Onkotrone

Package leaflet: Information for the patient

ONKOTRONE 10 mg concentrate for solution for infusion, 20 mg concentrate for solution for infusion, 25 mg concentrate for solution for infusion, 30 mg concentrate for solution for infusion

Mitoxantrone dihydrochloride
Please 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 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.

Contents of this leaflet:

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

1. What Onkotrone is and what it is used for

Onkotrone contains the active substance mitoxantrone. Onkotrone belongs to a group of medicines known as antineoplastic or anticancer agents. It also belongs to the subgroup of anticancer medicines called anthracyclines. Onkotrone prevents cancer cells from growing, causing them to die.

Onkotrone is used to treat:

• advanced breast cancer (metastatic form);
• a form of lymph node cancer (non-Hodgkin's lymphoma);
• a blood cancer in which the bone marrow (the spongy tissue inside large bones) produces too many white blood cells (acute myeloid leukaemia);
• a white blood cell cancer (chronic myeloid leukaemia) during phases when white blood cell counts are difficult to control (blast crisis). Onkotrone is used in combination with other medicines for this indication;
• pain caused by advanced prostate cancer, in combination with corticosteroids;

2. What you need to know before using Onkotrone

Do not use Onkotrone
If you are allergic to mitoxantrone or to any of the other ingredients of this medicine (listed in
section 6).

• if you are allergic to sulfites;
• if you have a form of asthma (bronchial asthma) with allergy to sulfites;
• if you are breastfeeding (see section “Pregnancy and breastfeeding”)

Warnings and precautions
Onkotrone must be administered under the supervision of a physician experienced in the use of anticancer drugs that are toxic to cells (cytotoxic chemotherapeutic agents).
Onkotrone must be administered by slow, free-flowing intravenous infusion.
Onkotrone must not be administered subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur if Onkotrone leaks into surrounding tissues (extravasation) during administration.
Onkotrone must not be injected into the space beneath the brain or spinal cord (intrathecal injection), as this may cause severe, permanent neurological damage.
Inform your doctor, pharmacist, or nurse before using Onkotrone:

• if you have liver problems.
• if you have kidney problems.
• if you have previously used Onkotrone.
• if your heart is not functioning properly.
• if you have previously received radiotherapy to the chest.
• if you have previously used other medicines that affect the heart.
• if you have previously received treatment with anthracyclines or anthracenediones, such as daunorubicin or doxorubicin.
• if your bone marrow is not functioning properly (suppressed) or if your general health condition is severe.
• if you have an infection. This infection must be treated before starting Onkotrone.
• if you are due to receive a vaccine or immunization during treatment. Vaccinations and immunizations may be ineffective during treatment with Onkotrone and for 3 months after treatment ends.
• if you are pregnant or if you and your partner are planning a pregnancy.
• if you are breastfeeding. You must stop breastfeeding before taking Onkotrone.

Inform your doctor, pharmacist, or nurse immediately if any of the following signs or symptoms occur during treatment with Onkotrone:

• fever, infections, unusual bleeding or bruising, weakness, and easy fatigue;
• shortness of breath (including nocturnal dyspnea), cough, fluid retention (swelling) in the ankles or legs, palpitations (irregular heartbeat). These may occur during Onkotrone therapy or months to years after therapy. Your doctor may adjust or interrupt Onkotrone treatment, either temporarily or permanently.

Blood tests before and during treatment with Onkotrone
Onkotrone may alter your blood cell counts. Before starting Onkotrone and during treatment, your doctor will perform blood tests to monitor your blood cell counts. Blood tests will be performed more frequently to monitor particularly the number of white blood cells (neutrophils):

• if you have a low count of a certain type of white blood cells (neutrophils) (less than 1,500 cells/mm³);
• if you are receiving high doses of Onkotrone (>14 mg/m² per day for 3 days).

Heart function tests before and during treatment with Onkotrone
Onkotrone may damage the heart and worsen cardiac function or, in more severe cases, cause heart failure. You are at higher risk of these adverse effects if you receive high doses of Onkotrone, or if:

• your heart is not functioning properly;
• you have previously received radiotherapy to the chest;
• you have previously used other medicines that affect the heart;
• you have previously received treatment with anthracyclines or anthracenediones, such as daunorubicin or doxorubicin.
  Your doctor will perform cardiac function tests before starting Onkotrone therapy and at regular intervals during treatment.

