Mitoxantrone 2 mg/ml Concentrate for Solution for Infusion

Each millilitre of concentrate contains 2 mg mitoxantrone (as hydrochloride). Each 10 ml vial contains 20 mg mitoxantrone (as hydrochloride).

This medicinal product contains 1.4 mmol sodium per 10 ml vial.

For full list of excipients, see section 6.1

Concentrate for Solution for Infusion.

Clear, dark-blue aqueous solution with a pH of 3.0-4.5

Mitoxantrone is indicated in the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and adult acute non-lymphocytic leukaemia.

Mitoxantrone has also been used in the palliation of non-resectable primary hepatocellular carcinoma.

Posology

Metastatic breast cancer, Non-Hodgkin's lymphoma, Hepatoma:

Single Agent Dosage: The recommended initial dosage of mitoxantrone 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 for patients with inadequate bone marrow reserves e.g. due to prior chemotherapy or poor general condition.

Dosage modification and the timing of subsequent doses 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, non-Hodgkin's lymphoma and hepatoma according to haematological nadir (which usually occurs about 10 days after dosing).

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. Reference should be made to the published literature for information on dosage modifications and administration. Mitoxantrone has also been used in various combinations for non-Hodgkin's lymphoma, however data are presently limited and specific regimens cannot be recommended.

As a guide, when mitoxantrone is used in combination chemotherapy with another myelosuppressive agent, the initial dose of mitoxantrone should be reduced by 2-4 mg/m² below the doses recommended for single agent use. Subsequent doses, as outlined in the table above, depend on the degree and duration of myelosuppression.

Adult acute non-lymphocytic leukaemia:

Single Agent Dosage 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: Mitoxantrone has been used in combination regimens for the treatment of acute non-lymphocytic leukaemia (ANLL). Most clinical experience has been with mitoxantrone combined with cytarabine. This combination has been used successfully for primary treatment of ANLL as well as in the treatment of relapse.

An effective regimen for induction in previously untreated patients has been mitoxantrone 10-12 mg/m² IV for 3 days combined with cytarabine 100 mg/m² IV for 7 days (by continuous infusion). This is followed by second induction and consolidation courses as thought appropriate by the treating clinician. In clinical studies, duration of therapy in induction and consolidation courses with mitoxantrone have been reduced to 2 days, and that of cytarabine to 5 days. However, modification to the above regimen should be carried out by the treating clinician depending on individual patient factors.

Efficacy has also been demonstrated with mitoxantrone in combination with etoposide in patients who had relapsed or who were refractory to primary conventional chemotherapy. The use of mitoxantrone in combination with etoposide, as with other cytotoxics, may result in greater myelosuppression than with mitoxantrone alone.

Reference should be made to the published literature for information on specific dosage regimens. Mitoxantrone should be used by clinicians experienced in the use of chemotherapy regimens. Dosage adjustments should be made by the treating clinician as appropriate, taking into account toxicity, response and individual patient characteristics. As with other cytotoxic drugs, mitoxantrone should be used with caution in combination therapy until wider experience is available.

Paediatrics: The safety and efficacy of mitoxantrone in paediatric patients have not been established.

Method of administration

FOR INTRAVENOUS USE ONLY.

Mitoxantrone should be given by intravenous infusion.

Syringes containing this product should be labelled 'MITOXANTRONE, FOR INTRAVENOUS USE ONLY.

Care should be taken to avoid contact of mitoxantrone with skin, mucous membranes or eyes; see section 6.6 Instructions for use and handling for further directions.

Dilute the required volume of Mitoxantrone Sterile Concentrate to at least 50 ml in either of the following infusion solutions: sodium chloride 0.9%, glucose 5%, or sodium chloride 0.18% and glucose 4%. Use Leur-lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.

Administer the resulting solution over not less than 3 minutes via the tubing of a freely running intravenous infusion of the above fluids. Mitoxantrone should not be mixed with other drugs in the same infusion.

If extravasation occurs the administration should be stopped immediately and restarted in another vein. The non-vesicant properties of mitoxantrone minimise the risk of severe local reaction following extravasation.

FOR INTRAVENOUS USE ONLY.

Mitoxantrone Sterile Concentrate is contraindicated in patients who have demonstrated prior hypersensitivity to mitoxantrone hydrochloride, other anthracylines or any of its components. Use in patients with profound bone marrow suppression is a relative contraindication depending on the clinical circumstances.

Mitoxantrone Sterile Concentrate should not be used during pregnancy or lactation.

