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药品说明

中文通用名称: 盐酸米托蒽醌 
英文通用名称: Mitoxantrone Hydrochloride

其 它 名 称:

能减瘤,能灭瘤,诺安托,二盐酸米托蒽醌,Novantron,Novantrone,Mitoxantrone Dihydrochloride,DAD,Novantrone Hydrochloride,米西宁,诺消灵,Militant,注射用盐酸米托蒽醌,盐酸米托蒽醌注射液,恒恩,诺肖林,Mitoxantrone Hydrochloride for Injection,Mitoxantrone Hydrochloride Injection

适应症 
主要用于乳腺癌、恶性淋巴瘤、急性白血病，对肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、肝癌、大肠癌、肾癌、前列腺癌、子宫内膜癌、睾丸肿瘤、卵巢瘤和头颈部癌也有效。 

用法用量 
成人 
·常规剂量 
·静脉滴注 
1.单药治疗：一次12-14mg/m☆2☆，溶于生理盐水或5%葡萄糖注射液中(至少50ml)静脉滴注，时间不少于30分钟，每3-4周1次。或一次4-8mg/m☆2☆，一日1次，连用3-5日，间隔2-3周重复。 
2.联合用药：本药一次5-10mg/m☆2☆。 
儿童 
·常规剂量 
·静脉滴注单次剂量最高可达24mg/m☆2☆。 
[国外用法用量参考] 
成人 
·常规剂量 
·静脉给药 
1.急性非淋巴细胞白血病：
(1)诱导缓解：第1-3日，本药一日12mg/m☆2☆；阿糖胞苷一日100mg/m☆2☆，第1-7日连续24小时静脉滴注。
(2)再次诱导：如果第1次诱导治疗后反应不完全，应给予再次诱导治疗，即本药一日12mg/m☆2☆，共用2日；阿糖胞苷一日100mg/m☆2☆，第1-5日连续24小时静脉滴注。
(3)巩固治疗：第1-2日，本药一日12mg/m☆2☆；阿糖胞苷一日100mg/m☆2☆，第1-5日连续24小时静脉滴注。在末次诱导治疗约6周后开始巩固治疗，在首次巩固疗程4周后进行第2次巩固治疗。 
2.多发性硬化症：推荐剂量为一次12mg/m☆2☆，静脉滴注5-15分钟。每3个月重复1次。 
3.前列腺癌(激素治疗无效)：合用皮质激素，本药一次12-14mg/m☆2☆，每21日1次。 
4.本药的最大剂量，与粒细胞-巨噬细胞集落刺激因子(GM-CSF)合用时为37mg/m☆2☆，与紫杉醇合用时为14mg/m☆2☆。在联合治疗方案中，本药的最大耐受量(MTD)为50-75mg/m☆2☆。 
·肾功能不全时剂量 
肾衰竭时似乎不需要进行剂量调整。 
·肝功能不全时剂量 
有严重肝脏损害者，本药总清除率显著降低，建议减少剂量。 
儿童 
·常规剂量 
·静脉给药儿童用药的安全性和疗效尚未确立，儿童耐受剂量似乎更高。 
1.非淋巴细胞白血病：一次8-33mg/m☆2☆，每3-4周1次。也有用法为一次10mg/m☆2☆，一日1次，静脉滴注1小时，连用3-5日。 
2.实体肿瘤：推荐用量为一次5-8mg/m☆2☆，一周1次。另一种推荐用法为一次18-20mg/m☆2☆，每3-4周1次。 
3.白血病：推荐用量为一次24mg/m☆2☆，每3-4周1次。 

给药说明 
1.不可通过动脉内、皮下、肌内或鞘内注射给药，鞘内注射有导致截瘫的可能。 
2.本药遇低温可能析出晶体，可温热待晶体溶解后使用。 
3.不宜与其它药物混合使用。 
4.给药时避免溶液与皮肤、粘膜或眼接触。 
5.静脉注射时如药液外渗，应立即更换另一静脉通道给药。 
6.用药时可大量饮水、碱化尿液以预防高尿酸血症及尿酸盐沉淀。 
7.使用本药后，患者的尿液及巩膜可呈蓝色。 
8.本药总累积量不宜超过140-160mg/m☆2☆。既往曾接受蒽环类药物、胸部放疗或有心脏病的患者应减少给药量(总累积量不超过100mg/m☆2☆)。使用多柔比星总累积量超过450mg/m☆2☆的患者不宜使用本药；多柔比星总累积量超过350mg/m☆2☆的患者，必须在心功能正常的情况下且在严密观察下用药。 
9.当白细胞计数低于1.5×10☆9☆/L时，应停用本药。 
10.药物过量的表现：据国外资料报道，有4例病人偶然注射本药140-180mg/m☆2☆，由于严重的白细胞减少伴感染而死亡。 

