Consumer medicine information

Mitozantrone Ebewe

Mitozantrone

BRAND INFORMATION

Brand name

Mitozantrone Ebewe

Active ingredient

Mitozantrone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mitozantrone Ebewe.

What is in this leaflet

This leaflet answers some common questions about Mitozantrone Ebewe.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking mitozantrone against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet You may need to read it again.

What Mitozantrone Ebewe is used for

Mitozantrone (My-toe-ZANtrone) belongs to the group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

It is used to treat some types of cancer, such as:

  • breast cancer, including breast cancer which has spread to other parts of the body
  • some types of leukaemia
  • non-Hodgkin's Lymphoma, a cancer of the lymph glands.

Mitozantrone is thought to work by interfering with the growth of cancer cells, which slows their growth and destroys them. The growth of normal cells in other parts of your body may also be affected.

Mitozantrone may also be used to treat other conditions as determined by your doctor.

Ask your doctor if you have any questions about why Mitozantrone Ebewe has been prescribed for you.

It is important to remember that Mitozantrone Ebewe is a PRESCRIPTION ONLY MEDICINE.

Mitozantrone Ebewe will only be given to you by specially trained personnel in a hospital environment.

Mitozantrone Injection is not recommended for use in children as there is not enough information on its effects in children.

Before you are given Mitozantrone Ebewe

When it must not be used

You must not be given Mitozantrone Injection if you have an allergy to:

  • mitozantrone
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include

  • rashes, itching and redness of the skin
  • shortness of breath, wheezing
  • swelling of the tongue, lips or face which may lead to difficulty swallowing or breathing.

You have or have had any other medical conditions, especially the following:

  • gout
  • severe liver problems
  • if you have previously been treated with mitozantrone or an anthracycline medicine and your cardiac (heart) function has not yet returned to normal
  • a reduced number of red blood cells, white blood cells, or platelets due to previous chemotherapy or radiotherapy treatment

This medicine is not recommended for intrathecal use.

If you are not sure whether any of these apply to you, check with your doctor or pharmacist.

Before you are given mitozantrone

Your doctor and nurse need to know if you have any allergies to:

  • any other medicines
  • any other substances such as foods, preservatives or dyes

Your doctor and nurse need to know about all your medical conditions, especially if you have ever had any of the following:

  • liver problems
  • any heart problems, including a heart attack
  • gout
  • a blood disorder with a reduced number of red blood cells, white blood cells or platelets

Tell your doctor or nurse if you have an infection or high temperature. Your doctor may need to treat the infection before you are given mitozantrone.

Tell your doctor or nurse if you have had medicines in the past which belong to the group called anthracyclines. Their effects on your body may add to those caused by mitozantrone so that you may not be able to be given it, or may need less. If you are unsure whether you have had anthracycline medicines before, ask your doctor

Tell your doctor or nurse if you are pregnant or intend to become pregnant. Like most medicines used to treat cancer, mitozantrone is not recommended to be used during pregnancy.

Tell your doctor or nurse if you are breast-feeding or plan to breastfeed. It is recommended that you do not breast-feed while taking mitozantrone, as it passes into breast milk and may cause serious side effects in your baby.

If you have not told your doctor or nurse about any of the above, tell them before you are given mitozantrone.

You are taking other medicines

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

Some medicines may interfere with mitozantrone and some may cause unwanted side effects if taken while you are on mitozantrone treatment.

This is especially true if you are on any other medicines with similar side effects as mitozantrone. In some cases, two different medicines may be used together by your doctor even if an interaction might occur. In these cases, your doctor may change your dose

If you are in doubt, check with your doctor.

How Mitozantrone Ebewe is given

How it is given

Mitozantrone Ebewe must only be given by a doctor or nurse.

This medicine is diluted and given as a slow injection into a vein. You may be given Mitozantrone Ebewe every 3 weeks if you are being treated for breast cancer or lymphoma, or daily for 5 days for leukaemia treatment.

How much is given

Your doctor will decide what dose, how often and how long you will receive it. This depends on your condition and other factors, such as your weight, age, blood tests, how well your liver and kidneys work and whether or not other medicines are being given at the same time.