Acute myeloid leukemia (AML) and myelodysplastic syndrome
A group of anticancer drugs (topoisomerase II inhibitors), including Onkotrone, may cause the following conditions, especially when used in combination with other chemotherapy and/or radiotherapy:

• cancer of the white blood cells (acute myeloid leukemia, AML);
• a bone marrow disorder causing abnormally shaped blood cells and leading to leukemia (myelodysplastic syndrome).

Change in color of urine and other tissues
Mitoxantrone may cause a blue-green discoloration of the urine for up to 24 hours after administration. Bluish discoloration of the whites of the eyes, skin, and nails may also occur.

Contraception in men and women
Men must not father a child and must use effective contraception during treatment and for at least 6 months after therapy. Women of childbearing potential must have a negative pregnancy test before each dose and must use effective contraceptive methods during treatment and for at least 4 months after stopping therapy. If this medicine is used during pregnancy, or if pregnancy occurs while taking this medicine, inform your doctor immediately, as there may be risks to the fetus.

Fertility
This medicine may increase the risk of persistent absence of menstruation (amenorrhea) in women of childbearing age.

Children and adolescents
Experience in children and adolescents is limited.
Do not administer this medicine to children and adolescents from birth to 18 years of age, as the safety and efficacy in this population have not been established.

Other medicines and Onkotrone
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. It is very important that you report any of the following medicines.
Medicines that may increase the risk of side effects with Onkotrone:

• Medicines that may damage your heart (e.g., anthracyclines);
• Medicines that suppress blood cell and platelet production by the bone marrow (myelosuppressive agents);
• Medicines that suppress your immune system (immunosuppressive agents);
• Vitamin K antagonists (anti-vitamin K);
• Topoisomerase II inhibitors (a group of anticancer drugs including mitoxantrone) when used in combination with other chemotherapy and/or radiotherapy. These combinations may cause:
  o cancer of the white blood cells (acute myeloid leukemia, AML);
  o a bone marrow disorder causing abnormally shaped blood cells and leading to leukemia (myelodysplastic syndrome).
  Ask your doctor or pharmacist if you are unsure whether a medicine is included in the list above. These medicines should be used with caution or avoided during treatment with Onkotrone. If you are taking any of these medicines, your doctor may prescribe an alternative. You must also inform your doctor if you are already taking Onkotrone and are prescribed a new medicine that you have not previously taken together with Onkotrone. Vaccinations and immunizations (protection against vaccine antigens) may be ineffective during treatment with Onkotrone and for three months after treatment ends.

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Onkotrone may harm the unborn child. Therefore, you must avoid becoming pregnant.
If you become pregnant during treatment with Onkotrone, inform your doctor immediately and discontinue Onkotrone treatment.
You must avoid becoming pregnant. Men must use an effective contraceptive method during treatment and for at least 6 months after the end of therapy. Women of childbearing potential must have a negative pregnancy test before each dose and must use effective contraceptive methods for at least 4 months after stopping Onkotrone treatment.
Breastfeeding
Onkotrone is excreted in breast milk and may cause serious adverse reactions in the breastfed infant. You must not breastfeed during treatment with mitoxantrone and for at least one month after the last dose.
Fertility
Onkotrone may increase the risk of transient or persistent absence of menstruation (amenorrhea) in women of childbearing age. Therefore, you should inform your doctor if you are planning a future pregnancy; it may be necessary to freeze your eggs. There are no available data in men. However, in male animals, testicular damage and reduced sperm count have been observed.

Driving and using machines
Onkotrone has a minor effect on the ability to drive and use machines. This is due to possible side effects such as confusion or fatigue (see section 4).
If you experience these side effects, do not drive or operate any kind of machinery.

3. How to use Onkotrone

Posology and method of administration
Onkotrone will be administered to you under the supervision of a physician experienced in the use of cytotoxic chemotherapeutic agents. It must always be given as an intravenous infusion (into a vein) and must always be diluted prior to administration. The infusion fluid may leak out of the vein and spread into surrounding tissues (extravasation). In such a case, the infusion must be stopped immediately and restarted in a different vein. Contact with Onkotrone should be avoided, particularly with skin, mucous membranes (moist body surfaces such as the inside of the mouth), and eyes. Your individual dose of Onkotrone will be calculated by your physician. The recommended dose is based on your body surface area, expressed in square meters (m²), calculated using your height and weight. Additionally, regular blood tests will be performed during treatment. The dosage of the medication will be adjusted according to the results of these tests.

