovery.

Any duration

Repeat

prior dose

Combination Therapy
Mitoxantrone has been given as part of combination therapy. In metastatic breast cancer,
combinations of Mitoxantrone with other cytotoxic agents including cyclophosphamide and 5fluorouracil or methotrexate and mitomycin C have been shown to be effective.
Mitoxantrone has also been used in various combinations for non-Hodgkin's lymphoma, however
data are presently limited and specific regimens cannot be recommended.
In combination regimens mitoxantrone, in starting doses ranging from 7 to 8 to 10 to 12 mg/m2,
dependent on the combination and frequency used, has shown effectiveness.
As a guide, when Mitoxantrone is used in combination chemotherapy with another
myelosuppressive agent, the initial dose of Mitoxantrone should be reduced by 2-4mg/m2 below
the doses recommended for single agent usage; subsequent dosing, as outlined in the table above,
depends on the degree and duration of myelosuppression.
Acute myeloid Leukaemia
Single Agent Therapy in Relapse
The recommended dosage for remission induction is 12 mg/m2 of body surface area, given as a
single intravenous dose daily for five consecutive days (total of 60 mg/m2). In clinical studies with
a dosage of 12 mg/m2 daily for 5 days, patients who achieved a complete remission did so as a
result of the first induction course.
Combination Therapy
For induction, the recommended dosage is 12 mg/m2 of mitoxantrone daily on Days 1 to 3 given as
an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour
infusion on Days 1 to 7.
Most complete remissions will occur following the initial course of induction therapy. In the event
of an incomplete antileukaemic response, a second induction course may be given with
mitoxantrone given for 2 days and cytarabine for 5 days, using the same daily dosage levels. If
severe or life-threatening non-haematological toxicity is observed during the first induction course,
the second induction course should be withheld until toxicity resolves.
Consolidation therapy, which was used in two large randomised multicentre trials, consists of
mitoxantrone 12 mg/m2 given by intravenous infusion daily on Days 1 and 2, and cytarabine, 100
mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1 to 5. The first course was

given approximately 6 weeks after the final induction course; the second was generally
administered 4 weeks after the first.
A single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 intravenous
for a period of 1 hour, and cytarabine (Ara-C) 1 g/m2 intravenous for a period of 6 hours daily for
6 days (MEC) showed antileukaemic activity as salvage therapy for refractory AML.
Treatment of blast crisis in (chronic) myeloid leukaemia
Single dose therapy in relapse
The recommended dosage in relapse is 10 to 12 mg/m2 body surface area given as a single
intravenous dose daily over 5 consecutive days (total of 50 to 60 mg/m2).
Advanced castrate-resistant prostate cancer
Based on data from two comparative trials of mitoxantrone plus corticosteroids versus
corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m2 given as a short
intravenous infusion every 21 days, in combination with low oral doses of corticosteroids.
Cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with
other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart
failure. For this reason, patients should be monitored for evidence of cardiac toxicity and
questioned about symptoms of heart failure prior to the initiation of and during treatment.
Multiple Sclerosis
The treatment with mitoxantrone should be administered under the supervision of a physician
experienced in the use of cytotoxic chemotherapeutic agents for the treatment of multiple sclerosis.
This treatment should be used only after assessment of the benefit-risk, particularly concerning the
haematological and cardiac risks (see section 4.4).
The treatment must not be initiated in patients who have been previously treated with
mitoxantrone.
The recommended dosage of mitoxantrone is usually 12 mg/m2 body surface area given as a short
(approximately 5 to 15 minutes) intravenous infusion that may be repeated every 1-3 months. The
maximum lifetime cumulative dose should not exceed 72 mg/m2 (see section 5.1).
If mitoxantrone is administered repeatedly dosing adjustments should be guided by extent and
duration of bone marrow suppression.
Differential blood count within 21 days after mitoxantrone infusion
Signs and symptoms of infection and differential blood count with WHO grade 3: following dose
10 mg/m²
Signs and symptoms of infection and differential blood count with WHO grade 4: following dose
8 mg/m²
Differential blood count 7 days before mitoxantrone infusion
Signs and symptoms of infection and differential blood count with WHO grade 1: following dose
9 mg/m²
Signs and symptoms of infection and differential blood count with WHO grade 2: following dose
6 mg/m²
Signs and symptoms of infection and differential blood count with WHO grade 3 to 4:
discontinuation of therapy
In case of non-haematological toxicities WHO grade 2 to 3 the following dose should be adjusted
to 10 mg/m2, in case of non-haematological toxicity grade 4 the treatment should be discontinued
Special populations
Elderly

In general, dose selection for an elderly patient should be initiated at the low end of the dosing
range, reflecting the greater frequency of decreasing hepatic, renal, or cardiac function, and of
concomitant disease or treatment with other medicinal products.
Renal Impairment
The safety of mitoxantrone in patients with renal impairment is not established. Mitoxantrone
should be used with caution.
Hepatic Impairment
The safety of mitoxantrone in patients with hepatic insufficiency is not established. For patients
with hepatic impairment dose adjustment may be necessary as mitoxantrone clearance is reduced
by hepatic impairment. There are insufficient data that allows for dose adjustment
recommendations. Laboratory measurement cannot predict clearance of the active substance and
dose adjustments (see section 5.2).
Paediatric Population
Safety and efficacy in paediatric patients have not been established. There is no relevant use of
mitoxantrone in the paediatric population.
Method of administration
Mitoxantrone concentrate should be given by intravenous infusion only.
Mitoxantrone concentrate should be slowly injected into a free flowing intravenous infusion of
isotonic saline or 5% glucose solution over a period of not less than 3 to 5 minutes. The tubing
should be inserted preferably into a large vein. If possible, avoid veins over joints or in extremities
with compromised venous or lymphatic drainage.
Mitoxantrone concentrate also can be administered as a short infusion (15 to 30 minutes) diluted in
50 to 100 ml isotonic saline or 5% glucose solution.
Mitoxantrone concentrate must not be given subcutaneously, intramuscularly, or intra-arterially.
Severe local tissue damage may occur if there is extravasation during administration. The
medicinal product must also not be given by intrathecal injection.
If any signs or symptoms of extravasation have occurred, including burning, pain, pruritus,
erythema, swelling, blue discolouration, or ulceration, the administration should be stopped
immediately (see section 4.4).
4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, including
sulphites that may be produced during the manufacturing of mitoxantrone.
Mitoxantrone is contraindicated in women who are breast-feeding (see sections 4.4 and 4.6).
Mitoxantrone must not be used in treatment of multiple sclerosis in pregnant women (see sections
4.4 and 4.6).

4.4

Special Warnings and Precautions for use
Precautions to be taken before handling or administering the medicinal product
Mitoxantrone should be given slowly into a freely flowing intravenous infusion. Mitoxantrone
must not be given subcutaneously, intramuscularly, or intra-arterially. There have been reports of
local/regional neuropathy, some irreversible, following intra-arterial injection. Severe local tissue
damage may occur if there is extravasation during administration. To date, only isolated cases of
severe local reactions (necroses) have been described due to extravasation. Mitoxantrone must not
be given by intrathecal injection. Severe injury with permanent sequelae can result from
intrathecal administration. There have been reports of neuropathy and neurotoxicity, both central
and peripheral, following intrathecal injection. These reports have included seizures leading to
coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction.