Mitozantrone may be used in combination with other anti-cancer drugs.

If you have any concerns about the dosage you receive, ask your doctor.

In Case of Overdose

Your doctor will decide what dose of Mitozantrone Ebewe you need, and this will be administered in the clinic or hospital under close supervision from nursing and medical staff. The risk of overdose in these circumstances is low. In the event of overdose occurring, your doctor will decide on the necessary treatment.

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you may have been given too much Mitozantrone Injection. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of a mitozantrone overdose include the side effects listed below in the 'side effects' section, but are usually of a more severe nature.

While you are being given Mitozantrone Ebewe

Things you MUST do:

  • Be sure to keep all of your doctors appointments so that your progress can be checked.
  • If you become pregnant while under mitozantrone treatment, tell your doctor immediately

Things you MUST NOT do:

  • Take any additional medicines without the advice of your doctor or pharmacist.

Side Effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given Mitozantrone Ebewe.

Any medicine may cause some unwanted side effects, including mitozantrone. Sometimes they are serious, most of the time they are not. Side effects can sometimes be prevented or minimised by blood and urine tests as well as taking into account your overall physical condition.

Ask your doctor to answer any questions that you may have.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor immediately if you notice any of the following:

The following list includes serious side effects that may require medical attention. Serious side effects are less common

  • pain, redness or swelling at the site of injection or along a vein
  • diarrhoea
  • Stomach pain or dark, tarry stools or stools containing blood,
  • loss of appetite or altered taste.
  • sleepiness, confusion or anxiety
  • pins and needles
  • tiredness, headaches, dizziness or looking pale
  • gout
  • loosening or loss of fingernails
  • difficult or laboured breathing.
  • fever, fatigue and weakness.
  • rash on the skin or colour changes to the nails.
  • blue discolouration to the whites of the eyes

Tell your doctor if:

The following are the more common side effects of mitozantrone and are usually mild.

Tell your doctor if you notice any of the following and they worry you.

  • Nausea and vomiting. This medicine usually causes nausea and vomiting. If symptoms are severe or persistent you should contact your doctor or clinic.
  • Anaemia.
  • Loss of appetite.
  • Mouth ulcers, cold sores or sore red mouth
  • Temporary and total hair loss, especially of the scalp. After treatment with mitozantrone has ended, normal hair growth should return.
  • Blue discolouration of the urine. Mitozantrone may impart a blue-green colouration to the urine for approximately 24 hours after administration.

Go to hospital if:

The following list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • slow or irregular heartbeat, chest pain
  • unusual tiredness after light exercise such as walking
  • swelling of the feet or legs
  • frequent infections such as fever, severe chills or sore throat
  • bleeding or bruising more easily than normal.

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor or nurse. Some side effects may only be seen by your doctor.

Storage:

Mitoxantrone Ebewe will be stored appropriately at the pharmacy or on the ward. The injection is kept in a cool dry place where the temperature stays below 25°C.

Product Description

What it looks like

Mitozantrone Ebewe is clear blueblue solution in a glass vial.

Active Ingredients:

Each mL contains 2 mg of mitozantrone (equivalent to 2.328 mg of mitozantrone hydrochloride)

20mg/10mL:
Each 10 mL vial contains 20 mg of mitozantrone (equivalent to 23.284 mg of mitozantrone hydrochloride)

10mg/5mL:
Each 5 mL vial contains 10 mg of mitozantrone (equivalent to 11.642 mg of mitozantrone hydrochloride)

Other ingredients:

  • sodium chloride,
  • sodium sulphate,
  • hydrochloric acid,
  • acetic acid,
  • sodium acetate,
  • water for injections and
  • nitrogen

Vial stopper is not made with natural rubber latex.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

Australian Register Numbers

AUST R 132319
Mitozantrone Ebewe 10mg in 5mL glass vial (single vial).

AUST R 132327
Mitozantrone Ebewe 20mg in 10mL glass vial (single vial).

