Mitoxantrone 2mg/Ml Sterile Concentrate
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Mitoxantrone 2mg/ml Sterile Concentrate
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1ml contains mitoxantrone hydrochloride equivalent to 2.0mg mitoxantrone. The vial contains 10mg in 5ml or 20mg in 10ml.
For a full list of excipients, see section 6.1.
Sodium content:
10mg/5ml: 0.739mmol 20mg/10ml: 1.478mmol
3 PHARMACEUTICAL FORM
Concentrate for solution for infusion
The concentrate is a dark blue, aqueous solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
Posology
Metastatic Breast Cancer, Non-Hodgkin’s Lymphoma, Hepatoma:
(a) Single Agent Dosage
The recommended initial dosage of mitoxantrone used as a single agent is 14mg/m2 of body surface area, given as a single intravenous dose which may be repeated at 21-day intervals. A lower initial dosage (12mg/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 advanced breast cancer, non-Hodgkin's lymphoma and hepatoma according to the haematological nadir (which usually occurs about 10 days after dosing).
Nadir after prior dose
|
WBC (per mm3) |
Platelets (per mm3) |
Time to Recovery |
Subsequent dose after adequate haematological recovery | |
|
>1,500 |
AND |
>50,000 |
<21 days |
Repeat prior dose after recovery or increase by 2mg/m2 if myelosuppression is not considered adequate. |
|
>1,500 |
AND |
>50,000 |
> 21 days |
Withhold until recovery, then repeat prior dose. |
|
<1,500 |
OR |
<50,000 |
Any duration |
Decrease by 2mg/m2 from prior dose after recovery. |
|
<1,000 |
OR |
<25,000 |
Any duration |
Decrease by 4mg/m2 from prior dose after recovery. |
(b) 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 2-4mg/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.
Acute Non-Lymphocytic Leukaemia
(a) Single Agent Dosage in Relapse
The recommended dosage for remission induction is 12mg/m2 of body surface area, given as a single intravenous dose daily for five consecutive days (total of 60mg/m2). In clinical studies with a dosage of 12mg/m2 daily for 5 days, patients who achieved a complete remission did so as a result of the first induction course.
(b) Combination Therapy
Mitoxantrone has been used in combination regimens for the treatment of ANLL. Most clinical experience has been with mitoxantrone combined with cytosine arabinoside. This combination has been used successfully for primary treatment of ANLL as well as in relapse.
An effective regimen for induction in previously untreated patients has been mitoxantrone 10-12mg/m2 IV for 3 days combined with cytosine arabinoside 100mg/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 has been reduced to 2 days and that of cytosine arabinoside 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.
(c) Paediatric Leukaemia
As experience with mitoxantrone in paediatric leukaemia is limited, dosage recommendations in this patient population cannot at present be given.
Method of administration
Mitoxantrone should be given by intravenous infusion. Not for intrathecal use.
Syringes containing this product should be labelled “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.
4.3 Contraindications
• NOT FOR INTRATHECAL USE.
• Hypersensitivity to the active substance , other anthracyclines or to any of the excipients
• Lactation
Mitoxantrone Sterile Concentrate should not be used during pregnancy (see section 4.6).
4.4 Special warnings and precautions for use
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. The majority of these cardiac events have occurred in patients who have had prior treatment with anthracyclines, prior mediastinal/thoracic radiotherapy, or with pre-existing heart disease. 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.
As experience of prolonged treatment with mitoxantrone is presently limited, it is suggested that cardiac examinations also be performed in patients without identifiable risk factors during therapy exceeding a cumulative dose of 160mg/m2.
Careful supervision is recommended when treating patients with severe hepatic insufficiency.
Mitoxantrone is mutagenic in vitro and in vivo in the rat. In the same species there was a possible association between administration of the drug and development of malignant neoplasia.
Topoisomerase II inhibitors, including mitoxantrone, when used concomitantly with other antineoplastic agents and/or radiotherapy, have been associated with the development of Acute Myeloid leukaemia (AML) or Myelodysplastic Syndrome (MDS).
Mitoxantrone is not indicated for intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection. Safety for intrathecal use has not been established. There have been reports of neuropathy, including paralysis and bowel and bladder dysfunction following intrathecal injection.
Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.
Mitoxantrone is an active cytotoxic drug which should be used by clinicians familiar with the use of antineoplastic agents, and having 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.
Immunisation may be ineffective when given during mitoxantrone therapy. Immunisation with live virus vaccines are generally not recommended.
Mitoxantrone 10mg in 5 ml contains 0.74mmol of sodium in each vial. Mitoxantrone 20mg in 10ml contains 1.48mmol of sodium in each vial. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
Not applicable
4.6 Pregnancy and lactation
The effects of mitoxantrone on human fertility or pregnancy have not been established. As with other antineoplastic agents, patients and their partner should be advised to avoid conception for at least six months after cessation of therapy. Mitoxantrone should not normally be administered to patients who are pregnant.
Mitoxantrone is excreted in human milk and significant concentrations (18ng/ml) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants, breast feeding should be discontinued before starting treatment.
4.7 Effects on ability to drive and use machines
Not relevant.
4.8 Undesirable effects
Very common (>1/10) common (>1/10 to <1/10) uncommon (>1/1,000 to <1/100) rare (>1/10,000 to <1/1,000)
very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Cardiac disorders
Common
Decreased left ventricular ejection fraction, ECG changes and acute arrhythmia
Uncommon
Congestive heart failure has been reported and has generally responded well to treatment with digitalis and/or diuretics. 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 as most patients had received prior therapy with anthracyclines and since the clinical course in leukaemic patients is often complicated by anaemia, fever, sepsis and intravenous fluid therapy.
Rare
Rare reports of cardiomyopathy have been received.
Blood and lymphatic system disorders
Very common
Some degree of leucopenia is to be expected following recommended doses of mitoxantrone. With a 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 21st day. Thrombocytopenia can occur and anaemia occurs less frequently. Myelosuppression may be more severe and prolonged in patients who have had extensive prior chemotherapy or radiotherapy or in debilitated patients.
Nervous system disorders
Common
Non-specific neurological undesirable effects such as somnolence, neuritis, confusion, convulsion, anxiety and mild paresthesia have been reported.
Eye disorders
Very rare Conjunctivitis.
Reversible blue coloration of the sclerae
Respiratory, thoracic and mediastinal disorders
Uncommon
Dyspnoea.
Gastrointestinal disorders
Very common
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.
stomatitis, diarrhoea, abdominal pain and anorexia, constipation, mucositis Uncommon Gastrointestinal bleeding.
Renal and urinary disorders
Common
Mitoxantrone may impart a blue-green coloration to the urine for 24 hours after administration and patients should be advised that this is to be expected.
Uncommon
elevated serum creatinine and blood urea nitrogen levels
Skin and subcutaneous tissue disorders
Very common
Alopecia may occur, but is most frequently of minimal severity and reversible on cessation of therapy.
Uncommon
Transient discoloration of the skin
Blue discoloration of skin and nails has been reported occasionally.
Rare
Tissue necrosis following extravasation.
Skin rashes
Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discoloration 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.
Nail dystrophy
Neoplasm benign, malignant and unspecified (incl cysts and polyps)
Rare
Topoisomerase II inhibitors, including mitoxantrone, when used concomitantly with other antineoplastic agents, and/or radiotherapy, have been associated with the development of Acute Myeloid leukaemia (AML) of Myelodysplastic Syndrome (MDS).
Hyperuricaemia
General disorders and administration site conditions
Uncommon
Allergic reactions , fatigue, weakness and fever.
Hepatobiliary disorders
Uncommon
Increased liver enzyme values (with occasional reports of severe impairment of hepatic function in patients with leukaemia).
Reproductive system and breast disorders
Common
Amenorrhoea
4.9 Overdose
There is no known specific antidote for mitoxantrone. Haemopoietic, gastrointestinal, hepatic or renal toxicity may be seen depending on dosage given and the physical condition of the patient. In cases of overdosage the patient 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 is extensively tissue-bound and peritoneal dialysis or haemodialysis is unlikely to be effective in managing overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytotoxic antibiotics and related substances/Anthracyclines and related substances, 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.
5.2 Pharmacokinetic properties
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% primarily comprised of two inactive metabolites and their glucuronide conjugates. Approximately two thirds of the excretion occurred during the first day.
5.3 Preclinical safety data
Animal pharmacokinetic studies in rats, dogs and monkeys given radiolabeled 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride Sodium acetate Acetic acid Sodium sulphate Water for injections
6.2 Incompatibilities
Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form. Mitoxantrone should not be mixed in the same infusion as other drugs.
Shelf life
6.3
18 months After dilution
Chemical and physical in-use stability has been demonstrated for 24 hours at 25oC. From a microbiological point of view, the 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 8oC, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Do not store above 25oC Do not refrigerate or freeze.
Mitoxantrone Sterile Concentrate does not contain an antimicrobial preservative. For storage conditions of the diluted medicinal product, see section 6.3
6.5 Nature and contents of container
Colourless Type I glass vial (5ml or 10ml) with fluropolymer-coated chlorobutyl rubber stoppers and aluminium overseal.
Packs of 1 vial containing 5ml or 10ml sterile concentrate
6.6 Special precautions for disposal
a) Instructions for use
Syringes containing this product should be labelled " For intravenous use only”
Care should be taken to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes.
Vials should be dispensed in the upright position in order to prevent drops of mitoxantrone collecting in the stopper during preparation and leading to potential aerosolisation of the solution.
Dilute the required volume of Mitoxantrone Injection to at least 50 ml in the following intravenous infusions: Sodium Chloride 0.9% or Glucose 5%. Use Luer-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 freely running intravenous infusion of one 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.
b) Handling Cytotoxic drugs
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.
c) Spillage disposal
The following clean-up procedure is recommended if mitoxantrone 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 (eg, syringes, needles, tissues, etc) should be treated as toxic waste and disposed of accordingly. Incineration is recommended.
7 MARKETING AUTHORISATION HOLDER
EBEWE Pharma Ges.m.b.H Nfg. KG A-4866 Unterach,
AUSTRIA
8 MARKETING AUTHORISATION NUMBER(S)
PL 14510/0033 (10mg in 5ml)
PL 14510/0034(20mg in 10ml)
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/07/2009
10 DATE OF REVISION OF THE TEXT
02/07/2009