Mitoxantrone Baxter

1 ml of the solution for injection contains 2.328 mg Mitoxantrone hydrochloride, equivalent to 2 mg Mitoxantrone, as medicinally active ingredient.
Excipients/Inactive Ingredients: Other constituents: Sodium chloride, sodium acetate, acetic acid, water for injection.

Cytostatic agent, Anthracenedione-derivative.

Carcinoma of the breast, malignant lymphomas, acute leukaemias, primary liver cell carcinoma, ovarian carcinoma.

Mitoxantrone should be administered only by physicians experienced with this drug.
Dosage must be individualized.
Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient's general state of health, organ function, and the results of laboratory monitoring.
Unless otherwise prescribed the following dosages are recommended: Intravenous application: Mammary carcinoma, non-Hodgkin's lymphoma, primary liver cell carcinoma, carcinoma of the ovaries: During monotherapy, a dose of 14 mg Mitoxantrone/m² body surface area is recommended as the initial dose for the first cycle. This dose can be repeated after 21 days.
In patients with diminished bone marrow reserves as a result of previous radiation and/or chemotherapy or those in a general poor state of health, the initial dose should be reduced to 12 mg/m² or corresponding to the haematological parameters.
For each repeated application of Mitoxantrone Baxter, the dose has always to be adjusted in accordance with individual patient progress, the extent and duration of myelosuppression.
The following general recommendations can be given: see Table.

Click on icon to see table/diagram/image

On combination of Mitoxantrone Baxter with other myelotoxic acting cytostatic agents, it is advisable to reduce the initial dose recommended in case of monotherapy by 2 to 4 mg Mitoxantrone/m² body surface area. In further treatment cycles, the Mitoxantrone dose should be likewise tailored to individual progress or to the duration and degree of myelosuppression.
Acute leukaemias: For the induction treatment of acute leukaemia in adults, it is recommended that a daily dose of 10 to 12 mg Mitoxantrone/m² body surface area is applied for five consecutive days (total dose 50 to 60 mg Mitoxantrone/m²). Higher remission rates can be achieved after daily dose of 12 mg/m² for five days. The higher dosage, however, should only be administered when the condition of the patient permits.
By combined use of Mitoxantrone Baxter with other cytostatic agents, dose modifications may be required depending on the condition of the patient. This must be taken into consideration either in the first induction course and/or in subsequent treatment courses.
If severe or life-threatening non-haematological side effects occur even during the first induction course, a second course of treatment should only be begun after these side effects have subsided.
Intrapleural instillation (eg to pleural metastases in cases of breast cancer and non-Hodgkin's lymphoma): A single dose of 20 to 30 mg Mitoxantrone is recommended for intrapleural instillation. Any pleural exudate should be drained off as far as possible before therapy. The retention time of this first Mitoxantrone dose in the pleural cavity is 48 hours.
The patients should be kept in a non-resting state during this period in order to achieve a good intrapleural distribution of the cytostatic agent.
After these 48 hours, further drainage of any exudate is carried out. The first treatment cycle is terminated if the volume of the drained exudate is less than 200 ml. if the volume is greater than 200 ml, a further instillation of 30 mg Mitoxantrone is given. Before this second application, the haematological parameters must be checked. The second intrapleural Mitoxantrone dose can be left in place. The maximum dose for one treatment cycle is 60 mg Mitoxantrone.
If the blood leucocyte and platelet counts show normal values after 4 weeks, the intrapleural instillation can be repeated.
Systemic therapy with cytostatic agents should be avoided for 4 weeks before and after intrapleural Mitoxantrone application.
Administration and duration of treatment: The application of Mitoxantrone Baxter should only be carried out by a physician specialising in oncology.
Intravenous application: Mitoxantrone Baxter should be administered slowly as an intravenous infusion over a period of 15-30 minutes (not less than 5 minutes).
Mitoxantrone Baxter is ideally injected slowly into a well-running intravenous infusion system. Isotonic saline or a 5% glucose solution are suitable carrier solutions.
The calculated dose should be diluted with 50 to 100 ml of one of the previously mentioned infusion solutions.
If a paravenous administration occurs, the infusion should be immediately stopped and restarted using a different venous access. Isolated cases of severe local reactions (necroses) have been reported due to inadvertent paravenous injection.
Intrapleural instillation: For intrapleural instillation, Mitoxantrone Baxter is diluted with isotonic sodium chloride solution. The Mitoxantrone containing solution must be warmed to body temperature and instilled very slowly (from 5 to 10 min), avoiding any noticeable injection pressure.
Duration of treatment: When a cumulative total dose of 200 mg Mitoxantrone/m² body surface area has been given, the administration of Mitoxantrone Baxter is to be stopped for all indications.