This leaflet was prepared in October 2018.

®Registered Trademark

Published by MIMS December 2018

BRAND INFORMATION

Brand name

Mitozantrone Ebewe

Active ingredient

Mitozantrone

Schedule

S4

 

1 Name of Medicine

Mitozantrone hydrochloride.

2 Qualitative and Quantitative Composition

Mitozantrone Ebewe 10 mg/5 mL contains mitozantrone hydrochloride equivalent to 10 mg mitozantrone.
Mitozantrone Ebewe 20 mg/10 mL contains mitozantrone hydrochloride equivalent to 20 mg mitozantrone.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Mitozantrone Ebewe is a sterile, clear, blue, aqueous, isotonic solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Mitozantrone Ebewe is indicated for the treatment of:
metastatic carcinoma of the breast;
non-Hodgkin's lymphoma;
adult acute non-lymphocytic leukaemia (ANLL);
chronic myelogenous leukaemia in blast crisis.

4.2 Dose and Method of Administration

Dosage.

Doses greater than 140 mg/m2 are not recommended, particularly as a single bolus injection. Such administrations have caused fatal overdose as a result of severe leucopenia and infection.
Breast cancer and lymphoma.

Single-agent therapy.

The recommended initial dosage for use as 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 dose (12 mg/m2 or less) is recommended in patients with inadequate marrow reserves due to prior therapy or poor general condition.
Dosage modification and timing of subsequent dosing should be determined by clinical judgement depending on the degree and duration of myelosuppression. If 21-day white blood cell and platelet counts have returned to adequate levels, prior doses can usually be repeated. Table 1 indicates a guide to dosing based on myelosuppression for the treatment of breast cancer and non-Hodgkin's lymphoma.

Combination therapy.

Mitozantrone has been given in various combination regimens with the following cytotoxic agents for the treatment of breast cancer and lymphomas: cyclophosphamide; fluorouracil; vincristine; vinblastine; bleomycin; methotrexate (standard dose or 200 mg/m2 with leucovorin rescue); glucocorticoids.
As a guide, the initial dose of mitozantrone when used with other myelosuppressive agents should be reduced by 2 to 4 mg/m2 below the doses recommended for single agent usage; subsequent dosing depends upon the degree and duration of myelosuppression.
Long-term survival data for non-Hodgkin's lymphoma are as yet inadequate to establish comparability between combinations containing mitozantrone and similar combinations containing doxorubicin.
Leukaemia.

Single agent dosage for patients with acute non-lymphocytic leukaemia or chronic myelogenous leukaemia in blast crisis.

Mitozantrone as 'single-agent therapy' is also indicated in the treatment of acute non-lymphocytic leukaemia. The recommended dosage for 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 five days, patients who achieved a complete remission did so as a result of the first induction course.
Reinduction upon relapse may be attempted with mitozantrone and again the recommended dosage is 12 mg/m2 daily for five days.

Combination therapy for leukaemia.

Mitozantrone, together with cytosine arabinoside, has been used successfully for the treatment of both first- and second-line patients with acute nonlymphocytic leukaemia.
For induction, the recommended dosage is 10 to 12 mg/m2 of mitozantrone for three days and 100 mg/m2 of cytosine arabinoside for seven days (the latter given as a continuous 24 hour infusion).
If a second course is indicated, then the second course is recommended with the same combination at the same daily dosage levels but with mitozantrone given for only two days and cytosine arabinoside for only five days.
If severe or life-threatening non-haematological toxicity is observed during the first induction course, the second induction course should be withheld until the toxicity clears.

Method of administration.

Mitozantrone Ebewe should be diluted to at least 50 mL with either sodium chloride for injection or 5% glucose for injection. Mitozantrone Ebewe should be introduced slowly into the tube of a freely running intravenous infusion of sodium chloride for injection or 5% glucose for injection over not less than three to five minutes. Follow administration with a flush of the appropriate diluent. If extravasation occurs, the administration should be stopped immediately and restarted in another vein.

Pharmaceutical precautions.