The usual dose is:
Metastatic breast carcinoma, non-Hodgkin's lymphoma
When Onkotrone is used alone:
The recommended initial dose of Onkotrone is 14 mg/m² of body surface area, administered as a single intravenous dose, repeatable every 21 days if your blood values have returned to acceptable levels.
A lower initial dose (12 mg/m² or less) is recommended for patients with reduced bone marrow reserve, for example due to prior chemotherapy or compromised general condition.
Your doctor will determine the exact subsequent dose you require.
For subsequent cycles, the previous dose may usually be repeated if platelet and blood cell counts have returned to normal levels after 21 days.

Combination therapy (when used with other agents)
Onkotrone has been administered as part of combination therapy. In metastatic breast carcinoma, combinations of Onkotrone with other cytotoxic agents, including cyclophosphamide and 5-fluorouracil or methotrexate and mitomycin C, have proven effective.
Onkotrone has also been used in various combinations for non-Hodgkin's lymphoma; however, data are currently limited and specific dosage regimens cannot be recommended.
As a general guideline, when Onkotrone is used in combination chemotherapy, the initial dose of Onkotrone should be reduced by 2–4 mg/m² compared to the doses recommended for monotherapy.

Acute myeloid leukemia:
When used alone for relapses (return of cancer)
The recommended dose for induction of remission is 12 mg/m² of body surface area, administered daily as a single intravenous dose for five consecutive days (60 mg/m² total over 5 days).
When used with other anticancer agents:
Your doctor will determine the exact dose you require. The dose may be adjusted if:

• The combination of medications causes greater suppression of red and white blood cells and platelets in the bone marrow than Onkotrone alone.
• You have severe liver or kidney problems.

Treatment of blast crisis in (chronic) myeloid leukemia
Used alone for relapses
The recommended dose for relapse is 10 to 12 mg/m² of body surface area, administered daily as a single intravenous dose for five consecutive days (50 to 60 mg/m² total).

Advanced castration-resistant prostate cancer
The recommended dose of Onkotrone is 12 or 14 mg/m² administered as a short intravenous infusion every 21 days, in combination with low oral doses of corticosteroids (hormonal therapy used to suppress the immune system).

Elderly patients
Elderly patients should receive a dose at the lower end of the recommended dosage range, as they may have reduced liver, kidney, or heart function, or may have other comorbidities or be taking other medications.

If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. The most serious side effects are heart damage (myocardial toxicity) and myelosuppression (reduced bone marrow activity).
Some side effects could be serious
Contact your doctor immediately if any of the following occur:

• If your skin becomes pale and you feel weak or suddenly become short of breath, this may be a sign of reduced red blood cells.
• Unusual bruising or bleeding, for example coughing up blood, blood in vomit or urine, or black stools (possible sign of reduced platelets).
• Changes or worsening in breathing.
• Chest pain, shortness of breath, changes in heartbeat (faster or slower), fluid retention (swelling) in the ankles or legs (possible signs or symptoms of heart problems).
• Severe rash with itching (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty swallowing or breathing), feeling faint: these may be signs of a severe allergic reaction.
• Fever or infections.

Very common (may occur in more than 1 in 10 people)

• Infections
• Reduction in red blood cells, which may cause tiredness and shortness of breath (anaemia). You may need a blood transfusion.
• Reduction in certain white blood cells (neutrophils and leukocytes)
• Nausea
• Vomiting
• Hair loss

Common (may occur in up to 1 in 10 people)

• Reduction in platelet levels, which may cause bleeding or bruising.
• Reduction in certain white blood cells (granulocytes).
• Loss of appetite.
• Tiredness, weakness and lack of energy.
• Congestive heart failure (a serious condition in which the heart can no longer pump enough blood).
• Heart attack.
• Shortness of breath.
• Constipation.
• Diarrhoea.
• Inflammation of the mouth and lips.
• Fever.

