Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Hospira UK Limited, Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, United Kingdom
Mitoxantrone is indicated in the treatment of metastatic breast cancer.
Mitoxantrone is indicated in the treatment of non-Hodgkin’s lymphoma.
Mitoxantrone is indicated for the treatment of acute myeloid leukaemia (AML) in adults.
Mitoxantrone in combination regimens is indicated in the remission-induction treatment of blast crisis in chronic myeloid leukaemia.
Mitoxantrone is indicated in combination with corticosteroids for palliation (e.g. pain relief) related to advanced castrate resistant prostate cancer.
Mitoxantrone is indicated for treatment of patients with highly active relapsing multiple sclerosis associated with rapidly evolving disability where no alternative therapeutic options exist (see sections 4.2, 4.4 and 5.1).
Mitoxantrone should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents.
Single Agent Therapy: The recommended initial dosage of mitoxantrone used as a single agent is 14 mg/m² of body surface area, given as a single intravenous dose, which may be repeated at 21-day intervals. A lower initial dosage (12 mg/m² or less) is recommended in patients with inadequate bone marrow reserves e.g. due to prior chemotherapy or poor general condition.
Dosage modification and the timing of subsequent dosing should be determined by clinical judgement depending on the degree and duration of myelosuppression. For subsequent courses, the prior dose can usually be repeated if white blood cell and platelet counts have returned to normal levels after 21 days.
The following table is suggested as a guide to dosage adjustment in the treatment of metastatic breast cancer and non-Hodgkin’s lymphoma according to haematological nadir (which usually occurs about 10 days after dosing).
| WBC and platelet nadir | Time to recovery | Subsequent dosing |
|---|---|---|
| If WBC nadir > 1,500 µl and platelet nadir > 50,000 µl | Recovery ≤ 21 days | Repeat prior dose |
| If WBC nadir > 1,500 µl and platelet nadir > 50,000 µl | Recovery > 21 days | Withhold until recovery, then repeat prior dose. |
| If WBC nadir < 1,500 µl or platelet nadir < 50,000 µl | Any duration | Decrease by 2 mg/m² from prior dose, after recovery. |
| If WBC nadir < 1,000 µl or platelet nadir < 25,000 µl | Any duration | Decrease by 4 mg/m² from prior dose, after recovery. |
Combination Therapy: Mitoxantrone has been given as part of combination therapy. In metastatic breast cancer, combinations of mitoxantrone with other cytotoxic agents including cyclophosphamide and 5-fluorouracil or methotrexate and mitomycin C have been shown to be effective.
Mitoxantrone has also been used in various combinations for non-Hodgkin’s lymphoma; however, data are presently limited and specific regimens cannot be recommended.
In combination regimens mitoxantrone, in starting doses ranging from 7 to 8 to 10 to 12 mg/m², dependent on the combination and frequency used, has shown effectiveness.
As a guide, when mitoxantrone is used in combination chemotherapy with another myelosuppressive agent, the initial dose of mitoxantrone should be reduced by 2 to 4 mg/m² below the doses recommended for single agent usage; subsequent dosing, as outlined in the table above, depends on the degree and duration of myelosuppression.
Single Agent Therapy in Relapse: The recommended dosage for remission induction is 12 mg/m² of body surface area, given as a single intravenous dose daily for five consecutive days (total of 60 mg/m²). In clinical studies with a dosage of 12 mg/m² daily for 5 days, patients who achieved a complete remission did so as a result of the first induction course.
Combination Therapy: For induction, the recommended dosage is 12 mg/m² of mitoxantrone daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m² of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1 to 7.
Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukaemic response, a second induction course may be given with mitoxantrone given for 2 days and cytarabine for 5 days, using the same daily dosage levels. If severe or life-threatening non-haematological toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.
Consolidation therapy, which was used in two large randomised multicentre trials, consists of mitoxantrone 12 mg/m² given by intravenous infusion daily on Days 1 and 2, and cytarabine, 100 mg/m² for 5 days given as a continuous 24-hour infusion on Days 1 to 5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first.
A single course of mitoxantrone 6 mg/m² intravenous (IV) bolus, etoposide 80 mg/m² intravenous for a period of 1 hour, and cytarabine (Ara-C) 1 g/m² intravenous for a period of 6 hours daily for 6 days (MEC) showed antileukaemic activity as salvage therapy for refractory AML.
The recommended dosage in relapse is 10 to 12 mg/m² body surface area given as a single intravenous dose daily over 5 consecutive days (total of 50 to 60 mg/m²).
Based on data from two comparative trials of mitoxantrone plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m² given as a short intravenous infusion every 21 days, in combination with low oral doses of corticosteroids.
Cancer patients who received cumulative doses of 140 mg/m² either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. For this reason, patients should be monitored for evidence of cardiac toxicity and questioned about symptoms of heart failure prior to the initiation of and during treatment.
The treatment with mitoxantrone should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapeutic agents for the treatment of multiple sclerosis.
This treatment should be used only after assessment of the benefit-risk, particularly concerning the haematological and cardiac risks (see section 4.4).