Care should be taken to avoid contact of mitozantrone with the skin, mucous membranes or eyes. The use of goggles, gloves and protective gowns is recommended during preparation and administration. To reduce the possibility of spillages and splashes when removing Mitozantrone Ebewe from the vial, it is recommended that a 21-gauge (or 0.8 mm internal diameter equivalent) needle be used.
Mitozantrone can cause staining.
Skin accidentally exposed to mitozantrone should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used. Equipment and spills on environmental surfaces may be cleaned up by using an aqueous solution of calcium hypochlorite (5.5 parts calcium hypochlorite in 13 parts by weight of water for each 1 part by weight of Mitozantrone Ebewe). Absorb the remaining solutions with gauze or towels and dispose of these in a safe manner. Appropriate safety equipment such as goggles and gloves should be worn while working with calcium hypochlorite solutions.
Mitozantrone Ebewe does not contain an antimicrobial preservative. Although Mitozantrone Ebewe has demonstrated significant self-preserving qualities, unused proportions of the undiluted solution should be discarded as soon as possible after opening. Following preparation of the infusion, mitozantrone solutions will maintain potency for 72 hours; however, to reduce microbiological hazards, the solution should be used as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2°C - 8°C for not more than 24 hours. Discard any unused portion within 24 hours of preparation.
Mitozantrone Ebewe is for single use in one patient only. Discard any residue.

Handling precautions.

As with all antineoplastic agents, trained personnel should prepare Mitozantrone Ebewe. This should be performed in a designated area (preferably a cytotoxic laminar flow cabinet). Protective gown, mask, gloves and appropriate eye protection should be worn while handling mitozantrone. Where solution accidentally contacts skin or mucosa, the affected area should be immediately washed thoroughly with soap and water. It is recommended that pregnant personnel not handle cytotoxic agents such as mitozantrone.
Luer-Lock fitting syringes are recommended. Large bore needles are recommended to minimise pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting needle during preparation.

Spills and disposal.

If spills occur, restrict access to the affected area. Wear two pairs of gloves (latex rubber), a respirator mask, a protective gown and safety glasses. Limit the spread of the spill by covering with a suitable material such as absorbent towel or adsorbent granules. Spills may also be treated with 5% sodium hypochlorite. Collect up absorbent/adsorbent material and other debris from spill and place in a leak-proof plastic container and label accordingly. (See Section 6.6 Special Precautions for Disposal.)

Dosage adjustment in.

Children.

Experience in paediatric patients is limited.

Intrathecal.

Safety for intrathecal use of mitozantrone has not yet been established.

4.3 Contraindications

Mitozantrone Ebewe is contraindicated in:
patients with prior hypersensitivity to mitozantrone;
patients who have received prior substantial anthracycline exposure may not be treated with mitozantrone if cardiac function is abnormal prior to the initiation of therapy (see Section 4.4 Special Warnings and Precautions for Use);
where patients have not recovered from severe myelosuppression due to previous treatment with other cytotoxic agents or radiotherapy;
in patients with severe hepatic impairment;
breast-feeding.
Not for intrathecal use.

4.4 Special Warnings and Precautions for Use

Mitozantrone Ebewe should be administered only under constant supervision by physicians experienced in therapy with cytotoxic agents and only when potential benefits of mitozantrone therapy outweigh the possible risks. Appropriate facilities should be available for adequate management of complications should they arise.
Full blood counts should be undertaken serially during a course of treatment. Dosage adjustments may be necessary based on these counts (see Section 4.2 Dose and Method of Administration).
Systemic infections should be treated concomitantly with, or just prior to, commencing therapy with mitozantrone.

Instructions to patients.

Patients should be instructed to inform their doctor of any prior abnormal heart conditions. Patients should also be advised of the signs and symptoms of myelosuppression.
Patients should be advised to expect a blue/green colouration to the urine for up to 24 hours after mitozantrone administration. Bluish discolouration of the sclera may also occur.

Administration.

Mitozantrone is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection.
Mitozantrone must not be given by intrathecal injection. 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 neurological sequelae, and paralysis with bowel and bladder dysfunction (see Section 4.3 Contraindications).