Uncommon (may occur in up to 1 in 100 people)

• Reduced bone marrow activity. If you have undergone chemotherapy or radiotherapy, your bone marrow may be more severely or more prolongedly suppressed.
• Inadequate production of blood cells in the bone marrow (bone marrow failure).
• Abnormal number of white blood cells.
• Severe allergic reaction (anaphylactic reaction, including anaphylactic shock) – you may develop a sudden rash with itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth or throat, which may cause difficulty swallowing or breathing, and you may feel faint.
• Upper respiratory tract infections.
• Urinary tract infections.
• Blood poisoning (sepsis).
• Infections caused by microorganisms that normally do not cause disease in a healthy immune system (opportunistic infections).
• Cancer of the white blood cells (acute myeloid leukaemia, AML).
• Bone marrow disorder causing the formation of abnormal blood cells and leading to leukaemia (myelodysplastic syndrome, MDS).
• Changes in weight.
• Metabolic disorders (tumour lysis syndrome).
• Anxiety.
• Confusion.
• Headache.
• Tingling sensation.
• Irregular or slow heartbeat.
• Abnormalities in the electrocardiogram.
• Reduced volume of blood pumped by the left ventricle, in the absence of symptoms.
• Bruising.
• Severe bleeding.
• Low blood pressure.
• Abdominal pain.
• Bleeding in the stomach or intestine, which may cause blood in vomit, bleeding during defecation or tarry black stools.
• Inflammation of mucous membranes.
• Inflammation of the pancreas.
• Liver abnormalities.
• Skin inflammation (erythema).
• Nail abnormalities (e.g. nail detachment from the nail bed, changes in nail texture and structure).
• Rash.
• Changes in the colour of the white part of the eyes.
• Changes in skin colour.
• Leakage of fluid into surrounding tissue (extravasation):
  o Redness (erythema).
  o Swelling.
  o Pain.
  o Burning sensation and/or skin colour changes.
  o Tissue cell death, which may require removal of dead tissue and skin grafting.
• Abnormal blood test results for monitoring liver and kidney function (elevated levels of aspartate aminotransferase, elevated creatinine and blood urea nitrogen).
• Kidney damage, resulting in swelling and weakness (nephropathy).
• Changes in urine colour.
• Abnormal absence of menstruation (amenorrhoea).
• Swelling (oedema).
• Taste disturbances.

Rare (may occur in up to 1 in 1,000 people)

• Inflammation of the lung (pneumonitis).
• Damage to the heart muscle impairing its ability to pump normally (cardiomyopathy).

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the website http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
Reporting side effects may help provide more information on the safety of this medicine.

5. How to store Onkotrone

Keep this medicine out of the sight and reach of children.
Do not store above 25°C. Do not freeze.
Do not use this medicine after the expiry date stated on the label. The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Pack contents and other information

What Onkotrone contains

• The active substance is 10 mg 20 mg 25 mg 30 mg in 5 ml 10 ml 12.5 ml 15 ml

Mitoxantrone dihydrochloride mg 11,640 23,280 29,100 34,920
equivalent to Mitoxantrone mg 10 20 25 30

• The other components are sodium chloride, sodium acetate trihydrate (see section 2. Onkotrone contains sodium), acetic acid, water for injections.

Description of the appearance of Onkotrone and pack contents
Onkotrone is a dark blue liquid, supplied in glass vials sealed with a rubber stopper and metal cap.
Onkotrone is available in the following pack sizes:
1 vial containing 10 mg of Mitoxantrone in 5 ml of concentrate for infusion solution.
1 vial containing 20 mg of Mitoxantrone in 10 ml of concentrate for infusion solution.
1 vial containing 25 mg of Mitoxantrone in 12.5 ml of concentrate for infusion solution.
1 vial containing 30 mg of Mitoxantrone in 15 ml of concentrate for infusion solution.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder
Baxter S.p.A.
Piazzale dell’Industria, 20
00144 ROMA
Italy

Manufacturer
Baxter Oncology GmbH
Kantstrasse 2
D-33790 Halle/Westfalen (Germany)

Other sources of information
More detailed information on this medicinal product is available on the website of the Italian Medicines Agency (Agenzia Italiana del Farmaco).