Special warnings

There may be an increased risk of leukaemia when mitoxantrone is used as adjuvant treatment of non-metastatic breast cancer. In the absence of sufficient efficacy data, mitoxantrone must not be used as adjuvant treatment of non-metastatic breast cancer.

Mitoxantrone should be used with caution in patients with myelosuppression or poor general condition.

Cases of functional cardiac changes, including congestive heart failure and decreases in left ventricular ejection fraction have been reported during mitoxantrone therapy (see 4.8 Undesirable effects). These cardiac events have occurred most commonly in patients who have had prior treatment with anthracyclines, prior mediastinal/thoracic radiotherapy, or in patients with pre-existing heart disease. The concomitant administration of other cardiotoxic drugs may also increase the risk of cardiac toxicity. It is recommended that patients in these categories are treated with mitoxantrone at full cytotoxic dosage and schedule. However, added caution is required in these patients and careful regular cardiac examinations are recommended from the initiation of treatment.

Cardiac monitoring should also be performed in patients without identifiable risk factors during therapy exceeding 160 mg/m² of mitoxantrone, or during extended treatment.

Careful supervision is recommended when treating patients with hepatic insufficiency.

Topoisomerase II inhibitors, including mitoxantrone hydrochloride, when used concomitantly with other antineoplastic agents (particularly anthracyclines) and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS). Treatment with mitoxantrone alone has also been associated with an increased risk of development of secondary acute myeloid leukaemia (see 4.8 Undesirable effects).

Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.

Immunisation may be ineffective when given during mitoxantrone therapy. Immunisation with live virus vaccines are generally not recommended.

There is no experience with the administration of Mitoxantrone Sterile Concentrate other than by the intravenous route. Safety for intrathecal use has not been established.

Precautions for use

Mitoxantrone is an active cytotoxic drug which should be used by clinicians who are familiar with the use of antineoplastic agents and have the facilities for regular monitoring of clinical, haematological and biochemical parameters during and after treatment.

Full blood counts should be undertaken serially during a course of treatment. Dosage adjustments may be necessary based on these counts (see Dosage section).

Animal data suggest that if used in combination with other antineoplastic agents, additive myelosuppression may be expected. This has been supported by available clinical data on combination regimens. When used in combination regimens, the initial dose of Mitoxantrone Sterile Concentrate should be reduced by 2-4 mg/m² below the dose recommended for single agent usage. (see Posology and method of administration).

Combining mitoxantrone with potentially cardiotoxic drugs (anthracyclines) increases the risk of cardiac toxicity. The product must be used with caution in combination with immunosuppressive chemotherapy.

There are no adequate and well-controlled studies in pregnant women. Mitoxantrone should not normally be administered to patients who are pregnant. If the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazard to the fetus. Women of childbearing potential and their partners should be advised to avoid becoming pregnant and use effective contraception during therapy and for at least six months after cessation of therapy.

Mitoxantrone is excreted in human milk and significant concentrations (18 ng/ml) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breast-feeding should be discontinued before starting treatment.

Not applicable.

Serious or Life Threatening Reactions:

Blood and lymphatic system disorders: Some degree of leucopenia is to be expected following recommended doses of mitoxantrone. With the single dose every 21 days, suppression of WBC count below 1000/mm³ is infrequent. Leucopenia is usually transient reaching its nadir at about 10 days after dosing with recovery usually occurring by the 21^st day. Thrombocytopenia and anaemia occur less frequently. Myelosuppression may be more severe and prolonged in patients who have had extensive prior chemotherapy or radiotherapy or in debilitated patients.

When mitoxantrone is used as a single injection given every 21 days in the treatment of metastatic breast cancer and lymphomas, the most commonly encountered side effects are nausea and vomiting, although in the majority of cases these are mild and transient. Alopecia may occur, but is most frequently of minimal severity and reversible on cessation of therapy.

Cardiac disorders: Congestive heart failure may occur during therapy with mitoxantrone, or months to years after the end of treatment (see 4.4 Special Warnings and Special Precautions for Use). Some cases have been fatal. Treatment with digoxin and/or diuretics has been reported to be effective.

Other cardiovascular effects, which have been of clinical significance include decreased left ventricular ejection fraction, ECG changes and acute arrhythmia.

In patients with leukaemia an increase in the frequency of adverse cardiac events has been observed. The direct role of mitoxantrone in these cases is difficult to assess, since some patients had received prior therapy with anthracyclines and since the clinical course in leukaemic patients is frequently complicated by anaemia, fever, sepsis and intravenous fluid therapy. Cardiomyopathy has been reported in rare instances.

