Mitoxantrone hydrochloride
DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate is a dark blue, sterile solution of mitoxantrone hydrochloride, sodium chloride, sodium acetate trihydrate and glacial acetic acid in Water for Injection. Sodium metabisulfite is added to the formulation to prevent oxidation during manufacture. Each vial contains 2.33 mg of mitoxantrone hydrochloride equivalent to 2.00 mg mitoxantrone. The pH of the solution is between and 3.0 and 4.5.
Mitoxantrone is an antineoplastic agent. Although its mechanism of action has not been fully determined, mitoxantrone hydrochloride is a DNA-reactive agent. It has a cytocidal effect on proliferating and non-proliferating cultured human cells. In vitro studies suggest that mitoxantrone is not cell-cycle phase specific. In animals, the principal toxic effects of mitoxantrone hydrochloride at doses within the human therapeutic range are reversible myelosuppression (manifested predominantly as leucopenia; erythropenia and thrombocytopenia are normally less severe) and lymphocytic depletion of the lymphoid organs. Gastrointestinal haemorrhage and congestion were noted in continuous daily dosing studies, but not in the intermittent schedules to be used clinically. In dog and monkey studies with mitoxantrone hydrochloride, doxorubicin was studied simultaneously at equileucopenic doses as a positive control for anthracycline-induced cardiomyopathy. Dogs given mitoxantrone hydrochloride and untreated control dogs showed slight dilation of the sarcoplasmic reticulum which regressed over time. In monkeys, clinical signs of congestive heart failure were observed in animals given doxorubicin, but not mitoxantrone hydrochloride. Myocyte alterations in doxorubicin-treated monkeys were characteristic of degeneration, whereas myocyte alterations in monkeys treated with mitoxantrone hydrochloride were suggestive of cellular degeneration and repair. In rats, there was no evidence of the progressive cardiomyopathy characteristic of anthracyclines. An analysis of cardiotoxicity in clinical studies is presented under WARNINGS AND PRECAUTIONS. Toxicity studies with mitoxantrone in combination with other antineoplastic agents have been carried out in dogs. These studies suggest that additive myelosuppression might be expected in combination therapy.
Clinical studies of efficacy of mitoxantrone as a single agent in the treatment of late stage breast cancer have demonstrated response rates ranging from 20% in previously treated patients to 40% as first line chemotherapy. Responses have been reported in the primary site and in the following sites of metastases: lymph node, lung, liver, bone, skin. In a multicentre study of single agent mitoxantrone in the treatment of relapsed or refractory advanced non-Hodgkin's lymphoma, a response rate of 41% was demonstrated using a dosage schedule of 14 mg/m2 I.V. every three weeks. The optimal activity of single agent mitoxantrone in relapsed acute non-lymphocytic leukaemia (ANLL) was seen at a dose of 12 mg/m2, daily for five days. At this dose level a response rate of 39% was observed.
Following intravenous administration of mitoxantrone in patients, a triphasic plasma clearance is observed. The drug is rapidly and widely distributed into extravascular tissues. Elimination is slow with a terminal half-life of over 12 days (range 5-18). Similar estimates of the half-life were obtained from patients receiving mitoxantrone on either a schedule of daily for five days or a single dose every three weeks. Plasma accumulation of drug was not apparent on either schedule. Mitoxantrone is excreted via the renal and hepatobiliary systems. Renal excretion is limited; only 6%-11% of the dose is recovered in the urine within five days after drug administration. Of the material recovered in the urine, 65% is unchanged mitoxantrone. The remaining 35% is comprised primarily of two inactive metabolites, the mono and di-carboxylic acid derivatives of mitoxantrone and their glucuronide conjugates. One study demonstrated that in faeces the mean percent recovery of C14-labelled material was 18.3% (13.6-24.8%) of the administered dose over five days. The protein binding of the drug has been quoted as 78% at concentrations ranging from 26 to 455 ng C14-mitoxantrone/mL pooled human plasma. The extent of binding was independent of concentration. Animal pharmacokinetic studies using radiolabelled mitoxantrone indicate rapid, extensive, dose-proportional distribution into most tissues. Biliary excretion is the major route of elimination. The urine and bile of the rat contain the same metabolites that are present in human urine. No significant difference in the pharmacokinetics of mitoxantrone was observed in patients with moderately impaired liver function (serum bilirubin 1.3-3.4 mg/dL) as compared with 16 patients without hepatic dysfunction. Results of pharmacokinetic studies on 4 patients with severe hepatic dysfunction (bilirubin greater than 3.4 mg/dL) suggest that these patients have a lower total body clearance and a larger AUC than other patients at a comparable mitoxantrone dose. Mitoxantrone does not cross the blood brain barrier or the placental barrier. Distribution into testes is relatively low. Mitoxantrone is not absorbed significantly in animals following oral administration.
DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate is indicated for chemotherapy in patients with metastatic carcinoma of the breast, non-Hodgkin's lymphoma, adult acute non- lymphocytic leukaemia (ANLL) and chronic myelogenous leukaemia in blast crisis.
DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate should be diluted to at least 50 mL with either Sodium Chloride for Injection or 5% Glucose for Injection. This solution should be introduced slowly into the tube of a freely running intravenous infusion of Sodium Chloride for Injection or 5% Glucose for Injection over not less than three to five minutes. Follow administration with a flush of the appropriate diluent. If extravasation occurs, the administration should be stopped immediately and restarted in another vein. Product is for single use in one patient only. Although DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate has demonstrated significant self preserving qualities, unused portions of the non-diluted solution should be discarded as soon as possible after opening. DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate does not contain an antimicrobial preservative, any unused portions of the diluted product should be discarded after use in a patient. Following preparation of the infusion, mitoxantrone solutions will maintain potency for 72 hours; however, the solution should be used as soon as practicable and the unused portion discarded within 24 hours of preparation. Single Agent Therapy In Breast Cancer, Lymphoma: The recommended initial dosage for use 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 dose (12 mg/m2 or less) is recommended in patients with inadequate marrow reserves due to prior therapy or poor general condition. Dosage modification and timing of subsequent dosing should be determined by clinical judgement depending on the degree and duration of myelosuppression. If 21-day white blood cell and platelet counts have returned to adequate levels, prior doses can usually be repeated. The following table indicates a guide to dosing based on myelosuppression for the treatment of breast cancer and non-Hodgkin's lymphoma.
| WBC and Platelet Nadir | Time to Recovery | Subsequent Dosing |
| If WBC nadir>1,500 and platelet nadir>50,000 | Recovery <= 21 days | Repeat prior dose, or increase by 2 mg/m 2 if degree of myelo- Suppression indicates that a higher dose can be tolerated. |
| If WBC nadir>1,500 and platelet nadir>50,000 | Recovery > 21 days | Withhold until recovery, then repeat prior dose. |
| If WBC nadir<1,500 and platelet<50,000 | Any duration | Decrease by 2mg/m 2 from prior dose, after recovery. |
| If WBC nadir<1,000 and platelet<25,000 | Any duration | Decrease by 4 mg/m 2 from prior dose, after recovery. |
Combination Therapy For Breast Cancer, Lymphoma: Mitoxantrone has been given in various combination regimens with the following cytotoxic agents for the treatment of breast cancer and lymphomas: cyclophosphamide, fluorouracil, vincristine, vinblastine, bleomycin, methotrexate (standard dose or 200 mg/m2 with leucovorin rescue) and glucocorticoids. As a guide, the initial dose of DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate when used with other myelosuppressive agents should be reduced by 2-4 mg/m2 below the doses recommended for single agent usage; subsequent dosing depends upon the degree and duration of myelosuppression. Long term survival data for NHL are as yet inadequate to establish comparability between combinations containing mitoxantrone and similar combinations containing doxorubicin.
Mitoxantrone, together with cytosine arabinoside, has been used successfully for the treatment of both first line and second line patients with acute non-lymphocytic leukaemia.
For induction, the recommended dosage is 10-12 mg/m2 of DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate for three days and 100 mg/m2 of cytosine arabinoside for seven days (the latter given as a continuous 24 hour infusion). If a second course is indicated, then the second course is recommended with the same combination at the same daily dosage levels but with DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate given for only two days and cytosine arabinoside for only five days. If severe or life-threatening non-haematological toxicity is observed during the first induction course, the second induction course should be withheld until the toxicity clears.
Experience in paediatric patients is limited.
Mitoxantrone, as a single agent is also indicated in the treatment of acute non-lymphatic leukaemia.
The recommended dosage for 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 five days, patients who achieved a complete remission did so as a result of the first induction course. Re-induction upon relapse may be attempted with DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate and again the recommended dosage is 12 mg/m2 daily for five days.
Compatibilities:
Mitoxantrone must not be mixed in the same infusion as heparin as a precipitate may form.
It is recommended that Mitoxantrone not be mixed into the same infusion with other drugs, as specific compatibility data are not available.
NOT FOR INTRATHECAL USE. DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate is contraindicated in patients who have demonstrated prior hypersensitivity to mitoxantrone hydrochloride or other anthracylines. Patients who have received prior substantial anthracycline exposure may not be treated with DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate if cardiac function is abnormal prior to the initiation of therapy (see WARNINGS AND PRECAUTIONS). DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate treatment should not be initiated in patients who have not recovered from severe myelosuppression due to previous treatment with other cytotoxic agents or radiotherapy. DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate should not be used in patients with severe hepatic impairment.
DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate should be administered only under constant supervision by physicians experienced in therapy with cytotoxic agents and only when potential benefits of mitoxantrone therapy outweigh the possible risks. Appropriate facilities should be available for adequate management of complications should they arise. Full blood counts should be undertaken serially during a course of treatment. Dosage adjustments may be necessary based on these counts (see DOSAGE AND ADMINISTRATION). Mitoxantrone is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection, Mitoxantrone must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurological sequelae, and paralysis with bowel and bladder dysfunction (see CONTRAINDICATIONS).
Cases of functional cardiac changes, including congestive heart failure and decreases in left ventricular ejection fraction have been reported during mitoxantrone therapy. These cardiac events have occurred most commonly in patients who have had prior treatment with anthracyclines, prior mediastinal radiotherapy or with pre-existing heart disease, indicating a possible increased risk of cardiotoxicity in such patients. It is therefore recommended that regular cardiac monitoring be carried out in these patients, taking into account the extent to which individual patients have been exposed to these cardiac risk factors. A small proportion of endomyocardial biopsy reports have demonstrated changes consistent with anthracycline toxicity in patients who had not received prior anthracyclines. Based on current experience it is recommended that cardiac monitoring also be performed in patients without pre-existing cardiac risk factors before initiation of therapy and during therapy exceeding 140 mg/m2 of mitoxantrone.
Since mitoxantrone hydrochloride produces myelosuppression, it should be used with caution in patients in poor general condition or with pre-existing myelosuppression due to any cause. There is a high incidence of bone marrow depression, primarily of leucocytes, requiring careful haematological monitoring. Following recommended doses of mitoxantrone, leucopenia is usually transient, reaching its nadir at about 10 days after dosing, with recovery usually occurring by the 21st day. White blood cell counts as low as 1500 mm3 may be expected following therapy, but white blood cell counts rarely fall below 1000 mm3 at recommended dosage. Red blood cells and platelets should also be monitored since depression of these elements may also occur. Haematological toxicity may require reduction of dose or suspension or delay of mitoxantrone therapy. Hyperuricaemia may occur as a result of rapid lysis of tumour cells by mitoxantrone. Serum uric acid levels should be monitored and hypouricaemic therapy instituted prior to the initiation of antileukaemic therapy. Topoisomerase II inhibitors, including mitoxantrone hydrochloride, when use alone or in combination with other antineoplastic agents and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia (AML), Acute Promyelocytic Leukaemia (APL) or Myelodysplastic Syndrome (MDS). Mitoxantrone has been associated with the development of secondary AML in humans (see ADVERSE EFFECTS). Systemic infections should be treated concomitantly with or just prior to commencing therapy with DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate.
Instructions to be given to Patients
Patients should be advised to expect a blue/green colouration to the urine for up to 24 hours after mitoxantrone administration. Bluish discolouration of the sclera may also occur.
Patients should be instructed to inform their physician of any prior abnormal heart conditions.
3.
Patients should also be advised of the signs and symptoms of myelosuppression.
Full blood counts should be undertaken serially during a course of treatment. Dosage adjustments may be necessary based on these counts (see DOSAGE AND ADMINISTRATION).
DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate may cause foetal harm when administered to a pregnant woman. In reproductive toxicology and teratology studies at the highest tolerated daily doses allowing evaluation of reproduction and teratology, mitoxantrone had no effect on reproductive performance, fertility, or gestation in rats. Slight dose-related decreases in epididymal weights were noted in the F0 generation. However, F1 and F2 generations were not affected by dosing of the F0 generation. In rats treated at doses of <=0.1 mg/kg (0.05 fold the recommended human dose on a mg/m2 basis), low foetal weight (attributed to maternal toxicity) and retarded development of the foetal kidney were seen in greater frequency. In treated rabbits, an increased incidence of premature delivery was observed at doses <=0.01 mg/kg (0.01 fold the recommended human dose on a mg/m2 basis). Mitoxantrone given I.V. was not teratogenic in rats or rabbits. In contrast, doxorubicin is known to be embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits. There are no adequate and well-controlled studies in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child bearing potential should be advised to avoid becoming pregnant 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.
Animal studies have not demonstrated teratogenic activity due to mitoxantrone treatment. Decreased foetal bodyweight noted in high dose rats (0.2 mg/kg/day) and an increased incidence of premature delivery noted in rabbits (0.01 to 0.05 mg/kg/day) were attributed to maternal toxicity. Mitoxantrone caused point mutations, DNA damage and sister chromatid exchanges in vitro. Lifetime studies in mice and rats showed no residual clastogenic effect. Mitoxantrone did not induce cell transformation in mammalian cells in vitro. In a lifetime study in rats, there was a possible association between the administration of mitoxantrone and the development of malignant neoplasia.
Although adequate data on the use of DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate in patients with hepatic dysfunction are not yet available, the pharmacokinetic profile suggests that clearance of the drug in such patients may be reduced and dosage may need to be adjusted accordingly. Careful supervision is recommended when treating patients with hepatic insufficiency. DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate should be used with extreme caution in jaundiced patients. DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate is contraindicated in patients with severe hepatic dysfunction (see CONTRAINDICATIONS).
Patients with severe renal failure have not been studied. However, as mitoxantrone undergoes limited renal excretion and extensive tissue binding, it is unlikely that the therapeutic effect or toxicity in these patients would be reduced by peritoneal dialysis or haemodialysis.
Presumed to be safe or unlikely to produce an effect on the ability to drive or use machinery.
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 DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate should be reduced by 2-4 mg/m2 below the dose recommended for single agent usage (see DOSAGE AND ADMINISTRATION).
DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate must not be mixed in the same infusion as heparin since a precipitate may form. It is recommended that DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate not be mixed in the same infusion with other drugs, as specific compatibility data are not available.
Mitoxantrone is clinically well tolerated demonstrating a low overall incidence of adverse events particularly those of a severe, irreversible, or life threatening nature. When used as a single injection every three weeks in the treatment of solid tumours 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. 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 DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate well.
More Common Reactions:
Gastrointestinal:
Nausea, vomiting and stomatitis. In the majority of cases these are mild (WHO Grade 1) and transient.
Dermatological:
Alopecia, most frequently of minimal severity and reversible on cessation of
therapy.
Haematological:
Myelosuppression, especially leucopenia. Thrombocytopenia and anaemia are less common.
Renal:
Mitoxantrone may impart a blue-green colouration to the urine for 24 hours after administration.
Less Common Reactions:
Gastrointestinal:
Diarrhoea, anorexia, gastrointestinal bleeding, abdominal pain, altered taste.
Respiratory:
Dyspnoea, interstitial pneumonitis.
Local:
Phlebitis. Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discolouration of the skin. Tissue necrosis following extravasation has been reported rarely.
General:
Allergic reactions (hypotension, urticaria, anaphyllaxis) have been reported. Fever, fatigue and weakness, non-specific neurological side effects such as somnolence, confusion, anxiety and mild paraesthesia. 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.
Dermatological:
Rash, nail pigmentation, onycholysis.
Hepatic:
Increased liver enzyme levels and elevated bilirubin levels have been reported occasionally.
Renal:
Elevated serum creatinine and blood urea nitrogen levels have been reported occasionally.
Ophthalmic:
Reversible blue colouration of the sclerae has been reported.
Serious or Life Threatening Reactions:
Haematological: Some degree of leucopenia is to be expected following recommended doses of DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate in solid tumours. However, 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 21st day. Thrombocytopenia can occur and anaemia occurs less frequently. Myelosuppression may be more severe and prolonged in patients having had extensive prior chemotherapy or radiotherapy or in debilitated patients. Acute Promyelocytic Leukaemia (APL) has been reported.
Acute myeloid leukaemia/acute myelodysplatic syndrome (AML/AMS):
Secondary AML/AMS has been reported following chemotherapy with various DNA topoisomerase II poisons, including mitoxantrone. In one study a 5% incidence of secondary AML/AMS was reported after treatment with mitoxantrone and methotrexate - mitoxantrone was suspected as the causative agent. Features of the AML include a latency period of <3 years, short pre-leukaemic phase, and non-specific cytogenic alterations.
Cardiovascular:
Cardiovascular effects include decreased left ventricular ejection fraction (determined by ECHO or MUGA scan), ECG changes and acute arrhythmia. Congestive heart failure has been reported. Such cases have generally responded well to treatment with digitalis and/or diuretics. Bradycardia, tachycardia and chest pain have been reported.
In patients with leukaemia, there is an increase in the frequency of cardiac events. The direct role of mitoxantrone in these cases is difficult to assess, since some patients had received prior therapy with anthracyclines and since their clinical course is frequently complicated by anaemia, fever, sepsis and intravenous fluid therapy.
As would be expected from the pharmacological actions of the drug, haematopoietic, gastrointestinal, hepatic and renal toxicity may be seen, depending on the dosage given and the physical condition of the patient. Toxicity may be delayed and life threatening (e.g. myelosuppression). (See also the sections WARNINGS AND PRECAUTIONS and ADVERSE EFFECTS). Accidental overdosages have been reported. Some patients receiving 140-180 mg/m2 as a single bolus injection died as a result of severe leukopenia with infection. 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 (see also the sections WARNINGS AND PRECAUTIONS and ADVERSE EFFECTS).
There is no known specific antidote for mitoxantrone. In cases of overdosage the patient should be monitored closely and management should be symptomatic and supportive. Haematologic support and antimicrobial therapy may be required during prolonged periods of medullary hypoplasia. In case of overdose, immediately contact the Poisons Information Centre for advice (In New Zealand, call 0800 764 766.)
Store below 25degC. Do not freeze. The diluted solution should not be frozen.
Instructions for Handling
To reduce the possibility of spillages and splashes when removing DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate from the vial, it is recommended that a 20 gauge needle, or one with a narrower bore be used. Care should be taken to avoid contact of DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate with the skin, mucous membranes or eyes. The use of goggles, gloves and protective gowns is recommended during preparation and administration. Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and, if the eyes are involved, standard irrigation techniques should be used. Appropriate safety equipment such as goggles and gloves should be worn while working with calcium hypochlorite solutions. Mitoxantrone can cause staining.
If spill occurs, restrict access to the affected area. Wear two pairs of latex rubber gloves, a suitable mask, a protective gown and safety glasses. Limit the spread of the spill by covering with a suitable material such as absorbent towels or adsorbent granules. Collect the absorbent/adsorbent and other debris from the spill and place in a leak proof plastic container and label accordingly. Equipment and spills on environmental surfaces may be cleaned up by using an aqueous solution of calcium hypochlorite (5.5 parts calcium hypochlorite in 13 parts by weight of water for each one part by weight of DBL(tm) Mitoxantrone Hydrochloride Injection Concentrate). Cytotoxic waste should be regarded as toxic and hazardous and clearly labelled 'CYTOTOXIC WASTE FOR INCINERATION AT 1100degC'. Waste material should be incinerated at 1100degC for at least 1 second. Clean the remaining spill area with copious amounts of water.
Prescription Medicine
2 mg/mL 10 mL Onco-Tain(tm) Vial (Single)
FURTHER INFORMATION
The molecular formula of mitoxantrone hydrochloride is C22H28N4O6.2HCl. Its molecular weight is 517.4. The CAS Registry number of mitoxantrone hydrochloride is 70476-82-3. The structural formula of mitoxantrone appears below: Mitoxantrone hydrochloride is a dark blue hygroscopic solid. It is sparingly soluble in water, slightly soluble in methyl alcohol and practically insoluble in acetone, acetonitrile and chloroform.
SPONSOR DETAILS
Hospira NZ Limited 23 Haining Street Te Aro Wellington New Zealand
DATE OF PREPARATION
23 August 2013