Haematological.

Since mitozantrone produces myelosuppression, it should be used with caution in patients in poor general condition or with pre-existing myelosuppression due to any cause.
There is a high incidence of bone marrow depression, primarily of leucocytes, requiring careful haematological monitoring. Following recommended doses of mitozantrone, leucopenia is usually transient, reaching its nadir at about ten days after dosing, with recovery usually occurring by the twenty-first day. White blood cell counts as low as 1.5 x 109/L may be expected following therapy, but white blood cell counts rarely fall below 1.0 x 109/L at recommended dosages. Red blood cells and platelets should also be monitored since depression of these elements may also occur. Haematological toxicity may require reduction of dose or suspension or delay of mitozantrone therapy.
Topoisomerase II inhibitors, including mitozantrone, when used alone or concomitantly with other antineoplastic agents and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia (AML), Acute Promyelocytic Leukaemia (APL) or Myelodysplastic Syndrome (MDS).
Mitozantrone has been associated with the development of secondary AML in humans (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiovascular.

Cases of functional cardiac changes, including congestive heart failure and decreases in left ventricular ejection fraction (LVEF) have been reported during mitozantrone therapy. These cardiac events have occurred most commonly in patients who have had prior treatment with anthracyclines, prior mediastinal radiotherapy or with pre-existing heart disease, indicating a possible increased risk of cardiotoxicity in such patients. It is therefore recommended that regular cardiac monitoring also be performed in these patients, taking into account the extent to which individual patients have been exposed to these cardiac risk factors. A small proportion of endomyocardial biopsy reports have demonstrated changes consistent with anthracycline toxicity in patients who had not received prior anthracyclines. Based on current experience, it is recommended that cardiac monitoring also be performed in patients without pre-existing cardiac risk factors before initiation of therapy and during therapy exceeding 140 mg/m2 of mitozantrone.
Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit to risk ratio of mitozantrone therapy in such patients should be determined before starting therapy. Acute congestive heart failure may occasionally occur in patients treated with mitozantrone for acute myeloid leukaemia.

Uricacidaemia.

Hyperuricaemia may occur as a result of rapid lysis of tumour cells by mitozantrone. Serum uric acid levels should be monitored and hypouricaemic therapy instituted prior to the initiation of anti-leukaemic therapy.

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 mitozantrone. Therefore, live virus vaccines should not be administered during therapy.

Contraception in males and females.

Mitozantrone 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.

Use in hepatic impairment.

Careful supervision is recommended when treating patients with hepatic insufficiency. Although adequate data on the use of mitozantrone in patients with hepatic dysfunction are not yet available, the pharmacokinetic profile suggests that clearance of the medicine in such patients may be reduced and dosage may need to be adjusted accordingly. (See Section 4.3 Contraindications). Mitozantrone should be used with extreme caution in jaundiced patients.

Use in renal impairment.

Patients with impaired renal failure have not been studied. However, as mitozantrone undergoes limited renal excretion and extensive tissue binding, it is unlikely that the therapeutic effect or toxicity in these patients would be replaced by peritoneal dialysis or haemodialysis.

Use in the elderly.

No data available.

Paediatric use.

Experience in paediatric patients is limited.

Effects on laboratory tests.

Animal data suggest that if used in combination with other antineoplastic agents, additive myelosuppression may be expected. This has been supported by available clinical data on combination regimens (see Section 4.2 Dose and Method of Administration, Combination therapy).