Cardiac function
Myocardial toxicity, manifested in its most severe form by potentially irreversible and fatal
congestive heart failure (CHF), may occur either during therapy with mitoxantrone or months to
years after termination of therapy. This risk increases with cumulative dose. Cancer patients who
received cumulative doses of 140 mg/m2 either alone or in combination with other
chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In
comparative oncology trials, the overall cumulative probability rate of moderate or severe
decreases in LVEF at this dose was 13%.
Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the
mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or
concomitant use of other cardiotoxic medicinal products may increase the risk of cardiac toxicity.
Evaluation of the left-ventricular ejection fraction (LVEF) by echocardiogram or multiple-gated
acquisition (MUGA) is recommended prior to administration of the initial dose of mitoxantrone in
cancer patients. Cardiac function for cancer patients should be carefully monitored during
treatment. LVEF evaluation is recommended at regular intervals and/or if signs or symptoms of
congestive heart failure develop. Cardiotoxicity can occur at any time during mitoxantrone
therapy, and the risk increases with cumulative dose. Cardiac toxicity with mitoxantrone may
occur at lower cumulative doses whether or not cardiac risk factors are present.
Because of the possible danger of cardiac effects in patients previously treated with daunorubicin
or doxorubicin, the benefit-to-risk ratio of mitoxantrone therapy in such patients should be
determined before starting therapy.
Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for
acute myeloid leukaemia.
This also has been reported for MS patients treated with mitoxantrone. Functional cardiac changes
may occur in patients with multiple sclerosis treated with mitoxantrone. Evaluation of the leftventricular ejection fraction (LVEF) by echocardiogram or MUGA is recommended prior to
administration of the initial dose of mitoxantrone and prior to each dose in multiple sclerosis
patients and yearly for up to 5 years after the end of therapy. Cardiotoxicity can occur at any time
during mitoxantrone therapy, and the risk increases with cumulative dose. Cardiac toxicity with
mitoxantrone may occur at lower cumulative doses whether or not cardiac risk factors are present.
Ordinarily, patients with multiple sclerosis should not receive a lifetime cumulative dose greater
than 72 mg/m2. Mitoxantrone should not ordinarily be administered to multiple sclerosis patients,
with either LVEF of < 50% or a clinically-significant reduction in LVEF.
Bone marrow suppression
Therapy with mitoxantrone should be accompanied by close and frequent monitoring of
haematological and chemical laboratory parameters, as well as frequent patient observation. A
complete blood count, including platelets, should be obtained prior to administration of the initial
dose of mitoxantrone, 10 days following the administration and prior to each subsequent infusion
and in the event that signs and symptoms of infection develop. Patients should be informed about
risks, symptoms and signs of acute leukaemia and prompted to seek medical attendance if any such
symptoms should occur even after the five year period has passed.
Myelosuppression may be more severe and prolonged in patients with poor general condition, or
prior chemotherapy and/or radiotherapy.
Except for the treatment of acute myeloid leukaemia, mitoxantrone therapy generally should not
be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3. It is
recommended that frequent peripheral blood cell counts are performed on all patients receiving
mitoxantrone in order to monitor the occurrence of bone marrow suppression, primarily
neutropenia, which may be severe and result in infection.
When mitoxantrone is used in high doses (> 14 mg/m2/d x 3 days) such as indicated for the
treatment of leukaemia, severe myelosuppression will occur.

Particular care should be given to assuring full haematological recovery before undertaking
consolidation therapy (if this treatment is used) and patients should be monitored closely during
this phase. Mitoxantrone administered at any dose can cause myelosuppression.
Secondary acute myeloid leukaemia and myelodysplastic syndrome
Topoisomerase II inhibitors, including mitoxantrone, when used as monotherapy or especially
concomitantly with other antineoplastic agents and/or radiotherapy, have been associated with the
development of Acute Myeloid Leukaemia or Myelodysplastic Syndrome. Because of the risk of
development of secondary malignancies, the benefit-to-risk ratio of mitoxantrone therapy should
be determined before starting therapy.
Use after other MS-specific treatments
The safety and efficacy of mitoxantrone have not been studied after treatment with natalizumab,
fingolimod, alemtuzumab, dimethyl fumarate, or teriflunomide.
Non-metastatic breast cancer
In the absence of sufficient efficacy data in the adjuvant treatment of breast cancer and accounting
for the increased risk of leukaemia, mitoxantrone should only be used for metastatic breast cancer.
Infections
Patients who receive immunosuppressive agents like mitoxantrone have a reduced immunological
response to infection. Systemic infections should be treated concomitantly with or just prior to
commencing therapy with mitoxantrone.
Vaccination
Immunisation with live virus vaccines (e.g. yellow fever vaccination) increases the risk of
infection and other adverse reactions such as vaccinia gangrenosa and generalized vaccinia, in
patients with reduced immunocompetence, such as during treatment with mitoxantrone. Therefore,
live virus vaccines should not be administered during therapy. It is advised to use live virus
vaccines with caution after stopping chemotherapy, and vaccinate not sooner than 3 months after
the last dose of chemotherapy (see section 4.5).
Contraception in males and females
Mitoxantrone is genotoxic and is considered a potential human teratogen. Therefore men under
therapy must be advised not to father a child and to use contraceptive measures during and at least
6 months after therapy. Women of childbearing potential should have a negative pregnancy test
prior to each dose, and use effective contraception during therapy and for at least 4 months after
cessation of therapy.
Breast-feeding
Mitoxantrone has been detected in breast-milk for up to one month after the last administration.
Because of the potential for serious adverse reactions in infants from mitoxantrone, breast-feeding
is contraindicated (see section 4.3) and must be discontinued before starting treatment.
Fertility
Women of childbearing potential should be informed about increased risk of transitory or
persistent amenorrhoea (see section 4.6).
Mutagenicity and carcinogenicity
Mitoxantrone was found to be mutagenic in bacterial and mammalian test systems, as well as in
vivo in rats. The active substance was carcinogenic in experimental animals at doses below the
proposed clinical dose. Therefore, mitoxantrone has the potential to be carcinogenic in humans.
Tumour lysis syndrome
Cases of tumour lysis syndrome were reported with the use of mitoxantrone. Levels of uric acid,
electrolytes and urea should be monitored.