Other Undesirable Effects:

Hepato-biliary disorders: Mitoxantrone Sterile Concentrate may impart a blue-green colouration to the urine for 24 hours after administration, and patients should be advised to expect this during active therapy. Increased liver enzyme levels (with occasional reports of severe impairment of hepatic function in patients with leukaemia). Hyperuricaemia has also been reported. Elevated serum creatinine and blood urea nitrogen levels have been reported.

Skin and subcutaneous tissue disorders: Rash, onycholysis, blue discolouration of skin and nails and nail dystrophy has been reported occasionally.

Eye Disorders: Reversible blue colouration of the sclerae has been reported. Conjunctivitis.

Respiratory disorders: Dyspnoea.

Gastrointestinal Disorders: Diarrhoea, anorexia, constipation, gastrointestinal bleeding, abdominal pain, stomatitis, mucositis, altered taste.

Neoplasms: Secondary acute myeloid leukaemia (see 4.4 Special Warnings and Special Precautions for Use)

General disorders and administration site conditions: Allergic reaction, amenorrhoea, fever, fatigue and weakness, non-specific neurological side effects such as somnolence, confusion, anxiety and mild paraesthesia have been reported. Tumour lysis syndrome (characterised by hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia) has been observed rarely during single-agent chemotherapy with mitoxantrone, as well as during combination chemotherapy.

In patients with leukaemia, the pattern of side-effects is generally similar, although there is an increase in both frequency and severity, particularly of stomatitis and mucositis. Nevertheless, overall, patients with leukaemia tolerate treatment with mitoxantrone well.

Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discolouration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of infusion.

There is no known specific antidote for Mitoxantrone Sterile Concentrate. 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 and management should be symptomatic and supportive.

Fatalities have occurred on rare occasions as a result of severe leucopenia with infection in patients accidentally given single bolus injections of mitoxantrone at over ten times the recommended dosage. Mitoxantrone Sterile Concentrate is extensively tissue-bound and peritoneal dialysis or haemodialysis is unlikely to be effective in managing overdose.

ATC Code: L01D B07

Although its mechanism of action has not been determined, mitoxantrone is a DNA-reactive agent. It has a cytocidal effect on proliferating and non-proliferating cultured human cells, suggesting activity against rapidly proliferating and slow-growing neoplasms.

Pharmacokinetic studies in patients following intravenous administration of mitoxantrone demonstrated a triphasic plasma clearance. Distribution to tissues is rapid and extensive. Elimination of the drug is slow with a mean half-life of 12 days (range 5-18) and persistent tissue concentrations. Similar estimates of half-life were obtained from patients receiving a single dose of mitoxantrone every 21 days and patients dosed on 5 consecutive days every 21 days.

Mitoxantrone is excreted via the renal and hepatobiliary systems. Only 20-32% of the administered dose was excreted within the first five days after dosing (urine 6-11%, faeces 13-25%). Of the material recovered in the urine 65% was unchanged mitoxantrone and the remaining 35% is primarily comprised of two inactive metabolites and their glucuronide conjugates. Approximately two thirds of the excretion occurred during the first day.

Animal pharmacokinetic studies in rats, dogs and monkeys given radiolabelled mitoxantrone indicate rapid, extensive dose proportional distribution into most tissues.

Mitoxantrone does not cross the blood-brain barrier to any appreciable extent. Distribution into testes is relatively low. In pregnant rats the placenta is an effective barrier.

Plasma concentrations decrease rapidly during the first two hours and slowly thereafter. Animal data established biliary excretion as the major route of elimination. In rats, tissue elimination half-life of radioactivity ranged from 20 days to 25 days as compared with plasma half-life of 12 days. Mitoxantrone is not absorbed significantly in animals following oral administration.

Glacial acetic acid

Sodium acetate trihydrate

Sodium chloride

Sodium metabisulphite (E223)

Water for Injections

Mitoxantrone Sterile Concentrate must not be mixed in the same infusion as heparin since a precipitate may form.

It is recommended that Mitoxantrone Sterile Concentrate not be mixed in the same infusion with other drugs, as specific compatibility data are not available.

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^oC, unless dilution has taken place in controlled and validated aseptic conditions.

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 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.

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire CV31 3RW

United Kingdom

PL 04515/0127

19^th September 2006

26^th November 2007