4.5 Interactions with Other Medicines and Other Forms of Interactions

It is recommended that mitozantrone not be mixed in the same infusion with other medicines, as specific compatibility data are not available.
Mitozantrone must not be mixed in the same infusion as heparin as a precipitate may form.
When used in combination regimens, the initial dose of mitozantrone should be reduced by 2 to 4 mg/m2 below the dose recommended for single agent usage (see Section 4.2 Dose and Method of Administration).
The combination of mitozantrone with other immunosuppressive agents may increase the risk of excessive immunodepression and lymphoproliferative syndrome.
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 mitozantrone 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. Mitozantrone has been demonstrated to be a substrate for the BCRP transporter protein in vitro. Inhibitors of the BCRP transporter could result in an increased bioavailability. Inducers of the BCRP transporter could potentially decrease mitozantrone exposure.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of mitozantrone on human fertility have not been established. No adequate studies have been conducted in animals to determine the effect of mitozantrone on fertility. Women treated with mitozantrone have an increased risk of transitory or persistent amenorrhoea and therefore preservation of gametes should be considered prior to therapy.
(Category D)
Category D. Medicines, which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These medicines may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Decreased foetal bodyweight noted in high-dose rats (0.2 mg/kg/day) and an increased incidence of premature delivery noted in rabbits (0.01 to 0.05 mg/kg/day) were attributed to maternal toxicity.
There is no information on the use of mitozantrone in pregnancy. Therefore, the medicine should not be used in pregnant women or those likely to become pregnant unless the expected benefits outweigh any potential risks.
Women of child bearing potential should be advised to avoid becoming pregnant during therapy and for at least six months after cessation of therapy.
 Mitozantrone is contraindicated in women who are breast-feeding. Mitozantrone is excreted in breast milk and concentrations of 18 nanogram/mL have been reported for 28 days following the last administration. Because of potential for serious adverse reactions in infants, breastfeeding should be discontinued before starting treatment with Mitozantrone Ebewe.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

When used as a single injection every three weeks in the treatment of solid tumours and lymphomas, the most commonly encountered side effects are nausea and vomiting, although in the majority of cases these are mild and transient. Alopecia may occur, but is most frequently of minimal severity and reversible on cessation of therapy.
In patients with leukaemia, the pattern of side effects is generally similar, although there is an increase in both frequency of severity, particularly of stomatitis and mucositis. Nevertheless, overall, patients with leukaemia tolerate treatment with mitozantrone well.

Common reactions.

Gastrointestinal.

Nausea, vomiting and stomatitis. In the majority of cases these are mild (WHO Grade 1) and transient.

Dermatological.

Alopecia, most frequently of minimal severity and reversible on cessation of therapy.

Haematological.

Myelosuppression, especially leucopenia, neutropenia and granulocytopenia. Thrombocytopenia, bone marrow failure, abnormal white blood cell count and anaemia are less common.

Renal.

Mitozantrone may impart a blue-green colouration to the urine for 24 hours after administration.

Less common reactions.

Gastrointestinal.

Diarrhoea, anorexia, gastrointestinal bleeding, abdominal pain, altered taste, pancreatitis.

Respiratory.

Dyspnoea, interstitial pneumonitis.

Local.

Phlebitis. Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discolouration of the skin. Tissue necrosis following extravasation has been reported rarely.

General.

Allergic reaction (hypotension, urticaria, anaphylaxis) has been reported. Fever, fatigue and weakness, and non-specific neurological side effects such as somnolence, confusion, anxiety and mild paraesthesia. Tumour lysis syndrome (characterised by hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia) has been observed rarely during single-agent chemotherapy with mitozantrone, as well as during combination chemotherapy.

Infections and infestations.

Urinary tract infections, upper respiratory tract infections, sepsis, opportunistic infections.

Dermatological.

Rash, nail pigmentation, onycholysis, tissue necrosis, erythema.

Hepatic.

Increased liver enzyme levels and elevated bilirubin levels have been reported occasionally.

Renal.

Elevated serum creatinine and blood urea nitrogen levels have been reported occasionally. Toxic nephropathy.

Ophthalmic.

Reversible blue colouration of the sclerae has been reported.

Vascular disorders.

Contusion, haemorrhage.

Severe or life-threatening reactions.

Cardiovascular.

Cardiovascular effects include decreased left ventricle ejection fraction (determined by ECHO or MUGA scan), ECG changes and acute arrhythmia. Congestive heart failure has been reported. Such cases have generally responded well to treatment with digitalis and/or diuretics.
Bradycardia, tachycardia and chest pain have been reported.
In patients with leukaemia, there is an increase in the frequency of cardiac events. The direct role of mitozantrone in these cases is difficult to assess, since some patients had received prior therapy with anthracyclines, and since their clinical course is frequently complicated by anaemia, fever, sepsis and intravenous fluid therapy.