Discolouration of urine and other tissues
Mitoxantrone may cause a blue-green colouration to the urine for 24 hours after administration,
and patients should be advised to expect this during therapy. Bluish discolouration of the sclera,
skin and nails may also occur.
4.5

Interaction with other Medicinal Products and other Forms of Interaction

Combining mitoxantrone with potentially cardiotoxic active substances (e.g. anthracyclines)
increases the risk of cardiac toxicity.
Topoisomerase II inhibitors, including mitoxantrone, when used concomitantly with other
antineoplastic agents and/or radiotherapy, have been associated with the development of Acute
Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS) (see section 4.8).
Mitoxantrone causes myelosuppression as an extension of its pharmacological action.
Myelosuppresion can be increased when it is used in combination chemotherapy with another
myelosuppressive agent such as for treatment of breast cancer.
The combination of mitoxantrone with other immunosuppressive agents may increase the risk of
excessive immunodepression and lymphoproliferative syndrome.
Immunisation with live virus vaccines (e.g. yellow fever vaccination) increases the risk of
infection and other adverse reactions such as vaccinia gangrenosa and generalized vaccinia, in
patients with reduced immunocompetence, such as during treatment with mitoxantrone. Therefore,
live virus vaccines should not be administered during therapy. It is advised to use live virus
vaccines with caution after stopping chemotherapy, and vaccinate not sooner than 3 months after
the last dose of chemotherapy (see section 4.4).
The combination of vitamin K antagonists and cytotoxic agents may result in an increased risk of
bleeding. In patients receiving oral anticoagulant therapy, the prothrombin time ratio or INR
should be closely monitored with the addition and withdrawal of treatment with mitoxantrone and
should be reassessed more frequently during concurrent therapy. Adjustments of the anticoagulant
dose may be necessary in order to maintain the desired level of anticoagulation.
Mitoxantrone has been demonstrated to be a substrate for the BCRP transporter protein in vitro.
Inhibitors of the BCRP transporter (e.g. eltrombopag, gefitinib) could result in an increased
bioavailability. In a pharmacokinetic study in children with de novo acute myeloid leukaemia,
ciclosporin co-medication resulted in a 42% decreased clearance of mitoxantrone. Inducers of the
BCRP transporter could potentially decrease mitoxantrone exposure.
Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the
metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and
its metabolites undergo enterohepatic circulation (see section 5.2).
4.6

Fertility, pregnancy and lactation
Contraception in males and females
Mitoxantrone is genotoxic and is considered a potential human teratogen. Therefore men under
therapy must be advised not to father a child and to use contraceptive measures during and at least
6 months after therapy. Women of childbearing potential must be advised to avoid becoming
pregnant; should have a negative pregnancy test prior to each dose and use effective contraception
during therapy and for at least 4 months after cessation of therapy.
Pregnancy
There are very limited data on the use of mitoxantrone in pregnant women. Mitoxantrone was not
teratogenic in animal studies at doses below human exposure, but caused reproductive toxicity (see
section 5.3). Mitoxantrone is considered a potential human teratogen because of its mechanism of
action and the developmental effects demonstrated by related agents. For this reason, the use of

mitoxantrone to treat MS is contraindicated for pregnant women (see section 4.3). When used for
treatment in other indications mitoxantrone should not be administered during pregnancy in
particular during the first trimester of pregnancy. In each individual case the benefit of treatment
must be weighed up against the possible risk to the foetus. If this medicinal product is used during
pregnancy or if the patient becomes pregnant while using mitoxantrone, the patient should be
informed of the potential risk to the foetus and genetic counselling should be provided.
Breast-feeding
Mitoxantrone is excreted in breast-milk and has been detected in breast-milk for up to one month
after the last administration. Because of the potential for serious adverse reactions in infants from
mitoxantrone, breast-feeding is contraindicated (see section 4.3) and must be discontinued before
starting treatment.
Fertility
Women treated with Mitoxantrone have an increased risk of transitory or persistent amenorrhoea
and therefore preservation of gametes should be considered prior to therapy. In men, no data are
available, but tubular atrophy of the testes and reduced sperm counts were observed in animals
(see section 5.3).
4.7

Effects on Ability to Drive and Use Machines
Mitoxantrone has minor influence on the ability to drive and use machines. Confusion and fatigue
may occur following administration of mitoxantrone (see section 4.8).

4.8

Undesirable Effects
Summary of the safety profile
The most serious side effects with mitoxantrone are myocardial toxicity and myelosuppression.
The most common side effects with mitoxantrone (seen in more than 1 patient in 10) are anaemia,
leucopenia, neutropenia, infections, amenorrhoea, alopecia, nausea and vomiting.
Tabulated list of adverse reactions
The table below is based on safety data derived from clinical trials and spontaneous reporting in
oncological indications and from clinical trials, post authorisation safety studies and spontaneous
reporting for patients treated for multiple sclerosis. Frequencies are defined according to the
following convention: 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).

Frequency

Oncology

Multiple Sclerosis
Upper respiratory tract infection

Uncommon

Urinary tract infection

Pneumonia

Upper respiratory tract infection

Sepsis

Sepsis

Opportunistic infections

Opportunistic infections
Rare

Pneumonia

Neoplasms benign and malignant (including cysts and polyps)
Uncommon

Acute myeloid leukaemia,
myelodysplastic syndrome,
acute leukaemia

Blood and lymphatic system disorders

Acute myeloid leukaemia,
myelodysplastic syndrome,
acute leukaemia

Very common

Anaemia
Neutropenia
Leukopenia

Common

Thrombocytopenia

Anaemia

Granulocytopenia

Leukopenia
Granulocytopenia
White blood cell count
abnormal

Uncommon

Myelosuppression

Bone marrow failure

Bone marrow failure

Myelosuppression

White blood cell count
abnormal

Thrombocytopenia

Anaphylaxis/anaphylactoid
reactions (including shock)

Anaphylaxis/anaphylactoid
reactions (including shock)

Neutropenia

Immune system disorders
Uncommon

Metabolism and nutrition disorders
Common

Anorexia

Uncommon

Weight fluctuations

Anorexia

Tumour lysis syndrome*

Weight fluctuations

* Acute T and B lymphoblastic leukaemia and non-Hodgkin lymphomas (NHL) are most commonly
associated with TLS
Nervous system disorders
Common

Lethargy

Headache

Uncommon

Anxiety

Anxiety

Confusion

Confusion

Headache

Paraesthesia

Paraesthesia

Lethargy

Frequency

Oncology

Multiple Sclerosis

Scleral discolouration

Scleral discolouration

Congestive heart failure

Arrhythmia

Myocardial infarction
(including fatal events)

Electrocardiogram abnormal

Arrhythmia

Congestive heart failure

Sinus bradycardia

Cardiomyopathy

Electrocardiogram abnormal

Sinus bradycardia

Left ventricular ejection
fraction decreased

Myocardial infarction
(including fatal events)

Eye disorders
Uncommon
Cardiac disorders
Common

Uncommon

Rare

Left ventricular ejection
fraction decreased

Cardiomyopathy

Vascular disorders
Uncommon

Contusion

Contusion

Haemorrhage

Haemorrhage

Hypotension

Hypotension

Respiratory, thoracic and mediastinal disorders
Common

Dyspnoea

Uncommon

Dyspnoea

Gastrointestinal disorders
Very common

Nausea

Nausea

Vomiting
Common

Constipation

Constipation

Diarrhoea

Diarrhoea

Stomatitis

Stomatitis
Vomiting

Uncommon

Abdominal pain

Abdominal pain

Gastrointestinal haemorrhage

Gastrointestinal haemorrhage

Mucosal inflammation

Mucosal inflammation

Pancreatitis

Pancreatitis

Hepatobiliary disorders
Common
Uncommon

Elevated aspartate
aminotransferase levels
Hepatotoxicity
Elevated aspartate
aminotransferase levels

Skin and subcutaneous tissue disorders

Hepatotoxicity

Frequency

Oncology

Multiple Sclerosis

Very common

Alopecia

Alopecia

Uncommon

Erythema

Nail disorders

Nail disorders

Rash

Rash

Skin discolouration

Skin discolouration

Tissue necrosis (after
extravasation)

Tissue necrosis (after
extravasation)
Renal and urinary disorders
Uncommon

Elevated serum creatinine

Elevated serum creatinine

Elevated blood urea nitrogen
levels

Elevated blood urea nitrogen
levels

Nephropathy toxic

Nephropathy toxic

Urine discolouration

Urine discolouration

Reproductive system and breast disorders
Very common
Uncommon

Amenorrhoea*
Amenorrhoea

* Amenorrhea may be prolonged and may be consistent with premature menopause
General disorders and administration site conditions
Common

Asthenia
Fatigue
Pyrexia

Uncommon

Oedema

Asthenia

Extravasation*

Fatigue

Dysgeusia

Oedema
Pyrexia
Extravasation*
Sudden death**

* Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain,
burning and/or blue discolouration of the skin. Extravasation can result in tissue necrosis with
resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of
infusion.

** The casual relationship to mitoxantrone administration is uncertain.
Description of selected adverse reactions
Myocardial toxicity, manifested in its most severe form by potentially irreversible and fatal congestive
heart failure (CHF), may occur either during therapy with mitoxantrone or months to years after
termination of therapy. This risk increases with cumulative dose. In clinical trials cancer patients who
received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic
agents had a cumulative
2.6% probability of clinical congestive heart failure.

Myelosuppression is a dose-limiting undesirable effect of mitoxantrone. Myelosuppression can be more
pronounced and longer-lasting in patients who have previously received chemotherapy or radiotherapy.
In a clinical trial with acute leukaemia patients, significant myelosuppression occurred in all patients
who were given mitoxantrone therapy. Amongst the 80 enrolled patients the median values for the
lowest white blood cell count and platelet count were 400/μl (WHO grade 4), and 9.500/μl (WHO
grade 4), respectively. Haematological toxicity is difficult to evaluate in acute leukaemia because
traditional parameters of bone marrow depression such as white blood cell and platelet counts are
confounded by marrow replacement with leukemic cells.
Multiple sclerosis population
Haematological toxicity
A neutropenia can occur after each administration. This is in general a transient neutropenia with the
lowest count of leucocytes at day 10 after the infusion and recovered around day 20. A reversible
thrombocytopenia can also be observed. Haematological parameters should be regularly monitored (see
section 4.4).
Fatal cases of Acute Myeloid Leukaemia (AML) have been reported (see section 4.4).
Cardiac toxicity
Cases of ECG anomalies have been reported. Cases of congestive heart failure with left-ventricular
ejection fraction (LVEF) < 50 % have also been reported (see section 4.4).
Paediatric population
Treatment with mitoxantrone is not recommended in the paediatric population. Safety and efficacy
have not been established.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9

Overdose
There is no known specific antidote for mitoxantrone. Accidental overdoses have been reported. Four
patients receiving 140 to 180 mg/m2 as a single bolus injection died as a result of severe leukopenia
with infection. Haematological support and antimicrobial therapy may be required during prolonged
periods of severe myelosuppression.
Although patients with severe renal failure have not been studied, mitoxantrone is extensively tissue
bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or
haemodialysis.
Haematopoietic, gastrointestinal, hepatic or renal toxicity may be seen, depending on the dosage given
and the physical condition of the patient. In cases of overdosage patients should be monitored closely.
Treatment should be symptomatic and supportive.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic Properties
Pharmacotherapeutic group: Antineoplastic agents, Anthracyclines and related substances
ATC-Code: L01DB07
Mechanism of action

Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through
hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic
acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and
repairing damaged DNA. It has a cytocidal effect on both proliferating and non-proliferating
cultured human cells, suggesting lack of cell cycle phase specificity and activity against rapidly
proliferating and slow-growing neoplasms. Mitoxantrone blocks the cell cycle in G2-phase leading
to an increase of cellular RNA and polyploidy.
Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and
impair antigen presentation, as well as the secretion of interferon gamma, tumour necrosis factor
alpha, and interleukin-2.
Pharmacodynamic effects
Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic
agent. Its therapeutic efficacy has been reported in numerous malignancies. Its presumed mechanism
of action in MS
is immunosuppression.

