Novantrone (Mitoxantrone)

NOVANTRONE®

Wyeth-Ayerst

Mitoxantrone HCl

Antineoplastic

Action And Clinical Pharmacology: Although its mechanism of action has not been determined, mitoxantrone is a DNA-reactive agent. It induces nuclear aberrations with chromosome scattering in cell cultures (human colon carcinoma line) and is a potent inhibitor of RNA and DNA synthesis.

Compared on an equimolar basis, mitoxantrone is 7 times more potent than doxorubicin in inhibiting the uptake of -uridine and 4 times more potent in inhibiting the uptake of -thymidine by mouse lymphoma L5178Y cells in vitro.

Indications And Clinical Uses: For chemotherapy in patients with carcinoma of the breast, including locally advanced and metastatic disease. Also for relapsed adult leukemia, lymphoma patients and patients with hepatoma.

Mitoxantrone in combination with other drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. The category includes myelogenous, promyelocytic, monocytic and erythroid acute leukemias.

Contra-Indications: In patients who have demonstrated prior hypersensitivity to anthracyclines.

Manufacturers’ Warnings In Clinical States: Caution: Mitoxantrone is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). Blood counts should be taken at frequent intervals prior, during, and post-therapy. Cardiac monitoring is advised in those patients who have received prior anthracyclines, prior mediastinal radiotherapy, or with pre-existing cardiac disease.

Since mitoxantrone produces myelosuppression (see Adverse Effects), it should be used with caution in patients in poor general condition or with pre-existing myelosuppression.

Cases of functional cardiac changes, including congestive heart failure and decreases in left ventricular ejection fraction (LVEF) have been reported. These cardiac events may be more common in patients who have had prior treatment with anthracyclines, prior mediastinal radiotherapy or with pre-existing heart disease. Cardiac monitoring of LVEF is advisable in such patients from the initiation of therapy. It is suggested that cardiac monitoring also be performed in all other patients before initiation of therapy and during therapy exceeding 140 mg/m(after approximately 10 courses of mitoxantrone).

Mitoxantrone may impart a blue-green coloration to the urine for 24 hours after administration, and patients should be advised to expect this during active therapy. A reversible blue coloration in the sclerae has been reported in 2 cases.

Pregnancy and Lactation: Mitoxantrone may cause fetal harm when administered to a pregnant woman.

In rats treated at doses of ³0.1 mg/kg (0.05 times the recommended human dose on a mg/mbasis), low fetal weight and retarded development of the fetal kidney were seen in greater frequency. In treated rabbits, an increased incidence of premature delivery was observed at doses ³0.01 mg/kg (0.01 times the recommended human dose on a mg/mbasis). Mitoxantrone was not teratogenic in rabbits.

There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

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.

Hepatic Impairment: Mitoxantrone should not be used in patients with severe hepatic dysfunction and poor performance status. If performance status is favorable, mitoxantrone in reduced dosage may be used, with careful supervision.

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

It is recommended that mitoxantrone not be mixed in the same infusion with other drugs. Mitoxantrone should not be mixed in the same infusion with heparin since a precipitate may form.

Topoisomerase II inhibitors, including mitoxantrone, in combination with other antineoplastic agents, have been associated with the development of acute leukemia.

Adverse Reactions: Some degree of leukopenia is to be expected following recommended doses of mitoxantrone. With dosing every 21 days, suppression of WBC counts below 1 000/mmis infrequent. Leukopenia is usually transient, reaching its nadir at about 10 days after dosing, with recovery usually occurring by the 21tday. Thrombocytopenia can occur, and anemia occurs less frequently. Myelosuppression may be more severe and prolonged in patients having had extensive prior chemotherapy or radiotherapy or in debilitated patients.

The most commonly encountered side effects are nausea and vomiting, although in the majority of cases these are mild (WHO Grade 1) and transient. Alopecia may occur, but is most frequently of minimal severity and reversible on cessation of therapy.

Other side effects which have occasionally been reported include allergic reactions (one with anaphylaxis), abdominal pain, amenorrhea, constipation, anorexia, diarrhea, dyspnea, fatigue, weakness, fever, gastrointestinal bleeding, stomatitis/mucositis, and nonspecific neurological side effects. Tissue necrosis following extravasation has been reported rarely.