Haematological.

Some degree of leucopenia is to be expected following recommended doses of mitozantrone in solid tumours; however, suppression of white blood cell counts below 1.0 x 109/L is infrequent. With dosing every 21 days, leucopenia is usually transient, reaching its nadir at about ten days after dosing, with recovery usually occurring by the twenty-first day. Thrombocytopenia can occur and anaemia occurs less frequently. Myelosuppression may be more severe and prolonged in patients with solid tumours, who have had extensive prior chemotherapy or radiotherapy, or in debilitated patients. Acute Promyelocytic Leukaemia (APL) has been reported.
Secondary AML/acute myelodysplastic syndrome (AMS) has been reported following chemotherapy with various DNA topoisomerase II poisons, including mitozantrone. In one study, a 5% incidence of secondary AML/AMS was reported after treatment with mitozantrone and methotrexate, mitozantrone was suspected as the causative agent. Features of the AML include a latency period of less than three years, short preleukaemic phase and non-specific cytogenic alterations.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

The symptoms of overdosage are likely to be an extension of the pharmacological actions of mitozantrone. Possible symptoms of toxicity are those listed (see Section 4.8 Adverse Effects (Undesirable Effects)). Haematopoietic, gastrointestinal, hepatic or renal toxicity may be seen depending on the dosage given and the physical condition of the patient. Toxicity may be delayed and life-threatening (e.g. myelosuppression).

Treatment.

There is no known specific antidote for mitozantrone. In cases of overdosage, the patient should be monitored closely. Haematological support and antimicrobial therapy may be required during prolonged periods of myelosuppression. Management should be symptomatic and supportive.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) and 0800 POISON or 0800 764766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Class of medicine.

Antineoplastic.

Mechanism of action.

Mitozantrone is a potent cytotoxic synthetic anthracenedione. Although its mechanism of action has not been fully determined, mitozantrone is a DNA-reactive agent. It has a cytocidal effect on proliferating and nonproliferating cultured human cells. In vitro studies suggest that mitozantrone is not cell cycle phase-specific.
In animals, the principal toxic effects of mitozantrone at doses within the human therapeutic range are reversible myelosuppression (manifested predominantly as leucopenia; erythropenia and thrombocytopenia are normally less severe) and lymphocytic depletion of the lymphoid organs. Gastrointestinal haemorrhage and congestion were noted in continuous daily dosing studies but not in the intermittent schedules to be used clinically.
In dog and monkey studies with mitozantrone, doxorubicin was studied simultaneously at equileucopenic doses as a positive control for anthracycline-induced cardiomyopathy. Dogs given mitozantrone and untreated control dogs showed slight dilatation of the sarcoplasmic reticulum which regressed over time. In monkeys, clinical signs of congestive heart failure were observed in animals given doxorubicin, but not mitozantrone. Myocyte alterations in doxorubicin-treated monkeys were characteristic of degeneration, whereas myocyte alterations in monkeys treated with mitozantrone were suggestive of cellular regeneration and repair. In rats, there was no evidence of the progressive cardiomyopathy characteristic of anthracyclines. For an analysis of cardiotoxicity in clinical studies, see Section 4.4 Special Warnings and Precautions for Use.
Toxicity studies with mitozantrone in combination with other antineoplastic agents have been carried out in dogs. These studies suggest that additive myelosuppression might be expected in combination therapy.

Clinical trials.

Efficacy.

Clinical studies of efficacy of mitozantrone as a single agent in the treatment of late stage breast cancer have demonstrated response rates ranging from 20% in previously treated patients to 40% as first-line chemotherapy. Responses have been reported in the primary site and in the following sites of metastases: lymph node, lung, liver, bone and skin.
In a multicentre study of single-agent mitozantrone in the treatment of relapsed or refractory advanced non-Hodgkin's lymphoma, a response rate of 41% was demonstrated, using a dosage schedule of 14 mg/m2 intravenously every three weeks. The optimal activity of single-agent mitozantrone in relapsed acute non-lymphocytic leukaemia (ANLL) was seen at a dose of 12 mg/m2, daily for five days. At this dose level, a response rate of 39% was observed.

