Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Baxter Healthcare Ltd., Caxton Way, Thetford, Norfolk, IP24 3SE, United Kingdom
Onkotrone Injection is indicated for the treatment of:
Onkotrone should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents.
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 judgment 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. |
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.
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.
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.
Single dose therapy in relapse
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.
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.
Onkotrone concentrate should be given by intravenous infusion only.
Onkotrone concentrate should be slowly injected into a free flowing 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.
Onkotrone 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.
Onkotrone 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.
Haematopoietic, 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.
3 years unopened.
8 hours after dilution.
Do not store above 25°C.
Do not freeze.
Containers:
Clear glass type 1 injection vial with rubber stopper and aluminium flange cap.
Contents:
Onkotrone Injection is a sterile dark blue aqueous solution of mitoxantrone hydrochloride equivalent to 2 mg/ml. It is available in the following vial sizes:
Onkotrone Injection should only be handled by adequately trained personnel. Pregnant and lactating staff should not be involved in the dilution or administration of Onkotrone Injection.
Care should be taken when handling Onkotrone Injection to avoid contact with the skin, mucous membranes and eyes. The use of protective gloves, gown and safety goggles is recommended during preparation, administration and disposal. Work surfaces should be covered with disposable plastic backed absorbent paper. Aerosol generation should be minimised. Onkotrone injection can cause staining. If contact of Onkotrone Injection with the skin or mucous membranes does occur, the contact area should be immediately copiously washed with warm water. Eyes must be thoroughly rinsed with water and if necessary, an ophthalmologist should be consulted.
If Onkotrone Injection 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 Onkotrone Injection contaminated items (eg, syringes, needles, tissues, etc) should be treated as toxic waste and disposed of accordingly. High temperature incineration is recommended.
The manufacturing process may cause a slight over-pressure in the injection vial. Caution should therefore be exercised when piercing the injection vial.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