Changes in laboratory test values have been observed infrequently, e.g., increased liver enzyme levels, elevated serum creatinine and blood urea nitrogen levels (with occasional reports of severe impairment of hepatic function in patients with leukemia).

Cardiovascular effects, which have only occasionally been of clinical significance, 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 generally responded well to treatment with digitalis and/or diuretics.

In patients with leukemia there is an increase in the frequency of cardiac events, the direct role of mitoxantrone in these cases is difficult to assess, since most patients had received prior therapy with anthracyclines and since their course is frequently complicated by anemia, fever, sepsis, and i.v. fluid therapy.

In leukemia patients treated with a single course of 12 mg/mi.v. daily for 5 days, the following drug-related toxicities occurred: moderate or severe jaundice or hepatitis (8%), moderate nausea or vomiting (8%), moderate or severe stomatitis/mucositis (9 to 29%), diarrhea (9 to 13%), and moderate or severe alopecia (11%).

Clinical Results: Introduction: Clinical trials experience has established the dosage range, efficacy and safety profile of mitoxantrone.

A single dose can be given intermittently every 3 or 4 weeks. The recommended initial treatment dose in good risk patients is 14 mg/m

The following efficacy and safety results were generated from analyses of all data during January, 1985. The database, by its nature, is dynamic and there has been no change in benefit to risk noted to date.

Efficacy: Breast: Efficacy data are available on 349 patients with locally advanced or metastatic breast carcinoma. Results are dependent on many predisposing factors including prior chemotherapy and/or radiotherapy, the health of the patients, sites of metastases, and dose of the agent employed. In a European multicenter, first-line, single-agent trial using an initial dose of 14 mg/m the overall response rate was 39%, which compared favorably to doxorubicin therapy at a dose of 60 to 75 mg/mwhen given to patients with 9 similar stage disease. In an ongoing study of a direct comparison with doxorubicin, given as second-line therapy to breast cancer patients who failed a standard first-line combination, response rates are 27% for mitoxantrone and 23% for doxorubicin. The mean duration of response observed after mitoxantrone was greater than those reported after doxorubicin. Responses have been seen in all major sites of metastases including lymph nodes, lung, bone, skin and viscera, in patients both with and without prior hormonal therapy. Available data suggest that mitoxantrone is comparable in efficacy with doxorubicin in the treatment of advanced breast cancer. Myelosuppression with 21-day treatment intervals is comparable with that observed with doxorubicin. Multiple courses of single-agent mitoxantrone therapy, in some cases for longer than 12 cycles, have been administered with excellent tolerance and a good response. Mitoxantrone showed incomplete cross-resistance with doxorubicin since responses have been observed in patients in whom doxorubicin had failed or who relapsed after response to that drug. A continuing large-scale clinical trials program with combination therapy also demonstrated early positive results for efficacy and safety. In seven studies, over 100 cycles of combination therapy have been given to 77 patients.

Additional Indications: A total of 966 patients have been treated with mitoxantrone for 3 other indications of which 259 patients had non-Hodgkin’s lymphoma (NHL), 546 had leukemia, and 161 had hepatocellular carcinoma (HCC). The accrual of these 966 patients:

Non-Hodgkin’s Lymphoma: Three key studies evaluated single agent mitoxantrone in 148 patients with relapsed or refractory advanced NHL at a dose of 14 mg/m i.v., every 3 weeks. Of 127 patients evaluable for response in 2 trials, there were 10 complete responses (CR) and 42 partial responses (PR) producing an overall therapeutic response rate of 41%. The median duration of responses in the multicenter study (122 evaluable patients) was 195 days. Many patients’ responses lasted in excess of 1 year. Responses were seen in all histological subtypes of NHL. Response to mitoxantrone was independent of prior chemotherapy and independent of whether the patient received prior doxorubicin. This demonstrated a lack of complete cross-resistance between mitoxantrone and other drugs including anthracyclines.