In case of acute or chronic overdose, the observed side effects may be increased, including renal, hepatic, and cardiac toxicities (see Adverse reactions).
If bone marrow aplasia occurs as a result of acute overdose with mitoxantrone, it may continue for up to 3 weeks.
The extent of bone marrow depression and thrombocytopenia will determine the course of treatment in acute and chronic overdose.
To counteract agranulocytosis and thrombocytopenia, granulocyte colony-stimulating factor and thrombocyte concentrates may be necessary.
There is no specific antidote for mitoxantrone overdose. Emergency procedures should include appropriate corrective and supportive measures.
Mitoxantrone is rapidly eliminated from the blood plasma and shows high tissue affinity; therefore it cannot be eliminated by dialysis.
Infection prophylaxis with antibiotics should be considered.
Every overdose requires careful monitoring to identify as early as possible, any delayed complications.

Mitoxantrone is contraindicated in patients with a known hypersensitivity to the product; for intraarterial, subcutaneous, intramuscular or intrathecal administration due to associated toxicities (see Dosage & Administration); during pregnancy and lactation (see Use in Pregnancy & Lactation).

Cardiotoxicity and Use in Patients with Cardiac Disease: Use with caution in patients with severe cardiovascular disease, as well as patients with prior treatment with anthracyclines and/or prior mediastinal radiotherapy (see Adverse Reactions).
In patients with cardiovascular risk factors or when mitoxantrone is used in combination with other cardiotoxic drugs, treatment should be carefully monitored and dose adjustment may be necessary (see Interactions).
Close monitoring of cardiac functions is advisable. More pronounced cardiotoxicity is observed after a total cumulative dose of 160 mg mitoxantrone/m² body surface area (BSA) (in at risk patients: 140 mg/m² BSA).
Secondary Acute Myelocytic Leukemia: Secondary acute myelocytic leukemia (therapy related AML or t-AML) has been reported in cancer patients treated with mitoxantrone. The risk is increased when topoisomerase II inhibitors are given in combination with other DNA-damaging antineoplastic agents and/or radiotherapy, if patients have been previously treated with high doses of cytotoxic drugs, or if doses of topoisomerase II inhibitors have been increased.
Genotoxicity and Effects on Fertility: Mitoxantrone may be genotoxic.
Women should not become pregnant during treatment with mitoxantrone and for up to 6 months after treatment (see Use in Pregnancy & Lactation).
Men who are treated with mitoxantrone should not father children during treatment and for up to 6 months after treatment with mitoxantrone.
Women and men should use effective methods of contraception during these periods of time.
Patients on mitoxantrone therapy should seek advice on the risk of irreversible infertility.

Myelosuppression or Other Severe Infections: A complete blood count must be checked before each administration of mitoxantrone, as well as at least once during each treatment cycle (see Adverse Reactions).
Mitoxantrone should be administered with caution to patients suffering from myelosuppression and/or pancytopenia or severe infections.
Renal Impairment: Use with caution in patients with severe renal impairment.
Hepatic Impairment: Use with caution in patients with severe hepatic impairment.
Liver function parameters must be checked before each administration of mitoxantrone, as well as at least once during each treatment cycle (see Adverse Reactions).
Dose reduction may be required, dependent on liver function parameters (i.e., bilirubin).
Effects on ability to drive and use machines: No information on the effects of mitoxantrone on the ability to operate an automobile or other heavy machinery.
Use in Children: There have been no studies performed by Baxter Healthcare Corporation in the pediatric population.
Use in the Elderly: In geriatric patients, monitoring for toxicities and the need for dose adjustment should reflect the higher frequency of decreased hepatic, renal, cardiac, or other organ function, and concomitant diseases or other drug therapy in this population.

Mitoxantrone must not be used during pregnancy and lactation.
There are no adequate data from the use of mitoxantrone in pregnant women.
If mitoxantrone is used during pregnancy, or if the patient becomes pregnant during treatment with mitoxantrone, medical consultation about the risk of damaging effects to the embryo associated with the treatment should occur.
The effects of mitoxantrone can damage the genotype and influence the development of the embryo (see Precautions).
It is unknown if mitoxantrone can cross the placental barrier.
Breastfeeding should be discontinued before starting treatment with mitoxantrone. Mitoxantrone passes into breast milk and may be harmful to the child.
In animal studies, mitoxantrone showed no teratogenic or embryotoxic effects, however, it is considered to be potentially teratogenous in humans, due to its mechanism of action by DNA intercalation.

Bone marrow depression can occur during Mitoxantrone treatment even in the therapeutical dose range. In such a case, a drop in the leucocyte count is observed in the first place. In patients who have previously undergone chemotherapy and/or radiation therapy as well as in patients in a generally poor state of health, marked bone marrow depression can occur. The lowest leucocyte count is generally observed between 6 and 15 days after Mitoxantrone administration. Subsequently, the bone marrow recovers and haematological parameters normalise which, as a rule, is completed by 21 days after administration. A severe thrombocytopenia and, even more rarely, a very low erythrocyte count are seldom observed.
Nausea and vomiting can occur temporarily. They are in most cases of mild to moderate severity. Loss of hair was observed in about 20% of the patients treated with Mitoxantrone, which was reversible in most cases when the treatment was discontinued.
Cardiac side effects such as transient ECG alterations, acute arrhythmia, reduced left ventricular ejection fraction as well as cases of cardiac insufficiency can occur after administration of Mitoxantrone. These cardiac phenomena are observed particularly in high risk patients (see Contraindications).
Patients with cardiac insufficiency generally respond well to supportive treatment with digitalis and/or diuretic agents.
Occasionally, a stomatitis and/or mucositis - in most cases of lower degree - can occur (in some cases more frequently and pronounced during treatment of leukaemia).
Occasionally, hypersensitivity reactions (hyperergias) are possible, which may appear as acute general allergic reactions (anaphylaxis) in exceptional cases.
Side effects such as loss of appetite, diarrhoea, abdominal pain, constipation, gastrointestinal bleeding, tiredness and debility, amenorrhoea, fever, dyspnea and nonspecific neurological disorders are occasionally observed. However, a connection between neurological disorders and the administration of Mitoxantrone could not be established so far.
Liver enzyme, serum creatinine and blood urea values may temporarily change in individual cases. Marked pathological alterations of the liver enzyme values and an impairment of liver function can occasionally occur in patients with acute leukaemia.
Mitoxantrone causes a blue-green coloration of the urine for 1 to 2 days after administration. In rare cases, reversible blue coloration of the sclera, veins and perivenous tissue as well as the nails (including onycholysis) were observed.
In case of intrapleural instillation, pain and side effects similar to those after systemic application may occur. The patient is requested to inform his doctor about all side effects not mentioned within this monograph.
Treatment in case of side effects: Bone marrow depression: Due to the severity of bone marrow depression, a consequent infection prophylaxis with antibiotics has to be initiated. To counteract agranulocytosis and thrombocytopenia, whole blood transfusions, leucocyte and thrombocyte concentrates are suitable. (Refer to Dosage & Administration for further information.)
Cardiac side effects: Patients with cardiac insufficiency generally respond well to a supportive treatment with digitalis and/or diuretic agents.
Post-marketing Adverse Reactions: Infections and Infestations: Sepsis, Infection.
Neoplasm Benign and Malignant (Including Cysts and Polyps): Acute myeloid leukemia, Myelodysplastic syndrome.
Blood and Lymphatic System Disorders: Bone marrow failure, Pancytopenia, Thrombocytopenia, Febrile neutropenia, Neutropenia, Leukopenia, Anemia.
Immune System Disorders: Hypersensitivity reactions.
Metabolism and Nutrition Disorders: Tumor lysis syndrome.
Psychiatric Disorders: Confusional state.
Cardiac Disorders: Cardiomyopathy, Cardiac failure, Left ventricular failure, Myocardial infarction, ECG alterations, Arrhythmia.
Vascular Disorders: Phlebitis.
Respiratory, Thoracic and Mediastinal Disorders: Interstitial pneumonitis, Dyspnea.
Gastrointestinal Disorders: Nausea, Vomiting, Stomatitis, Abdominal pain, Abdominal tenderness, Diarrhea.
Hepatobiliary Disorders: Hepatotoxicity.
Skin and Subcutaneous Tissue Disorder: Alopecia, Nail disorder, Onycholysis including nail discoloration.
Pregnancy, Puerperium and Perinatal Conditions: Fetal growth restriction.
Reproductive System and Breast Disorders: Amenorrhea, Oligospermia.
General Disorders and Administration Site Conditions: Injection site necrosis, Injection site discoloration, Injection site erythema, Injection site pain, Injection site warmth, Asthenia, Chest pain, Mucosal inflammation, Pain, Pyrexia.
Investigations: Ejection fraction decreased, Hepatic enzyme increased, Blood bilirubin increased.

Planned co-administration or sequential administration of other substances or treatments that could increase the likelihood or severity of toxic effects (by means of pharmacodynamics or pharmacokinetic interactions) requires careful individual assessment of the expected benefit and the risks. Patients receiving such combinations must be monitored closely for signs of toxicity to permit timely intervention.
Antineoplastic drugs: Combination therapy may result in increased myelotoxic and cardiotoxic effects.
Cytostatic drugs and/or radiation therapy: Combination therapy has been associated with t-AML and myelodysplastic syndrome (see Precautions and Adverse Reactions).
Vaccines: The immunosuppressive effects of mitoxantrone can be expected to reduce the response to vaccination. Use of live vaccines may lead to vaccine-induced infection.
Cyclosporine: Cyclosporine may reduce mitoxantrone clearance rate in patients with AML.

Incompatibilities: Mitoxantrone solution must not be mixed with other drugs in an infusion solution or in a syringe.
Heparin must not be added to Mitoxantrone solution as precipitation may occur.
Do not administer mitoxantrone through the same intravenous line as other drugs.
Special precautions for safe use/handling: When handling mitoxantrone, always wear protective gloves and safety goggles.
If contamination of the eyes, skin or mucous membrane occurs with mitoxantrone, the contact area should immediately be washed thoroughly with water.
If necessary, an ophthalmologist should be consulted. In the course of preparation, application and disposal of contaminated material as well as the decontamination of objects (e.g. sanitary facilities), protective gloves and safety goggles must always be worn. Objects, which have been in contact with Mitoxantrone containing solutions, can be cleaned with a suspension of 5.5 parts by weight of calcium hypochlorite in 13 parts of water. They should be copiously rinsed with water. Objects which were detoxificated with hypochlorite inside are to be reused as containers for Mitoxantrone solutions only after rinsing with diluted acetic acid and subsequent repeated rinsing with water.
Disposal of unused Mitoxantrone-containing solutions and empty vials: Mitoxantrone containing solutions and empty vials should be disposed separately from other drugs according to each current national legal requirement for special waste.
Mitoxantrone Baxter is available on prescription only.

Do not freeze.
Mitoxantrone Baxter, opened injection vials and the ready-to-use Mitoxantrone containing infusion solutions should not be stored above +25°C. The solutions should not be frozen.
Opening of the injection vial: The Mitoxantrone injection solution can be dispensed in portions, as required, for a maximum of 7 days when withdrawn aseptically.
Ready-to-use Mitoxantrone containing infusion solutions: The ready-to-use infusion solution should be used within 2 days. Thereafter, remaining solutions should be discarded.

Cytotoxic Chemotherapy

L01DB07 - mitoxantrone ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.

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