The treatment must not be initiated in patients who have been previously treated with mitoxantrone.
The recommended dosage of mitoxantrone is usually 12 mg/m² body surface area given as a short (approximately 5 to 15 minutes) intravenous infusion that may be repeated every 1-3 months. The maximum lifetime cumulative dose should not exceed 72 mg/m² (see section 5.1).
If mitoxantrone is administered repeatedly dosing adjustments should be guided by extent and duration of bone marrow suppression.
Differential blood count within 21 days after mitoxantrone infusion
Signs and symptoms of infection and differential blood count with WHO grade 3: following dose 10 mg/m²
Signs and symptoms of infection and differential blood count with WHO grade 4: following dose 8 mg/m²
Differential blood count 7 days before mitoxantrone infusion
Signs and symptoms of infection and differential blood count with WHO grade 1: following dose 9 mg/m²
Signs and symptoms of infection and differential blood count with WHO grade 2: following dose 6 mg/m²
Signs and symptoms of infection and differential blood count with WHO grade 3 to 4: discontinuation of therapy
In case of non-haematological toxicities WHO grade 2 to 3 the following dose should be adjusted to 10 mg/m², in case of non-haematological toxicity grade 4 the treatment should be discontinued.
In general, dose selection for an elderly patient should be initiated at the low end of the dosing range, reflecting the greater frequency of decreasing hepatic, renal, or cardiac function, and of concomitant disease or treatment with other medicinal products.
The safety of mitoxantrone in patients with renal impairment is not established. Mitoxantrone should be used with caution.
The safety of mitoxantrone in patients with hepatic insufficiency is not established. For patients with hepatic impairment dose adjustment may be necessary as mitoxantrone clearance is reduced by hepatic impairment. There are insufficient data that allows for dose adjustment recommendations. Laboratory measurement cannot predict clearance of the active substance and dose adjustments (see section 5.2).
Safety and efficacy in paediatric patients have not been established. There is no relevant use of mitoxantrone in the paediatric population.
Mitoxantrone concentrate should be given by intravenous infusion only.
Mitoxantrone concentrate should be slowly injected into a free fh4. lowing intravenous infusion of isotonic saline or 5% glucose solution over a period of not less than 3 to 5 minutes. The tubing should be inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage.
Mitoxantrone concentrate also can be administered as a short infusion (15 to 30 minutes) diluted in 50 to 100 ml isotonic saline or 5% glucose solution.
Mitoxantrone concentrate must not be given subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration. The medicinal product must also not be given by intrathecal injection.
If any signs or symptoms of extravasation have occurred, including burning, pain, pruritus, erythema, swelling, blue discolouration, or ulceration, the administration should be stopped immediately (see section 4.4).
There is no known specific antidote for mitoxantrone. Accidental overdoses have been reported. Four patients receiving 140 to 180 mg/m2 as a single bolus injection died as a result of severe leukopenia with infection. Haematological support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression.
Although patients with severe renal failure have not been studied, mitoxantrone is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or haemodialysis.
Haemopoietic, gastrointestinal, hepatic or renal toxicity may be seen, depending on the dosage given and the physical condition of the patient. In cases of overdosage patients should be monitored closely. Treatment should be symptomatic and supportive.
2 years.
Do not store above 25°C. Do not refrigerate or freeze.
Mitoxantrone Sterile Concentrate does not contain an antimicrobial preservative.
Chemical and physical stability of the diluted product has been demonstrated for 72 hours when stored at room temperature.
From a microbiological point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Not all pack sizes may be marketed.
20 mg/10 ml in a clear Type I glass vial (with or without Onco-Tain shrink wrapping) with rubber closure, presented in packs of single vials.
Single use only. Discard any unused contents. Any unused medicinal product or waste materials should be disposed of in accordance with local requirements.
Mitoxantrone, in common with other potentially hazardous cytotoxic drugs, should only be handled by adequately trained personnel. Pregnant staff should not be involved in the reconstitution or administration of mitoxantrone.
Care should be taken to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes. The use of goggles, gloves and protective gowns is recommended during preparation, administration and disposal and the work surface should be covered with disposable plastic-backed absorbent paper.
Aerosol generation should be minimised. Mitoxantrone can cause staining. Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved standard irrigation techniques should be used.
For instruction on dilution of Mitoxantrone Sterile Concentrate see Section 4.2 above.
Spillage disposal: The following clean-up procedure is recommended if Mitoxantrone Sterile Concentrate is spilled on equipment or environmental surfaces. Prepare a 50% solution of fresh concentrated bleach (any recognised proprietary brand containing either sodium or calcium hypochlorite) in water. Wet absorbent tissues in the bleach solution and apply the wetted tissues to the spillage. The spillage is deactivated when the blue colour has been fully discharged. Collect up the tissues with dry tissues. Wash the area with water and soak up the water with dry tissues. Appropriate protective equipment should be worn during the clean-up procedure. All mitoxantrone contaminated items (e.g. syringes, needles, tissues etc.) should be treated as toxic waste and disposed of accordingly. Incineration is recommended.
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