Mitoxantrone was evaluated in combination with other agents for the treatment of NHL. A total of 28 patients were treated with different regimens. A first-line comparative trial of the combination of intermediate dose methotrexate with leucovorin rescue + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone (m-BACOD) versus the same combination with 10 mg/mmitoxantrone replacing doxorubicin (m-BNCOD) has shown activity: 4 PR’s in 6 evaluable patients with m-BNCOD and 3 PR’s in 6 with m-BACOD. The combination of mitoxantrone at 10 mg/m daily for 3 days, + vincristine + dexamethasone (NOD) produced 3 PR’s in 5 evaluable patients. A first-line comparative trial of the combination of cyclophosphamide + vincristine + prednisone + doxorubicin (CHOP) versus the same combinations with 10 mg/mmitoxantrone replacing doxorubicin (CNOP) has only recently begun.

Mitoxantrone at 5 mg/m daily for 3 days every 3 weeks produced one CR and 2 PR’s in 8 evaluable patients with NHL; 10 patients were enrolled. Several other studies reported in the literature and not sponsored by Lederle support the activity of mitoxantrone in the treatment of NHL.

Leukemia: Four key studies sponsored by Lederle evaluated single agent mitoxantrone in 181 adult patients with refractory or relapsed acute non-lymphocytic leukemia (ANLL) or chronic myelogenous leukemia in blast crisis (B-CML) at doses ranging from 8 to 12 mg/m i.v., daily for 5 days, every 3 weeks. A dose response effect was evident. Optimal activity was seen at a dose of 12 mg/m daily for 5 days. At this dose level, there were 19 CR’s in 49 evaluable adult patients with ANLL in relapse producing an overall response rate of 39%. The median duration of complete response in the largest (121 patients) single agent study was 98 days. Several patients had remissions lasting in excess of 1 year.

There were 4 studies comprising 63 patients in which mitoxantrone was evaluated in combination with other agents in the treatment of leukemia. The highest complete remission rate of 49% (11 CR’s in 23 evaluable patients with ANLL) was obtained when mitoxantrone at 10 to 12 mg/m daily for 3 days, was combined with cytosine arabinoside at 100 mg/mdaily for 7 days. When mitoxantrone at 10 mg/m daily for 5 days was combined with the same dose of cytosine arabinoside, it produced 2 CR’s in 8 evaluable patients. Treatment of patients with acute lymphoblastic leukemia using 10 mg/mmitoxantrone, daily for 3 days, + vincristine + prednisone produced 10 responses in 16 evaluable patients, for a response rate of 62.5%.

Activity was also seen in B-CML. Since no standard therapy exists for this disease and bone marrow is never truly normal in this disorder, both CR’s and PR’s were considered evidence of efficacy. The optimal dose of mitoxantrone was 12 mg/m daily for 5 days, producing 6 responses in 17 evaluable patients.

Experience in pediatric leukemia patients is limited. Twenty-four patients were treated with 6 to 8 mg/mmitoxantrone, daily for 5 days. There were 3 responses in 24 evaluable children.

Fourteen adult leukemia patients received 20 to 37 mg/mmitoxantrone once every 2 weeks. No therapeutic responses were observed using this schedule.

Several other studies reported in the literature and not sponsored by Lederle support the activity of mitoxantrone in the treatment of ANLL and B-CML.

Hepatocellular Carcinoma: Three clinical trials sponsored by Lederle have been conducted using mitoxantrone in the therapy of HCC. Mitoxantrone was administered to 65 patients i.v. at 12 mg/mevery 3 weeks in 2 studies, and in 1 study with 10 patients at 6 to 10 mg/mday by continuous hepatic artery infusion for 3 consecutive days, every 3 weeks. Considering the short life span of patients presenting with HCC, a response of stable disease was included along with PR’s and CR’s in assessing efficacy. In these 3 studies, the overall therapeutic response rate was 46.7% (11 CR’s and PR’s + 10 stable disease in 45 evaluable patients). Activity was confirmed in other studies not sponsored by Lederle. Duration of response was variable among these studies and ranged between 3 and 52 weeks.

Safety: Data on the overall safety profile of mitoxantrone (based on 989 patients) demonstrated advantages of mitoxantrone compared to the anthracyclines with respect to both the quality of life and the long-term safety of patients. The majority of side effects with mitoxantrone are mild in nature. Removal of patients from mitoxantrone treatment for reasons of toxicity has been rare in clinical studies. A number of patients have reported no side effects at all. In addition, the relatively low risk of serious side effects has permitted treatment of patients on an out-patient basis. The most common acute effects were nausea and/or vomiting (only 3.5% severe or very severe with mitoxantrone, compared to 10 to 15% reported with doxorubicin), stomatitis/mucositis (only 0.3% severe or very severe with mitoxantrone) and alopecia (only 0.9% severe or very severe, and 15% overall with mitoxantrone compared with 85% severe or very severe and 100% overall reported with doxorubicin). Serious local reactions have been reported rarely following extravasation of mitoxantrone at the infusion site.

