INFORMATION FOR HEALTH PROFESSIONALS
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NOVANTRONE (mitozantrone hydrochloride) is a potent cytotoxic synthetic anthracenedione. Its molecular formula is C22H28N4O6.2HCl and molecular weight is 517.4.
Mitozantrone hydrochloride is a hygroscopic dark blue solid.
It is supplied as a sterile aqueous solution containing mitozantrone hydrochloride equivalent to 2 mg/mL mitozantrone free base. Its structural formula appears below:
Although its mechanism of action has not been fully determined, NOVANTRONE is a DNA-reactive agent. It has a cytocidal effect on proliferating and non-proliferating cultured human cells. In vitro studies suggest that NOVANTRONE is not cell-cycle phase specific.
In animals, the principal toxic effects of NOVANTRONE 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 NOVANTRONE, doxorubicin was studied simultaneously at equileucopenic doses as a positive control for anthracycline-induced cardiomyopathy. Dogs given NOVANTRONE 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 NOVANTRONE. Myocyte alterations in doxorubicin-treated monkeys were characteristic of degeneration, whereas myocyte alterations in monkeys treated with NOVANTRONE were suggestive of cellular regeneration 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.
Toxicity studies with NOVANTRONE in combination with other antineoplastic agents, have been carried out in dogs. These studies suggest that additive myelosuppression might be expected in combination therapy.
Following intravenous administration of NOVANTRONE 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 NOVANTRONE 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.
NOVANTRONE 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 NOVANTRONE. The remaining 35% is comprised primarily of two inactive metabolites, the mono- and di-carboxylic acid derivatives of NOVANTRONE and their glucuronide conjugates. One study demonstrated that in faeces the mean percent recovery of C14-labelled materials was 18.3% (13.6-24.8%) of the administered dose over five days.
In a paper by Batra et al(1) the protein binding of the drug was quoted as 78% at concentrations ranging from 26 to 455 ng C14-mitozantrone/mL pooled human plasma. The extent of binding was independent of concentration.
Animal pharmacokinetic studies using radiolabelled NOVANTRONE 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 NOVANTRONE 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 NOVANTRONE dose.
NOVANTRONE does not cross the blood brain barrier or the placental barrier. Distribution into testes is relatively low.
NOVANTRONE is not absorbed significantly in animals following oral administration.
NOVANTRONE 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.
NOVANTRONE is contraindicated in patients who have demonstrated prior hypersensitivity to the drug.
Patients who have received prior substantial anthracycline exposure may not be treated with NOVANTRONE if cardiac function is abnormal prior to the initiation of therapy. (See WARNINGS)
NOVANTRONE treatment should not be initiated in patients who have not recovered from severe myelosuppression due to previous treatment with other cytotoxic agents or radiotherapy.
NOVANTRONE should not be used in patients with severe hepatic impairment.
Cases of functional cardiac changes, including congestive heart failure and decreases in left ventricular ejection fraction, have been reported during NOVANTRONE 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 be performed in patients without pre-existing cardiac risk factors during therapy exceeding 160 mg/m² of NOVANTRONE.
NOVANTRONE should be administered only under the supervision of a physician experienced in the use of cancer chemotherapy.
Since NOVANTRONE 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 NOVANTRONE, 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 1,500 may be expected following therapy, but white blood cell counts rarely fall below 1,000 at recommended dosages. 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 NOVANTRONE therapy.
Topoisomerase II inhibitors, including mitoxantrone HCl, when used concomitantly with other antineoplastic agents and/or radiotherapy, have been associated with the development of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).
Safety for intrathecal use of NOVANTRONE has not yet been established.
Careful supervision is recommended when treating patients with hepatic insufficiency.
NOVANTRONE should be used with extreme caution in jaundiced patients.
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)
NOVANTRONE must not be mixed in the same infusion as heparin since a precipitate may form.
It is recommended that NOVANTRONE not be mixed in the same infusion with other drugs, as specific compatibility data are not available.
Hyperuricaemia may occur as a result of rapid lysis of tumour cells by NOVANTRONE. Serum uric acid levels should be monitored and hypouricaemic therapy instituted prior to the initiation of anti-leukaemic therapy. Systemic infections should be treated concomitantly with or just prior to commencing therapy with NOVANTRONE.
Doses greater than 140 mg/m² are not recommended, particularly as a single bolus injection. Such administrations have caused fatal overdose as a result of severe leukopenia and infection.
Patients with severe renal failure have not been studied. However, as NOVANTRONE 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.
Pregnancy Category D
There is no information on the use of NOVANTRONE in pregnancy. Therefore, the drug should not be used in pregnant women or those likely to become pregnant unless the expected benefit outweighs any potential risk.
Animal studies have not demonstrated teratogenic activity due to NOVANTRONE treatment. Decreased foetal body weight 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.
NOVANTRONE caused point mutations, DNA damage and sister chromatid exchanges in vitro. Lifetime studies in mice and rats showed no residual clastogenic effect. NOVANTRONE 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 NOVANTRONE and the development of malignant neoplasia.
It is not known whether NOVANTRONE is excreted in breast milk nor whether it has a harmful effect on the newborn. It is recommended that NOVANTRONE be administered to nursing mothers only if alternative arrangements for feeding the infant can be made.
Although adequate data on the use of NOVANTRONE 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.
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 NOVANTRONE should be reduced by 2-4 mg/m² below the dose recommended for single agent usage. (See DOSAGE AND ADMINISTRATION)
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 NOVANTRONE well.
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: NOVANTRONE may impart a blue/green colouration to the urine for 24 hours after administration.
Gastrointestinal: Diarrhoea, anorexia, gastrointestinal bleeding, abdominal pain, altered taste.
Respiratory: Dyspnoea.
Local: Phlebitis. Tissue necrosis following extravasation has been reported rarely.
General: Fever, fatigue and weakness and nonspecific neurological side effects.
Dermatological: Rash, nail pigmentation.
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.
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.
In patients with leukaemia, there is an increase in the frequency of cardiac events. The direct role of NOVANTRONE 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.
Myelosuppression: Some degree of leucopenia is to be expected following recommended doses of NOVANTRONE in solid tumours; however, suppression of WBC counts below 1,000 cells/mm³ is infrequent. With dosing every 21 days, 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 with solid tumours having had extensive prior chemotherapy or radiotherapy or in debilitated patients.
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/m² if degree of myelosuppression 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 nadir < 50,000 | Any duration | Decrease by 2 mg/m² from prior dose, after recovery. |
| If WBC nadir < 1,000 and platelet nadir < 25,000 | Any duration | Decrease by 4 mg/m² from prior dose, after recovery. |
NOVANTRONE 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 NOVANTRONE 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 mitozantrone and similar combinations containing doxorubicin.
NOVANTRONE, 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 NOVANTRONE 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 NOVANTRONE 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.
Note regarding paediatric usage: Experience in paediatric patients is limited; however, complete remissions have been observed with NOVANTRONE as single agent therapy at a dosage of 8 mg/m² daily for five days.
NOVANTRONE, as single agent, is also indicated in the treatment of acute non-lymphocytic 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 NOVANTRONE and again the recommended dosage is 12 mg/m² daily for 5 days.
The symptoms of overdosage are likely to be an extension of the pharmacological actions of NOVANTRONE. Possible symptoms of toxicity are those listed under ADVERSE REACTIONS. Haematopoietic, gastrointestinal, hepatic or 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).
There is no known specific antidote for NOVANTRONE. 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.
NOVANTRONE Injection 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.
Care should be taken to avoid contact of NOVANTRONE with the skin, mucous membranes or eyes. The use of goggles, gloves and protective gowns is recommended during preparation and administration.
To reduce the possibility of spillages and splashes when removing NOVANTRONE from the vial, it is recommended that a 20 gauge needle, or one with a narrower bore, be used.
NOVANTRONE can cause staining.
Skin accidentally exposed to NOVANTRONE should be rinsed copiously with warm water and, if the eyes are involved, standard irrigation techniques should be used. 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 NOVANTRONE.) Absorb the remaining solutions with gauze or towels and dispose of these in a safe manner. Appropriate safety equipment such as goggles and gloves should be worn while working with calcium hypochlorite solutions.
NOVANTRONE does not contain an antimicrobial preservative; although NOVANTRONE has demonstrated significant self preserving qualities, unused portions of the non-diluted solution should be discarded as soon as possible after opening.
Following preparation of the infusion, NOVANTRONE solutions will maintain potency for 72 hours; however, to reduce microbiological hazards, the solution should be used as soon as practicable and the unused portion discarded within 24 hours of preparation. (Any storage of the prepared solution should be at 2-8°C.) NOVANTRONE should NOT be mixed in an infusion containing other drugs.
NOVANTRONE should be stored below 25°C. Do not freeze. The diluted infusion should not be frozen.
When stored below 25°C, NOVANTRONE Injection will maintain its potency for two years.
NOVANTRONE Injection is supplied in 10, 12.5 and 15 mL vials. Each mL contains mitozantrone hydrochloride equivalent to 2 mg/mL mitozantrone free base, with sodium chloride, sodium acetate and acetic acid as excipients. NOVANTRONE injection is a clear blue liquid
NOVANTRONE 20 mg in 10 mL vial:
NOVANTRONE 25 mg in 12.5 mL vial:
NOVANTRONE 30 mg in 15 mL vial:
Prescription Only Medicine.
Zuellig Pharma Limited
54 Carbine Road
Mt Wellington
Auckland
Telephone: (09) 570 1080
19 May 2002
REFERENCES
1. Batra, V.K. et al: Pharmacokinetics of mitoxantrone in man and laboratory animals. Drug Metab. Rev. 17:311-329, 1986.