Active ingredients: Mitoxantrone
Mitoxantrone Sandoz 2 mg / ml, concentrate for solution for infusion
Why is Mitoxantrone used - Generic drug? What is it for?
Mitoxantrone belongs to a group of drugs known as antineoplastics or anticancer drugs. It also belongs to a subgroup of drugs called anthracycline derivatives. Mitoxantrone works by interfering with the growth of cancer cells and killing them progressively and is used to treat the following diseases:
- Advanced (metastatic) breast cancer.
- Non-Hodgkin's lymphomas, i.e. tumors of the lymphatic system.
- Acute non-lymphocytic leukemia in adults. Leukemia is a type of blood cancer in which the bone marrow produces too much white blood cells.
For the treatment of the above forms of cancer, Mitoxantrone Sandoz can be used alone or together with other anticancer medicines.
- Advanced prostate cancer pain when:
- Prostate cancer has not responded adequately to hormone treatment (it is refractory to therapy).
- The pain reliever treatment used is not effective or adequate pain medications cannot be taken.
In these circumstances Mitoxantrone Sandoz is administered together with low dose cortisone drugs (e.g. prednisone)
Contraindications When Mitoxantrone should not be used - Generic drug
Do not take Mitoxantrone Sandoz:
- If you are allergic (hypersensitive) to mitoxantrone.
- If you are allergic (hypersensitive) to any of the other ingredients of Mitoxantrone Sandoz (Further information).
- If you suffer from myelosuppression (the bone marrow does not produce enough red blood cells).
- If you are breast-feeding (see section "Pregnancy and breast-feeding" for more information).
- By injection into the spinal fluid (intrathecal administration).
- By injection into the artery (intra-arterial administration).
Precautions for use What you need to know before taking Mitoxantrone - Generic drug
Take special care with Mitoxantrone Sandoz:
- If your bone marrow is not functioning properly (you are depressed) or if your general health is not good:
- Your doctor will do more frequent blood tests, especially to check the number of white blood cells (neutrophils).
- If you have already had:
- A chest radiotherapy treatment.
- A heart disease.
In these cases, the likelihood of developing more serious heart problems increases, such as:
- Heart failure or decreased heart function.
If you have such heart problems:
- You should still take the total dose of Mitoxantrone Sandoz.
- You must have regular checks to check the functioning of the heart.
- If you have contracted infections: these must be treated before or at the time of treatment with Mitoxantrone Sandoz.
- Note that Mitoxantrone Sandoz can cause abnormal staining of:
- Urine (which may take on a blue-green color for up to a day after treatment).
- Skin and nails (which can turn blue).
- Whites of the eyes (which may take on a blue color).
In all these cases the coloring is temporary and can last a few days.
Interactions Which drugs or foods can modify the effect of Mitoxantrone - Generic drug
Tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Also take special care if you are taking any of the following medicines:
- Other drugs that decrease the activity of the bone marrow (myelosuppressive drugs eg other anticancer agents) which, when taken together with Mitoxantrone Sandoz, can be more harmful to the marrow and can aggravate the damage to it caused by Mitoxantrone Sandoz.
- Other medicines potentially harmful to the heart (eg anthracycline drugs), as the negative effect produced by these medicines may increase.
- Topoisomerase II inhibitors (a group of anticancer drugs including mitoxantrone) in combination with other antineoplastic agents and / or radiotherapy. They can cause:
- A cancer of the white blood cells (acute myeloid leukemia - AML).
- A bone marrow disease that causes abnormal blood cell formation and leads to the development of leukemia (myelodysplastic syndrome - MDS).
- Vaccines. Vaccines may not work during treatment with Mitoxantrone Sandoz.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor for advice before taking any medicine.
Mitoxantrone Sandoz can cause fetal harm, so you should not take Mitoxantrone if:
- are pregnant (especially in the first trimester of pregnancy)
- think you are pregnant or trying to conceive a child.
If you become pregnant while taking Mitoxantrone Sandoz, you must inform your doctor and stop treatment immediately. She must avoid getting pregnant. If you or your partner are being treated with Mitoxantrone Sandoz, effective contraception should be used both during therapy and for at least 6 months after stopping treatment.
Mitoxantrone Sandoz must not be taken while breastfeeding. You must stop breastfeeding before starting therapy with Mitoxantrone Sandoz as mitoxantrone can be absorbed by the baby through breast milk.
Driving and using machines
Mitoxantrone Sandoz may have a mild or moderate effect on the ability to drive or use machines as a result of possible side effects of the treatment (see section 4 "Possible side effects").
Do not drive or use any tools or machines if you experience symptoms.
Important information about some of the ingredients of Mitoxantrone Sandoz
This medicinal product contains 0.148 mmol / ml sodium.
1 vial of 5 ml of solution contains 0.739 mmol of sodium.
1 vial of 10 ml of solution contains 1.478 mmol of sodium.
This should be taken into account by patients on a controlled sodium diet.
Dosage and method of use How to use Mitoxantrone - Generic drug: Posology
Mitoxantrone Sandoz will be given to you by a doctor or nurse. The drug must always be administered by intravenous infusion (into a vein) and must always be diluted before use. During the infusion the drug may escape from the vein (extravasation) and in this case the infusion must be stopped immediately and resumed in another blood vessel.
You must avoid contact of Mitoxantrone Sandoz in particular with the skin, mucous membranes and eyes. The doctor will calculate the dose of Mitoxantrone Sandoz suitable for your case which will be obtained in relation to the extension of your body surface expressed in square meters. During the therapy you will also undergo regular blood tests on the basis of which the "adjusting the dosage of the medicine.
Children and adolescents
There is limited experience with the use of Mitoxantrone Sandoz in children and adolescents.
The usual dose of Mitoxantrone Sandoz is:
Metastatic breast cancer, Non-Hodgkin's lymphomas
When mitoxantrone is used on its own (alone):
- The first dose corresponds to 14 mg per square meter of body surface, administered as a single intravenous dose. Administration can be repeated after 21 days if blood values have returned to acceptable levels.
If your bone marrow reserve is low, the first dose of treatment should be lower (i.e. 12 mg per square meter) than usual.
The doctor will then establish the exact subsequent doses to be taken which will depend on the extent and duration of the decrease (myelosuppression) in the activity of the bone marrow.
In the case of use in combination therapy (for example with other cytotoxic agents such as cyclophosphamide and 5-fluorouracil or methotrexate and mitomycin C):
- In general, you will be given between 2 and 4 mg less per square meter than when Mitoxantrone Sandoz is used alone.
Acute non-lymphocytic leukemia
When Mitoxantrone Sandoz is used on its own to treat relapse (i.e. when the cancer has come back):
- the recommended dosage is 12 mg per square meter, administered as a single daily intravenous dose, for five days (corresponding to a total dose of 60 mg / m2 over five days).
When Mitoxantrone Sandoz is used in combination with other anticancer medicines (e.g. cytarabine, etoposide):
your doctor will work out the exact dose of each medicine you will need to take. Your dosage may need to be adjusted if:
The combination of drugs causes bone marrow depression greater than that produced by therapy with Mitoxantrone Sandoz alone.
You have liver or kidney disease.
Treatment of pain from hormone-refractory prostate cancer The recommended dose is 12 mg per square meter administered as follows:
- short-term intravenous infusion
- at intervals of 21 days
- in combination with oral prednisone 10 mg (a cortisone drug that helps depress the immune system).
Your doctor will decide on any dose adjustments that will depend on the extent and duration of the decrease (myelosuppression) in bone marrow activity.
Overdose What to do if you have taken an overdose of Mitoxantrone - Generic drug
If you take more Mitoxantrone Sandoz than you should, your liver, kidneys, digestive system and its ability to produce blood cells may be damaged. In rare cases, severe leukopenia (an abnormal decrease in the number of white blood cells) has occurred. with infection leading to death Your doctor will closely monitor your health and treat any of these symptoms that may arise.
If you have any questions about the use of this medicine, ask your doctor.
Side Effects What are the side effects of Mitoxantrone - Generic drug
Like all medicines, Mitoxantrone Sandoz can cause side effects, although not everybody gets them.
Very common:
- Myelosuppression (decrease in the activity of the bone marrow) which limits the amount of Mitoxantrone Sandoz that can be administered. The bone marrow may experience major and more prolonged depression if:
- you have had chemotherapy or radiotherapy.
- Bone marrow hypoplasia (abnormal decrease in the number of blood cells in an organ or tissue).
- Transient leukopenia: low number of leukocytes (white blood cells), with the lowest value reached between 10 and 13 days after treatment. In 6% of cases, leukopenia is severe.
- Anemia (when the number of red blood cells in the body is insufficient).
- Decrease in the number of a particular species of white blood cells (granulocytopenia and neutropenia).
- Abnormal amount of white blood cells (leukocytes).
- Nausea and (mild) vomiting occur in about half of patients. Only in 1% of subjects nausea and vomiting manifest in severe form.
- Stomatitis (inflammation of the mucous membrane of the mouth).
- Diarrhea.
- Abdominal pain.
- Constipation.
- Mucositis (inflammation of the mucous membranes).
- Alteration of taste.
- Alopecia (hair loss). Hair loss occurs in about half of patients. Alopecia rarely occurs in severe form.
- Transient changes in the electrocardiogram (ECG) after long-term treatment.
- Arrhythmia (irregular heartbeat).
- Increased concentration of urea in the blood.
- Infections.
- Upper respiratory tract infections.
- Urinary tract infections.
- Blood loss (haemorrhage).
- Fever.
- Amenorrhea (absence of menstruation).
Common:
- Dizziness
- Drowsiness.
- Neuritis (inflammation of the nerves).
- Convulsions (seizures).
- Mild paraesthesia (tingling).
- Headache.
- The amount of blood that can be pumped from the left chamber of the heart is reduced, but there are no symptoms.
- Rhinitis (itchy and runny nose).
- Change in the color of the urine. This happens within 24 hours of taking Mitoxantrone Sandoz.
- Kidney disorders (nephrotoxicity).
- Increased levels of liver enzymes (in blood tests).
- Changes in blood test results (increase in serum creatinine level and serum nitrogen).
- Thrombocytopenia (low platelet count - a type of cell involved in blood clotting).
- Heart failure after long-term treatment, sinus bradycardia (reduced heart rate).
- Heart problems which can cause shortness of breath or swelling of the ankles
- Chest pain
- Gastrointestinal bleeding (in the stomach or intestines).
- Rash.
- Erythema (inflammation of the skin).
- Anorexia (loss of appetite).
- Pneumonia (inflammation of the lungs).
- Sepsis (blood poisoning).
- Hypotension (lowering of blood pressure).
- Fatigue.
- Edema (swelling).
- Hepatotoxicity (liver changes).
Uncommon:
- Dyspnea (shortness of breath).
- Blue coloring of the skin and nails.
- Reversible blue coloring of the whites of the eyes.
- Allergic reactions including rash (rash or redness), wheezing (shortness of breath) and hypotension (low blood pressure).
- Anxiety.
- Confusion.
Rare:
- Tumor lysis syndrome. This syndrome causes hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia (high uric acid, potassium and phosphate levels and low calcium levels in the blood) and has occurred when Mitoxantrone Sandoz was used in combination with other medicines. It also occurred when Mitoxantrone Sandoz was given alone.
Very rare:
- Change in body weight.
Frequency not known:
- Acute leukemia (a type of white blood cell cancer).
- Acute myeloid leukemia (AML - a type of white blood cell cancer).
- Myelodysplastic syndrome (MDS - a bone marrow disease that causes abnormal blood cell formation leading to leukemia). AML and MDS can be caused by topoisomerase II inhibitors when used concomitantly with other anticancer drugs and / or radiotherapy. Topoisomerase II inhibitors are a group of anticancer drugs including mitoxantrone.
- Conjunctivitis (inflammation of the membrane covering the eye and eyelids).
- Cardiomyopathy (weakening or alteration of the structure of the heart muscle).
- Myocardial infarction (heart attack).
- Inflammation of the pancreas (pancreatitis).
- Opportunistic infections (infections caused by microorganisms that usually do not cause disease in a healthy immune system).
- Hyperuricaemia (increased levels of uric acid in the blood).
- Extravasation (leakage of the drug from the blood vessel onto the tissue surrounding the injection site) which can cause:
- Erythema (redness).
- Swelling.
- Ache.
- Burning and / or blue discoloration of the skin.
- Tissue necrosis (cell death of a tissue) resulting in the need for debridement (process of removing dead cells) and skin grafts (skin transplant).
- Phlebitis (local inflammation of a vein).
- Hematomas.
- Weakness.
- Anaphylactic reaction including anaphylactic shock (allergic reaction causing difficulty in breathing or swelling of the face, lips or tongue).
- Nail alterations (eg detachment of the nail from its bed, change in the texture and structure of the nails).
If you have leukemia you may experience more frequent and serious side effects and in particular stomatitis (inflammation of the inside of the mouth) and mucositis (inflammation of the mucous membranes).
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor.
Expiry and Retention
Keep Mitoxantrone Sandoz out of the reach and sight of children.
Do not use Mitoxantrone Sandoz after the expiry date which is stated on the label. The expiry date refers to the last day of the month.
Do not dispose of the medicine via wastewater or household waste: this will help protect the environment.
Other Information
What Mitoxatrone Sandoz contains
The active ingredient is mitoxantrone (as hydrochloride).
Each ml of Mitoxantrone Sandoz contains 2 mg of mitoxantrone (as hydrochloride).
The other excipients are:
- sodium chloride
- sodium acetate
- glacial acetic acid
- sodium sulfate
- hydrochloric acid (for pH adjustment) - water for injections
What Mitoxantrone Sandoz 2 mg / ml, concentrate for solution for infusion looks like and contents of the pack
Mitoxantrone Sandoz 2 mg / ml concentrate for solution for infusion is a clear, blue, particle-free solution supplied in clear glass vials inside a carton.
1, 5 or 10 identical vials, containing 10 mg of mitoxantrone in 5 ml or 20 mg of mitoxantrone in 10 ml, are packaged in cardboard boxes.
Vials containing 5ml or 10ml of mitoxantrone are available.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
MITOXANTRONE EBEWE 2 MG / ML, CONCENTRATE FOR SOLUTION FOR INFUSION.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of concentrate for solution for infusion contains 2 mg of mitoxantrone (as hydrochloride).
1 vial of 5 ml of concentrate for solution for infusion contains 10 mg of mitoxantrone (as hydrochloride).
1 vial of 10 ml of concentrate for solution for infusion contains 20 mg of mitoxantrone (as hydrochloride).
This medicinal product contains 0.148 mmol / ml sodium.
1 vial of 5 ml of solution contains 0.739 mmol of sodium.
1 vial of 10 ml of solution contains 1.478 mmol of sodium.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear, blue, particle-free solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Mitoxantrone is indicated for the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and acute non-lymphocytic leukemia in adults, as monotherapy or in combination with other anticancer drugs. It is also indicated in the treatment of pain from advanced prostate cancer refractory to hormonal treatment, in combination with low doses of corticosteroids, when the analgesic treatment used is insufficient or inappropriate.
04.2 Posology and method of administration
Adults and the elderly:
Breast cancer metastatic, Non-Hodgkin's lymphoma:
Monotherapy dosage: The recommended starting dose of mitoxantrone in monotherapy is 14 mg / m2 body surface area, in a single intravenous administration which can be repeated after 21 days if the leukocyte and platelet counts have reached acceptable levels. One dose is recommended. initial lower (12 mg / m2 or less) in patients with inadequate bone marrow reserves due, for example, to previous chemotherapy treatments or poor general conditions.
Changes in posology and timing of subsequent administrations should be determined by clinical judgment based on the degree and duration of myelosuppression. Mitoxantrone should not be administered to patients with a neutrophil count 3 and / or platelet counts 3. The table below serves as a guide to dose adjustment in the treatment of advanced metastatic breast cancer and Non-Hodgkin's lymphoma depending on the of the haematological nadir (which usually occurs about 10 days after administration).
Association therapy. Mitoxantrone was given as part of a combination therapy. In metastatic breast cancer, combinations of mitoxantrone with other cytotoxic drugs including cyclophosphamide and 5-fluorouracil or methotrexate and mitomycin C have been shown to be effective. posology and administration should be referred to the literature.
In general, when mitoxantrone is used in combination chemotherapy with another drug with myelosuppressive effects, the starting dose should be reduced by 2-4 mg / m2 compared to that recommended for use alone; the next dose, as reported in the table above, depends on the degree and duration of myelosuppression.
Acute non-lymphocytic leukemia:
Dosage of monotherapy in relapse: The recommended dose to induce remission is 12 mg / m2 body surface area, in a single daily intravenous administration for 5 consecutive days (total 60 mg / m2). of 12 mg / m2 daily for 5 days, patients achieved complete remission as a result of the first induction cycle.
Pain relief from prostate cancer refractory to hormone therapy:
12 mg / m2 administered as a short duration intravenous infusion at 21-day intervals in combination with oral prednisone 10 mg.
The following table is suggested as a guide to dosage adjustment in the treatment of pain from hormone refractory prostate cancer.
Blood cell count before next administration:
Nadir blood cell count (10-14 days after administration):
Association therapy: Mitoxantrone has been used in combination regimens for the treatment of acute non-lymphocytic leukemia (LANL). Most of the clinical experience concerns the combination of mitoxantrone with cytarabine which has been successful in both the primary treatment of LANL and in the case of relapse.
For induction in previously untreated patients, an effective regimen has been the administration of mitoxantrone 10-12 mg / m2 iv for 3 days in combination with cytarabine 100 mg / m2 iv for 7 days (by continuous infusion). . When deemed appropriate by the treating physician, this regimen was followed by a second induction and consolidation courses. In clinical trials, the duration of therapy in the induction and consolidation cycles with mitoxantrone was reduced to 2 days and that with cytarabine. to 5 days. In any case, any changes to the aforementioned regimen must be carried out by the attending physician according to the characteristics of the individual patient.
The combination of mitoxantrone and etoposide has also been shown to be effective in patients with relapse or in those refractory to primary conventional chemotherapy.The use of mitoxantrone in combination with both etoposide and other cytotoxic agents may result in more marked myelosuppression than that of mitoxantrone alone.
Dosage adjustments, if appropriate, should be made by the treating physician taking into account individual patient toxicity, response and characteristics.
Dose adjustment may be required in patients with abnormal liver function tests. Caution should also be exercised in the treatment of patients with liver disease.
The same caution should also be used in renal patients (see Section 5.2 Pharmacokinetic properties).
For information on specific dosing regimens, reference should be made to literature data.
Children and adolescents:
As there is limited experience with the use of mitoxantrone in pediatric leukemia, no recommendations regarding posology can be made at this time in this patient population.
Method of administration:
For intravenous use only.
The product must be diluted before use (see Section 6.6 Instructions for use, handling and disposal).
Care should be taken to prevent mitoxantrone from coming into contact with the skin, mucous membranes or eyes.
In the event of extravasation, administration should be stopped immediately and resumed in another vein. The non-blistering properties of mitoxantrone, however, minimize the risk of serious local reactions following extravasation (see section 6.2. Incompatibility 6.6 Special precautions for conservation).
04.3 Contraindications
Use in patients with severe bone marrow depression.
Hypersensitivity to mitoxantrone or to any of the excipients.
Breastfeeding (for what concerns pregnancy see Section 4.6
Pregnancy and breastfeeding).
Not for intrathecal use.
Not for intra-arterial use.
04.4 Special warnings and appropriate precautions for use
Mitoxantrone is an active cytotoxic drug that must be used under the supervision of an oncology specialist who has adequate equipment for clinical and laboratory monitoring during and after treatment. Like other cytotoxic agents, mitoxantrone should be handled with caution.
Regular monitoring of clinical haematological and biochemical parameters should be practiced during treatment and complete serial blood counts should be performed. Based on the results of these tests, dosage adjustments may be necessary (see section 4.2 Posology and method of administration).
Mitoxantrone should be used with caution in myelosuppressed patients or in poor general conditions. It is advisable to perform the blood count more frequently, paying particular attention to the number of neutrophils. In subjects previously treated with extensive chemotherapy or radiotherapy or in those who are debilitated, myelosuppression may be more severe and prolonged.
Cases of cardiac functional changes, including congestive heart failure and decreased left ventricular ejection fraction, have been reported, most of which involve patients previously treated with anthracycline derivatives or with mediastinal / thoracic radiotherapy or with pre-existing heart disease. It is therefore recommended that patients belonging to these categories be treated with mitoxantrone at regimen and full cytotoxic dosage even if it is emphasized the need to pay even greater attention to these subjects from the beginning of treatment and to perform accurate and regular cardiac function tests. Particular attention should then be paid to patients treated with the maximum cumulative dose of anthracyclines (eg doxorubicin and daunorubicin).
Since the experience with long-term treatment with mitoxantrone is currently limited, it is advisable to perform cardiac function tests even in patients who do not have identifiable risk factors when a cumulative dose of the drug has been reached during the course of therapy. higher than 160 mg / m2.
Careful supervision is advised in the treatment of patients with severe hepatic insufficiency, edema, ascites or pleural effusion.
Caution should be observed in patients with hepatic impairment (refer to section 4.2, Posology and method of administration and 5.2 Pharmacokinetic properties).
Sodium content per injection:
10 mg / 5 ml: 0.739 mmol of sodium.
20 mg / 10 ml: 1.478 mmol of sodium.
This content must be taken into account in patients on a controlled sodium diet.
The patient should also be advised that mitoxantrone can cause urine to be blue-green for up to 24 hours after administration.
Occasionally, a blue discoloration of the skin and nails and in very rare cases a blue discoloration of the sclerae, however reversible, has been reported.
Hyperuricaemia may occur in the treatment of leukemia as a result of the rapid lysis of tumor cells caused by mitoxantrone. Therefore, monitor serum uric acid levels and initiate uricemic treatment before starting leukemic therapy. Systemic infections should be treated at the same time as mitoxantrone therapy or immediately prior to its initiation.
There are no data regarding the administration of mitoxantrone by other than the intravenous route and the safety of the intrathecal administration has not been established.
L" immunization may be ineffective when performed during mitoxantrone therapy. Avoid immunization with live vaccines.
Patients of childbearing potential and their partners should be advised of the need to avoid pregnancy and to use adequate contraceptive methods throughout therapy and for at least 6 months after its termination (see section 4.6 Pregnancy and lactation).
04.5 Interactions with other medicinal products and other forms of interaction
The association with other drugs having myelosuppressive activity may increase the myelotoxicity of mitoxantrone and / or that of the compounds administered simultaneously.
The combination of mitoxantrone and potentially cardiotoxic drugs (e.g. other anthracyclines) increases cardiotoxicity.
Topoisomerase II inhibitors, including mitoxantrone, in combination with other antineoplastic drugs and / or radiotherapy, have been associated with the development of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (see also section 4.8 Undesirable effects ).
When performed during mitoxantrone therapy immunization it can be ineffective.
04.6 Pregnancy and breastfeeding
There are no adequate and well-controlled studies in pregnant women.
Preclinical studies have demonstrated reproductive toxicity, mutagenicity and carcinogenicity (see section 5.3 Preclinical safety data) indicative of a potential risk for humans. Regarding teratogenicity, animal studies have not produced sufficient results and the potential risk for the man is not known to date. Mitoxantrone should not be given to pregnant women especially during the first trimester of pregnancy. If the drug is administered during pregnancy or if the patient becomes pregnant during therapy, the patient should be informed of the potential dangers to the fetus. Women of childbearing potential and their partners should be advised of the need to avoid pregnancy and to use adequate contraceptive methods during therapy and for at least 6 months after it has ended.
Mitoxantrone is excreted in human breast milk and significant concentrations of the drug (18 ng / ml) have been observed for up to 28 days after the last administration. Due to the potential for serious adverse reactions in infants, the drug should not be used during pregnancy. lactation (see section 4.3 Contraindications) which must be discontinued before starting therapy.
Breastfeeding is therefore contraindicated (see section 4.3)
04.7 Effects on ability to drive and use machines
Due to possible side events, mitoxantrone may have a slight or moderate influence on the ability to drive or use machines.
04.8 Undesirable effects
The frequency of adverse events is determined using the following conventional definitions:
very common (≥1 / 10), common (≥1 / 100a
More than 10% of patients can experience side effects.
Myelosuppression represents dose-limiting toxicity due to mitoxantrone.
Myelosuppression may be more severe and prolonged in patients previously treated with chemotherapy or radiotherapy.
Diagnostic tests:
Very rare: weight change
Cardiac disorders:
Very common: transient changes in the electrocardiogram (ECG) after long-term treatment. Arrhythmia.
Common: reduction asymptomatic left ventricular ejection fraction (2.6% with a cumulative dose of 140 mg / m2), congestive heart failure after long-term treatment (2.6% with a cumulative dose of 140 mg / m2). Sinus bradycardia.
Cardiac function should be monitored in patients who have received cumulative doses of mitoxantrone> 160 mg / m2.
Patients previously treated with anthracyclines or other cardiotoxic oncolytic drugs and / or mediastinal radiotherapy and who also have underlying cardiovascular disease are at increased risk of developing heart disease.
Post-marketing reports have highlighted the cardiotoxicity of mitoxantrone treatment at cumulative doses below 100 mg / m2.
Frequency not known: Cases of cardiomyopathy and myocardial infarction have been reported.
Disorders of the blood and lymphatic system:
Very common: myelosuppression and bone marrow hypoplasia.
Transient leukopenia with nadir 10-13 days after treatment (severe leukopenia in 6% of cases), thrombocytopenia (severe in 1% of cases), anemia, granulocytopenia, neutropenia, altered white blood cell count.
Nervous system disorders:
Common: non-specific undesirable neurological effects such as dizziness, somnolence, neuritis, convulsions, mild paraesthesia. Headache.
Eye disorders:
UncommonReversible blue discoloration of the sclera has been reported.
Frequency not known: conjunctivitis.
Respiratory, thoracic and mediastinal disorders:
Common: rhinitis.
Uncommon: dyspnea.
Gastrointestinal disorders:
Very common: mild nausea and vomiting in about 50% of patients (severe in 1% of cases), stomatitis, diarrhea, abdominal pain, constipation, mucositis, altered taste.
Common: gastrointestinal bleeding.
Frequency not known: pancreatitis
Renal and urinary disorders:
Very common: increased concentration of urea in the blood.
Common: discoloration of the urine within 24 hours of administration.
Nephrotoxicity, increase in serum creatinine and increase in plasma nitrogen content.
Skin and subcutaneous tissue disorders:
Very common: Grade I-II alopecia in about 50% of patients (severe alopecia is rare).
Common: redness, erythema.
Uncommon: blue coloring of the skin and nails
Frequency not known:
Nail changes (eg onycholysis, nail dystrophy), infusion site extravasation which may result in erythema, edema, pain, burning and / or blue skin discoloration have been reported. Extravasation may induce tissue necrosis with a consequent need for debridement and skin grafts.
Metabolism and nutrition disorders:
Common: anorexia (loss of appetite)
Frequency not known: hyperuricemia
Infections and infestations:
Very common: infections, upper respiratory tract infections, urinary tract infections.
Common: pneumonia, sepsis, rhinitis.
Frequency not known: opportunistic infections.
Injuries, poisoning and procedural complications.
Frequency not known: hematomas.
Tumors benign, malignant and non-specific not specified (including cysts and polyps):
Frequency not known: acute leukemia.
Topoisomerase II inhibitors, including mitoxantrone, in combination with other antineoplastic agents and / or radiotherapy have been associated with the development of
acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (see also Section 4.5 Interaction with other medicinal products and other forms of interaction).
Vascular disorders:
Very common: bleeding.
Common: hypotension.
General disorders and administration site conditions:
Very common: fever.
Common: fatigue, edema.
Uncommon: allergic reactions (i.e. rash, dyspnoea, hypotension).
Frequency not known: The occurrence of phlebitis at the injection site has been reported. Weakness.
Immune system disorders:
Frequency not known: anaphylactic reactions (including anaphylactic shock).
Hepatobiliary disorders:
Common: hepatotoxicity, increased liver enzymes (ALAT).
Reproductive system and breast disorders:
Very common: amenorrhea (can be prolonged and correspond to premature menopause).
Psychiatric disorders:
Uncommon: anxiety, confusion.
Rare cases of tumor lysis syndrome (characterized by hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia) have been observed both in association with combination chemotherapy and mitoxantrone monochemotherapy.
In leukemic patients, the picture of undesirable effects is generally similar, although there is an increase in both frequency and severity, especially of stomatitis and mucositis.
Among patients with disseminated sclerosis treated with mitoxantrone there have been two sudden deaths for which it is not known whether there is a causal relationship with the use of mitoxantrone.
04.9 Overdose
In relation to the dose administered and the physical condition of the patient, toxicity to the haematopoietic, gastrointestinal, hepatic or renal system may occur.
In rare cases, fatal events have occurred as a result of severe leukopenia with infection in patients who were accidentally given a single "bolus injection of mitoxantrone at doses more than ten times the recommended dose."
There is no known specific antidote for mitoxantrone.
In case of overdose, the patient should be monitored closely with supportive and symptomatic therapy.
Since sterile mitoxantrone concentrate is largely tissue bound, peritoneal dialysis or hemodialysis is unlikely to be effective in the treatment of overdose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anthracyclines and related substances.
ATC code: L 01 DB 07
Mitoxantrone is an anthracenedionic derivative that binds to nucleus DNA, the exact mechanism of action of which has not been fully understood. The drug has a cytotoxic effect on proliferating and non-proliferating human cells in culture indicating that the substance is not cell cycle-specific.
Mitoxantrone can be administered in combination with several other cytostatic agents and with glucocorticoids. An increased effect on bone marrow function and gastrointestinal mucosa has been observed, although reversible in nature, which can be avoided by appropriate dosage adjustment. No serious or unexpected adverse reactions have been observed with other concomitantly administered drugs.
05.2 Pharmacokinetic properties
In patients receiving intravenous mitoxantrone, pharmacokinetic studies have shown a triphasic plasma clearance.
Distribution to tissues is rapid and extensive.
Protein binding: Mitoxantrone has a degree of protein binding of approximately 78%.
It is excreted through the kidneys and the hepatobiliary system. Only 20-320% of the dose was excreted within the first 5 days after administration (6-11% in urine, 13-25% in faeces). Of the material recovered in the urine, 65% consisted of unchanged mitoxantrone and the remaining 35% consisted essentially of two inactive metabolites and their glucuronide conjugates. About two thirds were excreted in the first 24 hours.
Elimination of the drug is slow, with a half-life of 12 days (range 5-18) and persistent tissue concentrations. Both in patients receiving a single dose of mitoxantrone every 21 days and in patients treated for 5 consecutive days every 21 days, the half-life values of the drug were similar.
05.3 Preclinical safety data
Reproductive toxicology: Intravenous administration of mitoxantrone to pregnant rats in doses equal to 0.05 times that used in humans (in mg / m2) resulted in low birth weight in rats and delayed kidney development. In rabbits, mitoxantrone gave rise to premature births when administered at doses equal to 0.01 times those used in man. Mitoxantrone showed no adverse reactions on the fertility of male or female rats.
Mutagenicity: Mitoxantrone has been shown to be mutagenic on both bacterial and mammalian systems in vitro. In vitro in rat hepatocytes and Chinese hamster ovary cells and in vivo in rat bone marrow, mitoxantrone produced clastogenic effects.
Carcinogenicity: Mitoxantrone administered intravenously to rats and mice at 21-day intervals caused a "higher incidence of fibroids and tumors of the external ear canal in rats and of hepatocellular adenoma in male mice at doses of 0.02 and 0.03 times the dose used in humans (in mg / m2).
Animal data, the conclusion, are currently too limited to justify conclusions regarding teratogenicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium chloride
Sodium acetate
Glacial acetic acid
Sodium sulfate
Water for injections
06.2 Incompatibility
Mitoxantrone should not be mixed with heparin in the same infusion as it can result in the formation of a precipitate. Mitoxantrone must not be mixed in the same infusion with another medicinal product.
06.3 Period of validity
Medicinal product as packaged for sale: 2 years (before reconstitution).
Diluted solutions: 24 hours at 2-8 ° C.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature. From a microbiological point of view, the> diluted product it must be used immediately. If not used right away, in-use storage times and conditions prior to use are the responsibility of the user and normally do not exceed 24 hours at a temperature between 2 and 8 ° C, unless dilution has taken place under controlled and validated aseptic conditions. See section 6.6 Instructions for use, handling and disposal.
Do not refrigerate or freeze.
06.5 Nature of the immediate packaging and contents of the package
Clear glass vials (Type I) with a gray Teflon-coated rubber stopper and aluminum cap.
5 ml vial: 10 mg of mitoxantrone
10 ml vial: 20 mg of mitoxantrone
1.5 or 10 vials packed in cardboard boxes
06.6 Instructions for use and handling
Mitoxantrone "Ebewe" must be diluted in at least 50 ml of one of the following solutions for intravenous infusion: 0.9% sodium chloride solution, 5% glucose solution. Administer the solution thus obtained in not less than 3 minutes through the free-flow infusion sets by intravenous infusion of the above solutions. Mitoxantrone must not be mixed in the same infusion with another medicinal product.
Take care to avoid contact of mitoxatrone with skin, mucous membranes or eyes. The vials should be kept upright to prevent drops of the drug from remaining in the stopper during preparation resulting in potential aerosolization of the solution.
As with other cytotoxic drugs, caution should be exercised in handling the mitoxantrone (wear gloves, mask, gown).
Avoid contact with skin and mucous membranes.
If mitoxantrone comes into contact with the skin, wash with water.
Pregnant female staff should not work in contact with this drug.
Disposing of the spilled medicine:
In case of spillage of mitoxantrone on machinery or surfaces of the environment, it is recommended to apply the following cleaning procedure: prepare a 50% solution of concentrated fresh bleach (containing about 10-13% of chlorine) (all known brands contain sodium or calcium hypochlorite) in water. Dampen absorbent cloths in the bleach solution and apply them to the spilled liquid. The loss will be rendered harmless when the blue color has completely disappeared. Then collect the wet cloths with dry tissues, wash the surface with water and absorb the water with dry cloths. Protective equipment must be worn throughout the procedure. All objects contaminated with mitoxantrone (eg syringes, needles, cloths, etc.) must be treated as toxic waste and disposed of in accordance with the relevant legal provisions. It is recommended that contaminated materials be incinerated.
Adhere to guidelines on handling cytotoxic drugs.
07.0 MARKETING AUTHORIZATION HOLDER
Ebewe Italia Srl,
Via Viggiano 90,
00178 Rome.
08.0 MARKETING AUTHORIZATION NUMBER
1 vial of 5 ml: AIC 036111019 / M
5 vials of 5 ml: AIC 036111033 / M
10 vials of 5 ml: AIC 036111045 / M
1 vial of 10 ml: AIC 036111021 / M
5 vials of 10 ml: AIC 036111058 / M
10 vials of 10 ml: AIC 036111060 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
August 2008