With respect to myelosuppression, initial mitoxantrone doses of 14 mg/mevery 3 weeks are well-tolerated in good-risk patients. Severe degrees of myelosuppression have been rare. The median white cell nadir in a European second-line study was 2.5´10 in a European first-line study only 4.8% (2/42) of patients experienced a nadir of less than 1 000. The nadir usually occurs around day 10 or 11 and returns to normal baseline value by day 21, in time for the next course of treatment. After multiple courses of mitoxantrone, white blood cell and platelet nadirs show no further decrease beyond those observed in the first few cycles, indicating no cumulative or permanent effects of mitoxantrone on marrow reserves.

Mitoxantrone had an exceptional safety profile and was well tolerated by patients treated for NHL, leukemia and hepatoma, as well as for breast cancer. However, due to the pathophysiology of leukemia and the higher doses of mitoxantrone employed, the safety profile differed from that seen in NHL and in hepatoma (see Adverse Effects). The most severe and life-threatening events, i.e. bleeding and infection, are well described morbid complications of acute leukemia. Many of the episodes of hepatic dysfunction were probably related to the increased bilirubin load and increased exposure to hepatitis viruses as a result of the multiple transfusions of blood products necessary in the proper treatment of this disorder.

Cardiotoxicity: In investigational trials of intermittent single doses, patients who received up to the cumulative dose of 140 mg/mhad a cumulative 2.6% probability of clinical congestive heart failure. The overall cumulative probability rate of moderate or serious decreases in LVEF at this dose was 13% in comparative trials. In contrast, doxorubicin has been reported to produce chronic cardiomyopathy and irreversible congestive heart failure in up to 11% of patients given 9 or more courses of that drug at the usual dose schedule (60 mg/mevery 3 weeks).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no known specific antidote for mitoxantrone. Accidental overdoses have been reported. Some patients receiving 140 to 180 mg/mas a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of medullary hypoplasia. Although patients with severe renal failure have been studied, mitoxantrone is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis (see Warnings, Precautions and Adverse Effects).

Dosage And Administration: Breast Cancer, Lymphoma, Hepatoma: The recommended initial dosage for use as a single agent is 14 mg/mof body surface area, given as a single i.v. dose, which may be repeated at 21-day intervals. A lower initial dose (12 mg/mor 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 judgment 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.
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/mwith leucovorin rescue) and glucocorticoids.

As a guide, the initial dose of mitoxantrone when used with other myelosuppressive agents should be reduced by 2 to 4 mg/mbelow the doses recommended for single agent usage; subsequent dosing depends on the degree and duration of myelosuppression.

Dosage for Patients With Acute Leukemia in Relapse: The recommended dosage for induction is 12 mg/mof body surface area, given as a single i.v. dose daily for 5 consecutive days (total of 60 mg/m.

In clinical studies, with a dosage of 12 mg/mdaily for 5 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 mitoxantrone and again the recommended dosage is 12 mg/mdaily for 5 days.

Combination Therapy for Leukemia: Mitoxantrone, together with cytosine arabinoside, has been used successfully for the treatment of both first line and second line patients with acute nonlymphocytic leukemia.

For induction, the recommended dosage is 10 to 12 mg/mof mitoxantrone for 3 days and 100 mg/mof cytosine arabinoside for 7 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 mitoxantrone given for only 2 days and cytosine arabinoside for only 5 days.

If severe or life-threatening nonhematological toxicity is observed during the first induction course, the second induction course should be withheld until the toxicity clears.

Children: Experience in pediatric patients is limited; however, complete remissions have been observed with mitoxantrone as single agent therapy at a dosage of 8 mg/mdaily for 5 days.

Administration of Solution: Mitoxantrone solution should be diluted to at least 50 mL with either Sodium Chloride for Injection USP or 5% Dextrose for Injection USP. This solution should be introduced slowly into the tubing of a freely running i.v. infusion of Sodium Chloride for Injection USP or 5% Dextrose for Injection USP administered over not less than 3 to 5 minutes i.v. If extravasation occurs, the administration should be stopped immediately and restarted in another vein. The nonvessicant properties of mitoxantrone minimize the possibility of severe reactions following extravasation, however, tissue necrosis has been reported rarely.

Mitoxantrone should be administered by individuals experienced in the use of antineoplastic therapy.

A 20 gauge or smaller needle size is recommended as the optimal needle size. Doses should be removed using slightly negative pressure.

Caution in the handling and preparation of mitoxantrone solutions must be exercised and the use of protective eyeglasses, gloves and other protective clothing is recommended. See Guidelines for Safe Use by Hospital Personnel.

Storage: Store at 15 to 25°C.

Following preparation of the infusion, the diluted solution should be stored at room temperature and used within 24 hours. Any original solution which remains in the vial should be discarded.

Note: Like the original solutions, the dilutions should also not be frozen.

Guidelines for Safe Use by Hospital Personnel: Handling: 1. Preparation of antineoplastic solutions should be done in a vertical laminar flow hood (Biological Safety Cabinet-Class II). 2. Personnel preparing mitoxantrone solutions should wear PVC gloves, safety glasses and protective clothing such as disposable gowns and masks. 3. Personnel regularly involved in the preparation and handling of antineoplastics should have bi-annual blood examinations.

Disposal: 1. Avoid contact with skin and inhalation of airborne particles by use of PVC gloves and disposable gowns and masks. 2. All needles, syringes, vials, ampuls and other materials which have come in contact with mitoxantrone should be segregated in plastic bags, sealed and marked as hazardous waste. Incinerate at 1 000°C or higher. Sealed containers may explode if a tight seal exists. 3. If incineration is not available, mitoxantrone HCI may be detoxified by adding 5.5 parts by weight of calcium hypochlorite to each 1 part by weight of mitoxantrone HCI in 13 parts by weight of water. The calcium hypochlorite should be added gradually and the procedure carried out with adequate ventilation since chlorine gas is liberated.

Vials: Prepare an adequate quantity of calcium hypochlorite solution (e.g., Add 43.5 g calcium hypochlorite to 100 mL of water*). Withdraw any mitoxantrone remaining in the vial with the aid of a hypodermic syringe. Add to the prepared calcium hypochlorite solution slowly, preferably in chemical fume hood or biological safety cabinet-Class II. Add an appropriate quantity of the calcium hypochlorite solution to the vial to detoxify any remaining drug.

*Appropriate sefety equipment such as goggles and gloves should be worn while working with calcium hypochlorite solution since it is corrosive.

Withdraw the solution and discard in the sewer system with running water. Dispose of the detoxified vials in a safe manner.

Needles, Syringes, Disposable and Nondisposable Equipment: Rinse equipment with an appropriate quantity of calcium hypochlorite solution (43.5 g/100 mL of water*). Discard the solution in the sewer system with running water and discard disposable equipment in a safe manner. Thoroughly wash nondisposable equipment in soap and water.

*Appropriate safety equipment such as goggles and gloves should be worn while working with calcium hypochlorite solution since it is corrosive.

Spillage/Contamination: Wear gloves, mask, protective clothing. Place spilled material in an appropriate container (i.e., cardboard for broken glass) and then in a polyethylene bag; absorb remains with gauze pads or towels; wash area with water and absorb with gauze or towels again and place in bag; seal, double bag and mark as a hazardous waste. Dispose of waste by incineration or by other methods approved for hazardous materials. Personnel involved in cleanup should wash with soap and water.

Availability And Storage: 20 mg: Each mL of clear, dark blue, sterile aqueous solution for injection contains: mitoxantrone HCl equivalent to mitoxantrone (free base) 2 mg. Nonmedicinal ingredients: acetic acid, sodium acetate, sodium chloride and water for injection. Preservative- and tartrazine-free. Vials of 10 mL.

25 mg: Each mL of clear, dark blue, sterile aqueous solution for injection contains: mitoxantrone HCl equivalent to mitoxantrone (free base) 2 mg. Nonmedicinal ingredients: acetic acid, sodium acetate, sodium chloride and water for injection. Preservative- and tartrazine-free. Vials of 12.5 mL.

NOVANTRONE® Wyeth-Ayerst Mitoxantrone HCl Antineoplastic

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