5.2 Pharmacokinetic Properties

Absorption.

Plasma accumulation of medicine was not apparent on either schedule.
Mitozantrone is not absorbed significantly in animals following oral administration.

Distribution.

The medicine is rapidly and widely distributed into extravascular tissues.
In a paper by Batra et al., the protein binding of the medicine was quoted as 78% at concentrations ranging from 26 to 455 nanogram 14C-mitozantrone/mL pooled human plasma. The extent of binding was independent of concentration.
Animal pharmacokinetic studies using radio-labelled mitozantrone indicate rapid, extensive, dose-proportional distribution into most tissues.
Mitozantrone does not cross the blood brain barrier or the placental barrier. Distribution into testes is relatively low.

Metabolism.

No data available.

Excretion.

Following intravenous administration of mitozantrone in patients, a triphasic plasma clearance is observed. Elimination is slow with a terminal half-life of over 12 days (range 5 to 18). Similar estimates of the half-life were obtained from patients receiving mitozantrone on either a schedule of daily for five days or a single dose every three weeks.
Mitozantrone is excreted via the renal and hepatobiliary systems. Renal excretion is limited; only 6 to 11% of the dose is recovered in the urine within five days after administration. Of the material recovered in the urine, 65% is unchanged mitozantrone. The remaining 35% comprises primarily two inactive metabolites, the mono and dicarboxylic acid derivatives of mitozantrone and their glucuronide conjugates. One study demonstrated that in the faeces the mean percent recovery of 14C-labelled material was 18.3% (13.6 to 24.8%) of the administered dose over five days.
Biliary excretion is the major route of elimination. The urine and bile of the rat contain the same metabolites that are present in human urine.
No significant difference in the pharmacokinetics of mitozantrone was observed in patients with moderately impaired hepatic function (serum bilirubin 20-60 micromol/L) as compared with 16 patients without hepatic dysfunction. Results of pharmacokinetic studies on 4 patients with severe hepatic dysfunction (bilirubin greater than 60 micromol/L) suggest that these patients have a lower total body clearance and a larger area under the curve (AUC) than other patients at a comparable mitozantrone dose.

5.3 Preclinical Safety Data

Genotoxicity.

Mitozantrone was found to be mutagenic in bacterial and mammalian test systems, as well as in vivo in rats.

Carcinogenicity.

The active substance was carcinogenic in experimental animals at doses below the proposed clinical dose. Therefore, mitozantrone has the potential to be carcinogenic in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, acetic acid, sodium acetate, sodium sulphate and hydrochloric acid in water for injections.

6.2 Incompatibilities

Mitozantrone should not be mixed in an infusion containing other medicines.
For information on interactions with other medicines and other forms of interactions, see Section 4.5.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Mitozantrone Ebewe 10 mg/5 mL injection, solution.

Glass vial. Pack of 1 vial.

Mitozantrone Ebewe 20 mg/10 mL injection, solution.

Glass vial. Pack of 1 vial.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

Cytotoxic waste should be regarded as hazardous or toxic and clearly labelled 'Cytotoxic waste for incineration at 1100°C'. Waste material should be incinerated at 1100°C for at least 1 second. Cleanse the remaining spill area with copious amounts of water.
Items used to prepare mitozantrone, or articles associated with body waste should be disposed of by placing in a double-sealed polythene bag, and incinerating at 1100°C.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Mitozantrone hydrochloride is a hygroscopic dark blue solid, sparingly soluble in water, slightly soluble in methanol, practically insoluble in acetone, acetonitrile or chloroform.
The molecular formula of mitozantrone (as hydrochloride) is C22H30Cl2N4O6 (Molecular weight: 517.4).

Chemical structure.

Its chemical structure is:

CAS number.

70476-82-3.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes