Onkotrone Injection 2 mg/ml concentrate for solution for infusion

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effect not listed in this leaflet. See section 4.

Throughout this leaflet, Onkotrone Injection 2mg/ml concentrate for solution for infusion will be called Onkotrone.

1. What Onkotrone is and what it is used for
2. What you need to know before you use Onkotrone
3. How to use Onkotrone
4. Possible side effects
5. How to store Onkotrone
6. Content of the pack and other information

• 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”).

Onkotrone 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).

Onkotrone should be given by slow and freely flowing infusion into the vein.

Onkotrone 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 Onkotrone leaks in surrounding tissue (extravasation) during administration.

Onkotrone 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 Onkotrone:

• if you have liver problems;
• if you have kidney problems;
• if you have use Onkotrone 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 taking Onkotrone;
• if you plan a vaccination or immunisation during treatment. Vaccinations and immunisations may not work during treatment with Onkotrone 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 taking Onkotrone.

Tell your doctor or pharmacist or nurse immediately if you get any of the following signs or symptoms during treatment with Onkotrone:

• 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 Onkotrone.

Your doctor may need to adjust your treatment or stop Onkotrone temporarily or permanently.

Onkotrone may affect your blood cell counts. Before you start Onkotrone 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 Onkotrone in high doses (>14 mg/m² per day x 3 days).

Onkotrone 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 take higher doses of Onkotrone 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 Onkotrone and at regular intervals during therapy.

A group of anticancer medicines (topoisomerase II inhibitors), including Onkotrone, 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)

Onkotrone 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.

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 9 months after cessation of therapy.

If this medicine is used during pregnancy or if you become pregnant while taking this medicine, inform your doctor as there may be risks to the foetus.

This medicine might increase the risk for transitory or persistent absence of menstruation (amenorrhoea) in women of childbearing age.

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.

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 Onkotrone:

• 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 taking Onkotrone 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:
  • 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).

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 Onkotrone. If you are taking any of these, your doctor might need to prescribe an alternative medicine for you.

You should also tell your doctor if you are already taking Onkotrone and you are prescribed a new medicine that you have not already taken at the same time as Onkotrone.

Vaccinations and immunisation (protection against the vaccination substances) may not work during treatment with Onkotrone and for three months after the end of treatment.

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

Onkotrone may cause damage to your unborn child. Therefore you should avoid becoming pregnant.

If you become pregnant during the treatment with Onkotrone, you must tell your doctor immediately and stop treatment with Onkotrone.

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 9 months after stopping the treatment with Onkotrone.

Breast-feeding

Onkotrone 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

Onkotrone 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.

Onkotrone 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.

Onkotrone 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 Onkotrone, especially with the skin, mucous membranes (moist body surfaces, such as the lining of the mouth) and eyes. The individual dose of Onkotrone 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 Onkotrone is used alone:

The recommended initial dosage of Onkotrone 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)

Onkotrone has been given as part of combination therapy.

In metastatic breast cancer, combinations of Onkotrone with other cytotoxic agents including cyclophosphamide and 5-fluorouracil or methotrexate and mitomycin C have been shown to be effective.

Onkotrone 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 Onkotrone is used in combination chemotherapy, the initial dose of Onkotrone should be reduced by 2-4 mg/m² below the doses recommended when Onkotrone 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 Onkotrone 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 Onkotrone 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).

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 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.
• Unusual 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.

Other side effects may include:

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 chemotherpy 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 fro 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):
  • Reddening (erythema).
  • Swelling.
  • Pain.
  • Burning feeling and/or discolouration of the skin.
  • 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).

If you get any side effects, talk to your doctor or, 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 or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

The active substance is mitoxantrone hydrochloride. The strength of Onkotrone is 2 mg mitoxantrone/ml. Each vial contains 20 mg, 25 mg or 30 mg mitoxantrone depending on the size of the vial.

The other ingredients are sodium chloride, sodium acetate, acetic acid, sterile water (called ‘water for injections’).

Onkotrone is a dark blue solution in clear glass vials.

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Onkotrone is manufactured by: