Mitoxantrone "ebewe"

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MITHOXANTRONE "EBEWE" (MITOXANTRONE "EBEWE")

Composition:

Active substance: mitoxantrone;

1 ml of concentrate contains 2 mg of mitoxantrone (as mitoxantrone hydrochloride);

Excipients: sodium chloride, sodium acetate trihydrate, glacial acetic acid, anhydrous sodium sulfate, diluted hydrochloric acid, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: clear blue solution, free from visible particles.

Pharmacotherapeutic group. Antineoplastic agents. Anthracyclines and related substances. ATC code L01DB07.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Mitoxantrone is a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) by forming hydrogen bonds, causing cross-link and strand breaks.

Mitoxantrone also interferes with ribonucleic acid (RNA) function and is a potent inhibitor of topoisomerase II, an enzyme responsible for unwinding and repairing damaged DNA. It exerts cytotoxic effects on both proliferating and non-proliferating human cells, meaning its action is independent of the cell cycle phase, acting against both rapidly proliferating and slowly growing neoplasms. Mitoxantrone arrests the cell cycle at the G2 phase, leading to increased cellular RNA and polyploidy.

In vitro, mitoxantrone inhibits the proliferation of B-cells, T-cells, and macrophages, and disrupts antigen presentation as well as the secretion of gamma-interferon, tumor necrosis factor-alpha, and interleukin-2.

Pharmacodynamic effects

Mitoxantrone, a synthetic anthracenedione derivative, is a well-established cytotoxic antineoplastic agent. Its therapeutic efficacy has been demonstrated in numerous cases of malignant neoplasms. Immunosuppression is the anticipated mechanism of action in multiple sclerosis (MS).

Clinical efficacy and safety

Treatment of various cancers with mitoxantrone at doses ranging from 12 to 14 mg/m² has been effective. This dose is administered over 21-day cycles: for induction therapy in acute myeloid leukemia (AML) over three consecutive days, and for consolidation therapy over two days. Mitoxantrone is active when used as monotherapy or in combination with other antineoplastic agents or corticosteroids.

Mitoxantrone in combination with other cytostatic agents is effective in the treatment of metastatic breast cancer, as well as in patients who did not respond to adjuvant therapy regimens containing anthracyclines.

Mitoxantrone in combination with corticosteroids improves pain control and quality of life in patients with advanced castration-resistant prostate cancer, although it has no impact on overall survival. As primary induction therapy, mitoxantrone in combination with cytarabine is at least as effective in inducing remission as daunorubicin in combination with cytarabine in adult patients with previously untreated AML. Mitoxantrone as monotherapy or in combination with other cytostatic agents achieves objective responses in patients with several types of non-Hodgkin's lymphoma (NHL). Long-term benefit from mitoxantrone is limited by the development of tumor resistance, which may ultimately lead to fatal outcomes when used as last-line therapy.

According to results from a clinical trial in highly active inflammatory MS, administration of mitoxantrone at a dose of 12 mg/m² every 3 months was more effective than mitoxantrone at 5 mg/m² or placebo. A reduction in neurological deterioration and frequency of clinical relapses was observed. In some studies on multiple sclerosis, the range of effective cumulative doses varied between 36 and 120 mg/m². Single doses ranged from 5 to 12 mg/m², and administration intervals varied from once monthly to once every 3 months. Additionally, the duration over which the cumulative dose was administered ranged from 3 to 24 months. However, the risk of cardiotoxicity increases with higher cumulative doses. A cumulative dose of 72 mg/m² remains effective and is associated with less pronounced cardiotoxicity compared to higher cumulative doses. Therefore, patients with MS should not receive a cumulative dose exceeding 72 mg/m² over their lifetime.

Pediatric population

Safety and efficacy in children have not been established.

Pharmacokinetics.

Absorption

The pharmacokinetics of mitoxantrone in patients after intravenous administration of a single dose can be described by a three-compartment model. In patients receiving doses of 15–90 mg/m², a linear relationship between dose and area under the concentration-time curve (AUC) is observed. When mitoxantrone was administered daily for 5 days or as a single dose every 3 weeks, no accumulation of the active substance in plasma was observed.

Distribution

Mitoxantrone is widely distributed into tissues: the volume of distribution at steady state exceeds 1,000 L/m². Plasma concentrations decrease rapidly within the first two hours, after which the process becomes slower. Mitoxantrone is 78% bound to plasma proteins. The bound fraction is independent of concentration and is unaffected by phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or acetylsalicylic acid. Mitoxantrone does not cross the blood-brain barrier. Distribution into the testes is relatively low.

Biotransformation and elimination

The metabolic pathways of mitoxantrone are not fully elucidated. Mitoxantrone is slowly eliminated via urine and feces, both as unchanged active substance and as inactive metabolites. In human studies, only 10% and 18% of the administered dose were recovered in urine and feces, respectively, as active substance and metabolites over a 5-day period following drug administration. Of the material excreted in urine, 65% was unchanged active substance. The remaining 35% consisted of mono- and dicarboxylic acid derivatives and their glucuronide conjugates.

Most reported elimination half-life values fall within the range of 10 to 40 hours, although some authors have reported much longer values of 7–12 days. Differences in estimates may be due to data collected long after dose administration and differences in data sensitivity and analytical methods.

Special populations

In patients with impaired liver function, mitoxantrone clearance may be reduced. Significant differences in mitoxantrone pharmacokinetics between elderly and younger patients are not observed. The effects of sex, race, and renal impairment on mitoxantrone pharmacokinetics are unknown.

The pharmacokinetics of mitoxantrone in the pediatric population is unknown.

Clinical characteristics.

Indications.

• Metastatic breast cancer;
• non-Hodgkin's lymphoma;
• acute myeloid leukemia in adults;
• in combination therapy for induction of remission in blast crisis phase of chronic myeloid leukemia treatment;
• in combination with corticosteroids for palliative (e.g., pain relief) treatment of progressive hormone-refractory prostate cancer;
• for treatment of patients with highly active relapsing-remitting multiple sclerosis associated with rapid disability progression, when alternative therapeutic options cannot be used.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product, including sulfites, which may be produced during the manufacturing process of mitoxantrone.
• Mitoxantrone is contraindicated in women who are breastfeeding (see sections "Special precautions", "Use during pregnancy or breastfeeding").

Mitoxantrone must not be used for the treatment of MS in pregnant women (see sections "Special precautions", "Use during pregnancy or breastfeeding").

Special safety precautions.

The drug should be administered in a specialized inpatient setting.

General safety rules for handling cytotoxic agents must be observed when working with the drug.

Protective clothing must be used (disposable gloves, masks, goggles, gowns, caps or coveralls).

Measures must be taken to prevent contact of mitoxantrone solutions with skin, mucous membranes, or eyes. If such contact occurs, the affected area should be immediately rinsed with copious amounts of water.

When withdrawing the drug from the vial, the vial should be held with the stopper facing upwards, as contact of the mitoxantrone solution with the stopper may potentially cause splashing.

Pregnant healthcare personnel must not handle the drug.

The following decontamination procedure is recommended for surfaces contaminated with mitoxantrone solutions: Prepare a 50% aqueous solution of freshly prepared concentrated bleaching powder (containing approximately 10–13% available chlorine). Commercially available products from any known manufacturer containing sodium or calcium hypochlorite may also be used. Moisten a piece of cloth with the bleaching powder solution and apply it to the contaminated area. Spilled mitoxantrone solution can be considered deactivated once the blue coloration has completely disappeared. Afterwards, the area should be rinsed with water and wiped dry with a clean cloth. All these procedures must be performed while wearing protective clothing.

Unused drug residues, as well as all instruments and materials that have come into contact with mitoxantrone during preparation and administration of infusion solutions or during cleanup, must be disposed of according to an approved cytotoxic waste disposal procedure, preferably by high-temperature incineration.

Interaction with other medicinal products and other types of interactions.

When mitoxantrone is used concomitantly with other medicinal products that suppress bone marrow function, the myelotoxicity of mitoxantrone and/or the other agents may be enhanced.

Combination therapy with mitoxantrone and other potentially cardiotoxic medicinal products (e.g., other anthracyclines) increases the risk of cardiotoxic effects.

Therapy with topoisomerase II inhibitors, including mitoxantrone, in combination with other antineoplastic agents and/or radiation therapy, is associated with an increased risk of developing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Immunization during mitoxantrone treatment may be ineffective.

Special precautions.

Treatment with mitoxantrone should be administered under the supervision of an oncologist and in the presence of facilities for clinical and laboratory monitoring of the patient during and after treatment. Appropriate precautions must be taken when handling the drug, in accordance with the safety procedures for cytotoxic substances.

Precautions to be taken before starting to handle or administer the medicinal product.

Mitoxantrone "EBEWE" should be administered slowly by intravenous infusion. Mitoxantrone "EBEWE" is not intended for subcutaneous, intramuscular, or intra-arterial injections. Following intra-arterial administration, cases of local/regional neuropathy, sometimes irreversible, have been reported. In case of extravasation during administration, serious local tissue damage may occur. To date, only isolated cases of severe local reactions (necrosis) due to extravasation have been reported.

Mitoxantrone "EBEWE" must not be administered intrathecally. Intrathecal administration may result in serious damage with long-term consequences. Neuropathy and neurotoxicity affecting the central and peripheral nervous systems have been reported following intrathecal injections. These reports included cases of epileptic seizures leading to coma, severe neurological sequelae, and paralysis associated with bowel and bladder dysfunction.

Cardiac function

Myocardial toxicity, which in its most severe form manifests as potentially irreversible and fatal congestive heart failure (CHF), may occur during mitoxantrone therapy or several months or years after treatment has been discontinued. This risk increases with cumulative dose. In cancer patients who received cumulative doses of 140 mg/m² body surface area as monotherapy or in combination with other chemotherapeutic agents, the cumulative incidence of clinical CHF was 2.6%. In comparative oncology studies, the overall cumulative incidence of moderate or severe reduction in left ventricular ejection fraction (LVEF) at this dose was 13%.

Active or latent cardiovascular disease, prior or concomitant radiotherapy to the mediastinum/pericardium, previous or concurrent treatment with other anthracyclines or anthracenediones, or use of other cardiotoxic medicinal products may increase the risk of cardiac toxicity. Prior to the initial dose of mitoxantrone, cancer patients should undergo assessment of LVEF by echocardiography or radionuclide ventriculography (MUGA). Cardiac function should be closely monitored during treatment of cancer patients. LVEF assessment is recommended at regular intervals and/or if signs or symptoms of CHF develop. Cardiotoxicity may occur at any time during mitoxantrone therapy, and the risk increases with cumulative dose. Cardiac toxic effects with mitoxantrone may occur at lower cumulative doses, regardless of the presence of cardiac risk factors.

Due to the potential risk of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-risk ratio should be carefully evaluated before initiating mitoxantrone therapy.

In isolated cases, acute CHF may develop in patients with acute myeloid leukemia (AML) undergoing treatment with mitoxantrone.

Similar reports have also been received in patients with multiple sclerosis (MS) receiving mitoxantrone. Furthermore, functional cardiac changes may occur in patients with MS undergoing mitoxantrone therapy. Therefore, in such patients, LVEF should be assessed by echocardiography or radionuclide ventriculography (MUGA) before the initial dose, prior to each dose, and for at least 5 years after completion of therapy. Cardiotoxicity may occur at any time during mitoxantrone therapy, and the risk increases with cumulative dose. Cardiac toxic effects with mitoxantrone may occur at lower cumulative doses, regardless of the presence of cardiac risk factors. Typically, patients with MS should not receive a cumulative dose exceeding 72 mg/m² body surface area. Mitoxantrone should generally not be administered to MS patients with LVEF < 50% or clinically significant reduction in LVEF.

Bone marrow suppression

Treatment with mitoxantrone should be conducted under conditions of careful and frequent monitoring of hematological and biochemical laboratory parameters, as well as continuous patient observation. A complete blood count, including platelets, should be performed before the initial dose, approximately 10 days prior to each infusion, after infusion, and before each subsequent infusion, as well as whenever signs or symptoms of infection occur. Patients should be informed about the risks, symptoms, and signs of acute leukemia and advised to seek medical attention if any such symptoms develop.

In patients with poor general condition or those previously treated with chemotherapy and/or radiotherapy, myelosuppression may be more severe and prolonged.

Except in the treatment of AML, mitoxantrone should generally not be administered to patients with a baseline neutrophil count below 1,500 cells/mm³. To monitor bone marrow suppression, particularly neutropenia, which may be severe and lead to infection, frequent peripheral blood cell counts are recommended in all patients receiving mitoxantrone.

When mitoxantrone is administered at high doses (>14 mg/m²/day for 3 days), as in the treatment of leukemia, severe myelosuppression may occur.

Particular attention should be paid to ensuring complete hematological recovery before initiating consolidation therapy (if applicable) and careful monitoring during this phase of treatment. Myelosuppression may occur with mitoxantrone at any dose.

Secondary AML and MDS

The use of topoisomerase II inhibitors, including mitoxantrone hydrochloride, as monotherapy or in combination with other antineoplastic agents and/or radiotherapy, has been associated with the development of AML or myelodysplastic syndrome (MDS). Due to the risk of secondary malignancies, the benefit-risk ratio should be carefully evaluated before initiating mitoxantrone therapy.

Use following prior treatment of MS with other agents

The safety and efficacy of mitoxantrone following therapy with natalizumab, fingolimod, alemtuzumab, dimethyl fumarate, or teriflunomide have not been studied.

Non-metastatic breast cancer

In the absence of adequate data on the efficacy of mitoxantrone as part of adjuvant therapy for breast cancer and considering the increased risk of leukemia, mitoxantrone should be used only for the treatment of metastatic breast cancer.

Infections

Patients receiving immunosuppressive agents such as mitoxantrone have a reduced immunological response to infections. Systemic infections should be treated concomitantly with the initiation of mitoxantrone therapy or immediately prior to it.

Vaccination

Immunization with live viral vaccines (e.g., yellow fever vaccine) increases the risk of infection and other adverse reactions, such as gangrenous vaccination and generalized vaccination, in patients with immunodeficiency, which occurs during mitoxantrone therapy. Therefore, live viral vaccines should not be administered during treatment. Caution is recommended when using live viral vaccines after completion of chemotherapy, and vaccination should not be performed earlier than 3 months after the last dose of chemotherapy.

Contraception in men and women

Mitoxantrone is genotoxic and considered a potential human teratogen. Therefore, men should be advised not to father a child and to use contraception during therapy and for at least 6 months after its completion. Women of childbearing potential must have a negative pregnancy test before each dose and must use effective contraception during therapy and for at least 4 months after its completion.

Lactation

Mitoxantrone is excreted in breast milk for up to one month after the last dose. Due to the potential for serious adverse reactions in infants, breastfeeding is contraindicated during mitoxantrone therapy and must be discontinued before treatment initiation.

Fertility

Women of childbearing age should be informed of the increased risk of temporary or permanent amenorrhea.

Mutagenicity and carcinogenicity

Mitoxantrone has been shown to be mutagenic in bacterial and mammalian test systems, as well as in vivo in rats. The active substance has been carcinogenic in experimental animal models at doses lower than the proposed clinical dose. Therefore, mitoxantrone has carcinogenic potential in humans.

Tumor lysis syndrome

Cases of tumor lysis syndrome have been reported during mitoxantrone therapy. Serum levels of uric acid, electrolytes, and urea should be monitored regularly.

Change in color of urine and other tissues

Mitoxantrone may turn urine blue-green for up to 24 hours after administration; patients should be informed of this possibility. Additionally, blue discoloration of the sclera, skin, and nails may occur.

Sodium content per vial:

10 mg/5 ml: 0.739 mmol (17.10 mg) sodium.

20 mg/10 ml: 1.478 mmol (34.14 mg) sodium.

This should be taken into account when administering the drug to patients on a sodium-restricted diet.

The medicinal product Mitoxantrone "EBEWE" is physically and chemically stable for 28 days after first opening of the container, when stored in the freezer, refrigerator, or at room temperature, protected or unprotected from light.

Infusion solutions containing mitoxantrone at concentrations of 0.3 mg/ml and 0.5 mg/ml, prepared by dilution with 0.9% sodium chloride solution, are physically and chemically stable for 28 days when stored at 2–8°C protected from light or at room temperature (20–25°C) protected or unprotected from light.

Infusion solutions containing mitoxantrone at concentrations of 0.3 mg/ml and 0.5 mg/ml, prepared by dilution with 5% glucose solution, are physically and chemically stable for 28 days when stored at 2–8°C protected from light, and for 7 days when stored at room temperature (20–25°C) protected or unprotected from light.

From a microbiological standpoint, the product should be used immediately after opening the container, and the infusion solution should be used immediately after preparation. If not used immediately, the duration and conditions of storage should be under the responsibility of the medical staff. Generally, storage should not exceed 24 hours at room temperature (20–25°C), unless all manipulations were performed under controlled and certified aseptic conditions.

Use during pregnancy or lactation.

Contraception in men and women

Mitoxantrone is genotoxic and considered a potential human teratogen. Therefore, men should be advised not to father a child and to use contraception during therapy and for at least 6 months after its completion. Women of childbearing potential should be advised to avoid pregnancy, must have a negative pregnancy test before each dose, and must use effective contraception during therapy and for at least 4 months after its completion.

Pregnancy

Data on the use of mitoxantrone in pregnant women are very limited. In animal studies at doses below human exposure, mitoxantrone did not demonstrate teratogenicity but caused reproductive toxicity. Mitoxantrone is considered a potential human teratogen due to its mechanism of action and the adverse effects on fetal development demonstrated by related agents. For this reason, the use of mitoxantrone is contraindicated for the treatment of multiple sclerosis in pregnant women. When used for other indications, mitoxantrone should not be administered during pregnancy, particularly during the first trimester. In each individual case, the benefit of therapy should be weighed against the potential risk to the fetus. If this medicinal product is used during pregnancy or if a patient becomes pregnant while being treated with mitoxantrone, the patient must be informed of the potential risk to the fetus and offered genetic counseling.

Lactation

Mitoxantrone is excreted in breast milk and can be detected for up to one month after the last dose. Due to the potential for serious adverse reactions in infants, breastfeeding is contraindicated during mitoxantrone therapy and must be discontinued before treatment initiation.

Fertility

Women receiving mitoxantrone therapy are at increased risk of temporary or permanent amenorrhea; therefore, gamete preservation should be considered before initiating therapy. There are no data on the effect on male fertility, although in animal studies, tubular atrophy of the testes and reduced sperm count were observed.

Ability to influence reaction speed when driving or operating machinery.

Mitoxantrone has a minor influence on the ability to drive or operate machinery. Confusion and fatigue may occur after mitoxantrone administration.

Administration and Dosage

Treatment with mitoxantrone should be conducted under the supervision of a physician experienced in the use of cytotoxic chemotherapeutic agents.

Metastatic Breast Cancer, Non-Hodgkin's Lymphoma (NHL):

Monotherapy

The recommended initial dose of mitoxantrone as monotherapy is 14 mg/m² of body surface area administered as a single intravenous infusion, which may be repeated every 21 days. For patients with reduced bone marrow reserves (e.g., due to prior chemotherapy or poor general condition), the initial dose should be reduced to 12 mg/m² or lower.

Subsequent doses and timing of administration are determined based on the degree and duration of myelosuppression. In subsequent treatment cycles, the previous dose may usually be repeated if, after 21 days, leukocyte and platelet counts have returned to normal levels. The table below provides dose modification recommendations for the treatment of advanced breast cancer and non-Hodgkin's lymphoma based on the lowest observed leukocyte and platelet counts (which typically occur approximately 10 days after drug administration).

Combination Therapy

Mitoxantrone is used as part of combination therapy. For metastatic breast cancer, efficacy has been demonstrated with combinations of mitoxantrone and other cytotoxic agents, including cyclophosphamide and 5-fluorouracil or methotrexate and mitomycin C.

Furthermore, mitoxantrone is used in various combinations for the treatment of NHL; however, data are limited to date, and therefore specific regimens cannot be recommended.

The use of mitoxantrone as a component of combination therapy at an initial dose ranging from 7–8 to 10–12 mg/m², depending on the combination and frequency of administration, has proven effective.

When mitoxantrone is used in combination with other myelosuppressive agents, the initial dose should be reduced by 2–4 mg/m² of body surface area compared to the recommended dose in monotherapy. As indicated in the table above, subsequent doses depend on the degree and duration of myelosuppression.

Acute Myeloid Leukemia (AML):

Monotherapy for Relapse

The recommended dose for induction of remission is 12 mg/m² body surface area administered as a single intravenous dose daily for 5 consecutive days (total 60 mg/m²). In clinical studies using doses of 12 mg/m² daily for 5 days, patients achieved complete remission after the first induction course.

Combination Therapy

The recommended induction dose is 12 mg/m² of mitoxantrone administered daily on days 1–3 by intravenous infusion, and 100 mg/m² of cytarabine administered continuously over 24 hours for 7 days on days 1–7.

Most cases of complete remission occurred after the initial induction course. In cases of incomplete antileukemic response, a second induction course may be initiated using mitoxantrone for 2 days and cytarabine for 5 days, with the same daily dose levels. If severe or life-threatening non-hematological toxicity occurs during the first induction course, the second induction course should be delayed until toxic effects have resolved.

Consolidation therapy used in two large randomized multicenter studies included mitoxantrone at a dose of 12 mg/m² administered by intravenous infusion daily on days 1 and 2, and cytarabine at 100 mg/m² administered by continuous 24-hour infusion for 5 days on days 1–5. The first course was initiated approximately 6 weeks after the last induction course, and the second course typically 4 weeks after the first.

A single course of mitoxantrone at 6 mg/m² administered as a rapid intravenous infusion, etoposide at 80 mg/m² intravenously over 1 hour, and cytarabine (Ara-C) at 1 g/m² intravenously over 6 hours daily for 6 days (MEC) demonstrated antileukemic activity as salvage therapy for refractory AML.

Treatment of Blast Crisis in (Chronic) Myeloid Leukemia:

Single-Dose Use in Relapse

The recommended dose in relapse is 10 to 12 mg/m² body surface area administered as a single intravenous dose daily for 5 consecutive days (total 50–60 mg/m²).

Metastatic Castration-Resistant Prostate Cancer:

Based on data from two trials comparing the mitoxantrone plus corticosteroid regimen with corticosteroids as monotherapy, the recommended dose of mitoxantrone is 12 to 14 mg/m² administered as a short intravenous infusion every 21 days in combination with low oral doses of corticosteroids.

For patients with cancer who receive cumulative doses of 140 mg/m², either as monotherapy or in combination with other chemotherapeutic agents, the cumulative probability of developing clinical heart failure is 2.6%. Therefore, patients should be continuously monitored for signs of cardiac toxicity and questioned about symptoms of heart failure before and during treatment.

Multiple Sclerosis (MS):

Treatment with mitoxantrone should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapeutic agents for the treatment of MS.

Such treatment should be initiated only after careful assessment of the benefit-risk ratio, particularly in the context of hematological and cardiac risks.

Treatment should not be initiated in patients who have previously received mitoxantrone.

The recommended dose of mitoxantrone is generally 12 mg/m² body surface area administered as a short (approximately 5–15 minutes) intravenous infusion, which may be repeated every 1–3 months. The maximum cumulative lifetime dose should not exceed 72 mg/m².

If mitoxantrone is administered repeatedly, dose adjustments should be based on the degree and duration of bone marrow suppression.

White Blood Cell Count 21 Days After Mitoxantrone Infusion

Signs and symptoms of infection and WHO Grade 3 leukocyte count: the next dose should be 10 mg/m².

Signs and symptoms of infection and WHO Grade 4 leukocyte count: the next dose should be 8 mg/m².

White Blood Cell Count 7 Days Prior to Mitoxantrone Infusion

Signs and symptoms of infection and WHO Grade 1 leukocyte count: the next dose should be 9 mg/m².

Signs and symptoms of infection and WHO Grade 2 leukocyte count: the next dose should be 6 mg/m².

Signs and symptoms of infection and WHO Grade 3–4 leukocyte count: discontinue treatment.

In case of non-hematological toxic effects of WHO Grade 2–3, the next dose should be 10 mg/m²; in case of non-hematological toxic effects of WHO Grade 4, treatment should be discontinued.

Special Populations:

Elderly Patients

Due to the increased incidence of impaired liver or kidney function, cardiac function, concomitant diseases, or concomitant medication use, in most cases, treatment with the drug in elderly patients should be initiated at the lower end of the dosing range.

Renal Impairment

The safety of mitoxantrone in patients with renal impairment has not been established. Mitoxantrone should be used with caution.

Hepatic Impairment

The safety of mitoxantrone in patients with hepatic insufficiency has not been established. Patients with hepatic impairment may require dose adjustment, as mitoxantrone clearance is reduced due to impaired liver function. Adequate data are not yet available to provide recommendations for dose adjustment. Laboratory measurements cannot reliably predict active substance clearance or guide dose adjustment.

Pediatric Population

Safety and efficacy in children have not been established. There is insufficient experience with the use of mitoxantrone in the pediatric population.

Administration

For intravenous use only. Mitoxantrone "EBEWE" should be administered slowly by intravenous infusion into isotonic saline or 5% glucose solution over intervals of at least 3–5 minutes. It is preferable to insert the catheter into a large vein. Whenever possible, veins over joints or in limbs with impaired venous or lymphatic drainage should be avoided.

Additionally, Mitoxantrone "EBEWE" should be administered as a short infusion (15 to 30 minutes) after dilution in 50–100 mL of isotonic saline or 5% glucose solution.

Mitoxantrone "EBEWE" must not be administered subcutaneously, intramuscularly, or intra-arterially. In case of extravasation during administration, severe local tissue damage may occur. Furthermore, the drug must not be administered by intrathecal injection.

If any signs or symptoms of extravasation occur, including burning, pain, itching, erythema, swelling, discoloration, or ulceration, administration should be stopped immediately.

Children

Treatment of children with mitoxantrone is not recommended. Safety and efficacy have not been established.

Overdose

There is no specific antidote for mitoxantrone. Cases of accidental overdose have been reported. Four patients who received single bolus doses of 140 to 180 mg/m² died due to severe leukopenia with infection. Hematological support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression.

Although the use of the drug in patients with severe renal impairment has not been studied, mitoxantrone is extensively tissue-bound; therefore, it is unlikely that therapeutic effect or toxicity would be reduced by peritoneal dialysis or hemodialysis.

Depending on the dose and the patient's physical condition, hematological, gastrointestinal, hepatic, and renal toxic effects may occur. In cases of overdose, patients must be closely monitored. Treatment should be symptomatic and supportive.

Adverse Reactions

The most serious adverse effects of mitoxantrone therapy are myocardial toxicity and myelosuppression. The most commonly observed adverse effects of mitoxantrone treatment (occurring in more than 1 in 10 patients) include anemia, leukopenia, neutropenia, infections, amenorrhea, alopecia, nausea, and vomiting.

List of adverse reactions (in table form)

The table below is based on safety data obtained from clinical trials and spontaneous reports in cancer treatment, as well as from clinical trials, post-marketing safety studies, and spontaneous reports in patients receiving treatment for multiple sclerosis (MS). Adverse reactions are categorized by frequency according to the following conventional classifications: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

General and local reactions.

Common. Fatigue, edema.

Uncommon. Allergic reactions (including exanthema, dyspnea, arterial hypotension, anaphylactic/anaphylactoid reactions), weakness, chills.

Rare. Local reactions at the site of extravasation (erythema, swelling, pain, burning sensation, bluish discoloration of the skin, necrosis); phlebitis, change in body weight, weakness.

Very rare. Anaphylactic shock.

Infections and infestations.

Frequency unknown. Opportunistic infections, life-threatening infections, skin infections, immunosuppression.

Injury, poisoning and procedural complications.

Frequency unknown. Bluish discoloration.

Description of selected adverse reactions

Myocardial toxicity, manifesting in its most severe form as potentially irreversible and fatal congestive heart failure (CHF), may occur during therapy with mitoxantrone or several months or years after discontinuation of treatment. This risk increases with increasing cumulative dose. In clinical trials in cancer patients who received cumulative doses of 140 mg/m² as monotherapy or in combination with other chemotherapeutic agents, the cumulative incidence of clinically manifest congestive heart failure was 2.6%.

Myelosuppression is the dose-limiting adverse effect of mitoxantrone. The most pronounced and prolonged myelosuppression is observed in patients who have previously received chemotherapy or radiotherapy. In a clinical trial in patients with acute leukemia, significant myelosuppression was observed in all patients receiving mitoxantrone. Among 80 enrolled patients, median nadir values of leukocyte and platelet counts were 400/μL (WHO grade 4) and 9,500/μL (WHO grade 4), respectively. Hematologic toxicity is difficult to assess in acute leukemia, as baseline values of conventional markers of bone marrow suppression, such as leukocyte and platelet counts, are distorted due to replacement of bone marrow by leukemic cells.

Patients with MS

Hematologic toxicity

Neutropenia may occur after any administration of the drug. This neutropenia is usually transient, with the lowest leukocyte count observed on day 10 after infusion and normalization by day 20. In addition, reversible thrombocytopenia may develop. Hematologic parameters should be monitored regularly.

Cases of fatal acute myeloid leukemia (AML) have been reported.

Cardiotoxicity

ECG abnormalities have been reported. Cases of CHF with left ventricular ejection fraction (LVEF) < 50% have also been observed.

Shelf life.

3 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Incompatibilities.

Mixing mitoxantrone with heparin in the same infusion vial is not permitted, as precipitation may occur.

Mitoxantrone "Ebewe" should not be mixed with other medicinal products in the same infusion vial.

Packaging.

5 ml (10 mg) or 10 ml (20 mg) in a vial; 1 vial with package leaflet in a carton.

Prescription category.

Prescription only.

Manufacturer.

Fareva Unterach GmbH

or

Ebewe Pharma Ges.m.b.H. Nfg. KG

Manufacturer's address and place of business.

Mondzeestrasse 11, 4866 Unterach am Attersee, Austria

Mondzeestrasse 11, 4866 Unterach am Attersee, Austria