Clinical efficacy and safety
Treatment with mitoxantrone 12 to 14 mg/m² was effective in the treatment of various cancers. This
dosage is given in 21 day-cycles, for induction therapy in AML during three consecutive days, for
consolidation therapy during two days. Mitoxantrone is active when given alone or in combination
with other anticancer agents or corticosteroids.
Mitoxantrone in combination with other cytostatic active substances is effective in the treatment of
metastatic breast cancer, also in patients who failed adjuvant therapy with an anthracyclinecontaining regimen.
Mitoxantrone in combination with corticosteroids improves pain control, and quality of life in
patients with advanced castrate resistant prostate cancer, without any improvement in overall
survival. Mitoxantrone in combination with cytarabine as initial induction treatment is at least as
effective for inducing remission as daunorubicin combinations in adult patients with previously
untreated AML. Mitoxantrone alone or in combination with other cytostatic medicinal products
shows objective response in patients with several types of NHL. The long-term usefulness of
mitoxantrone is limited by emerging cancer resistance which ultimately may result in fatal outcome
when used as last-line therapy.
Treatment with mitoxantrone 12 mg/m² administered every three months was superior to 5 mg/m²
and placebo in one clinical study with highly active inflammatory active MS disease. A reduction of
neurologic disability worsening and frequency of clinical relapses was observed. In the several
studies in multiple sclerosis the effective cumulative dose ranged from 36 mg/m2 to 120 mg/m2.
Single doses ranged from
5 to 12 mg/m2, dose intervals from once per month to once per 3 months. Also the time course over
which the cumulative dose was given ranged from 3 to 24 months. However, cardiotoxicity
increases with cumulative doses. A cumulative dose of 72 mg/m² is still effective and associated
with less cardiotoxicity
than higher cumulative doses. Hence, patients with multiple sclerosis should not receive a
lifetime cumulative dose greater than 72 mg/m².
Paediatric population
Safety and efficacy in paediatric patients have not been established.

5.2

Pharmacokinetic Properties
Absorption

The pharmacokinetics of mitoxantrone in patients following single-dose intravenous administration
can be characterised by a three-compartment model. In patients administered 15-90 mg/m2, there is a
linear relationship between dose and the area under the concentration curve (AUC). Plasma
accumulation of active substance was not apparent when mitoxantrone was administered either daily
for five days or as a single dose every three weeks.
Distribution
Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2. Plasma
concentrations decrease rapidly during the first two hours and slowly thereafter. Mitoxantrone is 78
% bound to plasma proteins. The fraction bound is independent of concentration and is not affected
by the presence of
phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin. Mitoxantrone
does not cross the blood-brain barrier. Distribution into testes is relatively low.
Biotransformation and elimination
The pathways leading to the metabolism of mitoxantrone have not been elucidated. Mitoxantrone is
excreted slowly in urine and faeces as either unchanged active substance or as inactive metabolites.
In human studies, only 10 % and 18 % of the dose were recovered in urine and faeces respectively as
either active substance or metabolite during the 5-day period following administration of the
medicinal product. Of the material recovered in urine, 65 % was unchanged active substance. The
remaining 35 % was composed of monocarboxylic and dicarboxylic acid derivatives and their
glucuronide conjugates.
Many of the reported half-life values for the elimination phase are between 10 and 40 hours, but
several other authors have reported much longer values of between 7 and 12 days. Differences in the
estimates may be due to the availability of data at late times after doses, weighing of the data and
assay sensitivity.
Special populations
Mitoxantrone clearance may be reduced by hepatic impairment.
There does not seem to be relevant differences in pharmacokinetics of mitoxantrone between elderly
and young adult patients. The effect of gender, race, and renal impairment on mitoxantrone
pharmacokinetics is unknown.
Mitoxantrone pharmacokinetics in the paediatric population is unknown.

5.3

Pre-clinical Safety Data
Single and repeat toxicity studies were conducted in mouse, rat, dog, rabbits, and monkey. The
haematopoietic system was the primary target organ of toxicity showing myelosuppression. Heart,
kidney, gastrointestinal tract, and testes were additional targets. Tubular atrophy of the testes and
decreased sperm counts were observed.
Mitoxantrone was mutagenic and clastogenic in all in vitro test systems and in rats in vivo.
Carcinogenic effects were seen in rat and in male mice. Treatment of pregnant rats during the
organogenesis period of gestation was associated with foetal growth retardation at doses > 0.01 times
the recommended human dose on an mg/m2 basis. When pregnant rabbits were treated during
organogenesis, an increased incidence of premature delivery was observed at doses > 0.01 times the
recommended human dose on an mg/m2 basis. No teratogenic effects were observed in these studies,
but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times
in rats and rabbits, respectively, on an mg/m2 basis). No effects were observed on pup development
or fertility in the two generation study in rats.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of Excipients

23

Sodium chloride
Anhydrous sodium acetate
Glacial acetic acid
Water for injections.
6.2

Incompatibilities
Mitoxantrone must not be mixed in the same infusion as heparin since a precipitate may form.
Because specific compatibility data are not available, it is recommended that Mitoxantrone should
not be mixed in the same infusion with other drugs.

6.3

Shelf-Life
24 months.

6.4

Special Precautions for Storage
Do not store above 25ºC. Do not freeze.
Chemical and physical stability of the diluted product has been demonstrated for 24 hours at when
stored at room temperature.
From a microbiological point of view, the diluted product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2 to 8º C unless dilution has taken place in controlled
and validated aseptic conditions.

6.5

Nature and content of container
5ml Type 1 glass vials filled to 5 ml, or 14 ml Type 1 glass vials filled to 10 or 12.5 ml, or a 20 ml
Type 1glass vial filled to 15ml. Each vial is sealed with a grey bromobutyl rubber stopper,
aluminium seal and plastic flip-off cap. The 14 ml size containers are colour coded with blue plastic
caps for the 10 ml fill and red for the 12.5 ml fill. Mitoxantrone is presented in packs of 1 vial.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements
a) Instructions for use
Mitoxantrone should be given by intravenous infusion.
For single use only. Any unused solution should be discarded.
Syringes containing this product should be labeled ‘FOR INTRAVENOUS USE ONLY’.
Care should be taken to avoid contact of Mitoxantrone with the skin, mucous membranes, or eyes.
Vials should be dispensed in the upright position in order to prevent drops of Mitoxantrone
collecting in the stopper during preparation and leading to potential aerosolisation of the solution.
Dilute the required volume of Mitoxantrone injection to at least 50 ml using a solution of Sodium
Chloride 0.9%, Glucose 5%,. 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. Administer the resulting solution over not less than 3
24

minutes via the tubing of freely running intravenous infusion of the above fluids. Mitoxantrone
should not be mixed with other drugs in the same infusion.
If extravasation occurs the administration should be stopped immediately and restarted in another
vein.
b) Handling Cytotoxic drugs
Mitoxantrone, in common with other potentially hazardous cytotoxic drugs, should only be handled
by adequately trained personnel. Pregnant staff should not be involved in the reconstitution or
administration of Mitoxantrone.
Care should be taken to avoid contact of Mitoxantrone with the skin, mucous membranes, or eyes.
The use of goggles, gloves and protective gowns is recommended during preparation, administration
and disposal and the work surface should be covered with disposable plastic-backed absorbent paper.
Aerosol generation should be minimised. Mitoxantrone can cause staining. Skin accidentally
exposed to Mitoxantrone should be rinsed copiously with warm water and if the eyes are involved
standard irrigation techniques should be used.
c) Spillage disposal
The following clean-up procedure is recommended if Mitoxantrone is spilled on equipment or
environmental surfaces. Prepare a 50% solution of fresh concentrated bleach (any recognised
proprietary brand containing either sodium or calcium hypochlorite) in water. Wet absorbent tissues
in the bleach solution and apply the wetted tissues to the spillage. The spillage is deactivated when
the blue colour has been fully discharged. Collect up the tissues with dry tissues. Appropriate
protective equipment should be worn during the clean-up procedure.
For single use only. Any unused solution should be discarded.
All Mitoxantrone contaminated items (e.g, syringes, needles, tissues, etc) should be treated as toxic
waste and disposed of accordingly. Incineration is recommended.
7.

MARKETING AUTHORISATION HOLDER
TEVA UK Limited,
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex,
BN22 9AG
United Kingdom

8.

MARKETING AUTHORISATION NUMBER
PL 00289/1370

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
06.04.2009

10.

DATE OF REVISION OF THE TEXT
14/10/2016

25

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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