不良反应 
1.血液骨髓抑制为本药剂量限制性毒性。白细胞减少常见，血小板减少较轻，一般用药后8-15日白细胞和血小板下降至最低值，停药后22日左右可恢复。多个疗程后可导致轻度贫血。 
2.胃肠道可有恶心、呕吐、食欲减退、腹泻等。 
3.心血管系统本药不易形成氧自由基及脂质体超氧化，故心脏毒性较多柔比星轻。主要表现为心肌肥大和纤维化；也可有心悸、期外收缩及心电图异常；心力衰竭罕见，主要发生于既往用过多柔比星的患者。心脏毒性与本药总累积量有关，当总累积量超过140-160mg/m☆2☆时，心肌损害增加。有文献报道，本药导致心力衰竭的最低剂量为55-255mg/m☆2☆，导致左心室排血量减少的最低剂量为21-150mg/m☆2☆。此外，用药后可出现静脉炎。 
4.泌尿生殖系统可引起闭经、精子缺乏及肾功能异常。偶有尿道感染等。 
5.局部偶见注射局部红斑和轻度肿胀，静脉注射药液外漏时，会发生严重的局部反应。 
6.其它可有脱发、皮疹、口腔炎、肝功能异常，偶有发热、呼吸困难等。 

注意事项 
1.禁忌症
(1)对本药过敏者。
(2)有骨髓抑制者。
(3)肝功能不全者。
(4)伴有心、肺功能不全的恶病质患者。
(5)孕妇。
(6)哺乳期妇女。 
2.慎用
(1)肝、肾疾病患者。
(2)老年患者。 
3.药物对妊娠的影响孕妇禁用本药。美国药品和食品管理局(FDA)对本药的妊娠安全性分级为D级。 
4.药物对哺乳的影响鉴于本药可能对哺乳婴儿产生严重影响，哺乳妇女应禁用本药。 
5.用药前后及用药时应当检查或监测用药过程中，应密切监测血常规、肝肾功能、心电图，必要时应行超声心动图检查。

 

Mitoxantrone Hydrochloride

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 1,4-dihydroxy-5,8-bis[[2-[2-hydroxyethyl)amino]ethyl]amino]9,10-anthracenedione dihydrochloride
Molecular Formula: C22H28N4O6• 2HCl
CAS Number: 70476-82-3
Brands: Novantrone

 

Warning

Experience of Supervising Clinician

· Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.1 9

Administration Warnings

· Administer slowly into a freely running IV infusion solution.1 2 Do not administer by IM, sub-Q, intra-arterial, or intrathecal injection.1 3

· Severe local tissue necrosis if extravasation occurs.1 (See Local Effects under Cautions.)

· Severe and sometimes irreversible neurotoxicity reported following intrathecal administration.1 (See Neurotoxicity under Cautions.)

Myelosuppression

· Severe myelosuppression may occur.1 Generally avoid use in patients with baseline neutrophil count <1500/mm3, except for treatment of acute myeloid (myelogenous, nonlymphocytic) leukemia.1 Monitor hematologic status carefully.1 (See Hematologic Effects under Cautions.)

Myocardial Toxicity

· Possible cardiotoxicity and potentially fatal CHF during or months to years after therapy;1 risk increases with increasing cumulative dose.2 18 26

· Risk factors (history of or current cardiovascular disease, prior or concomitant irradiation to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs) may increase risk of cardiotoxicity.1 2 3 18 19 20 26 However, toxicity may occur regardless of whether cardiac risk factors are present.1 (See Cardiotoxicity under Cautions.)

· Risk of CHF developing in cancer patients is estimated to be 2.6% at cumulative dose of up to 140 mg/m2.1

· Prior to initiation of therapy, evaluate all patients for cardiac signs/symptoms by history and physical examination and determine baseline left ventricular ejection fraction (LVEF) by echocardiogram or multigated radionuclide angiography (MUGA).1

· Do not initiate therapy in patients with multiple sclerosis if baseline LVEF is <50%.1

· In patients with multiple sclerosis, evaluate LVEF by echocardiogram or MUGA prior to each dose; do not administer additional doses if LVEF decreases to <50% or if a clinically important reduction in LVEF occurs.1

· Patients with multiple sclerosis should not receive cumulative dose >140 mg/m2.1

Secondary Acute Myelogenous Leukemia (AML)

· Secondary AML reported in patients treated with mitoxantrone; risk of refractory secondary leukemias increases when anthracyclines are combined with other DNA-damaging antineoplastics, after extensive exposure to cytotoxic drugs, or when anthracycline doses have been escalated.1 (See Carcinogenicity under Cautions.)

 

 

 

 

 

Introduction

Antineoplastic agent; a synthetic anthracenedione.1 2 3 4 26

SLIDESHOW

Women's Health: Separating Fact From Fiction

Uses for Mitoxantrone HydrochlorideAcute Myeloid Leukemia

A component of various chemotherapy regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL).1 2 3 7 8 9 10 11 24AML includes acute promyelocytic, monocytic, myelomonocytic, megakaryoblastic, and erythroid leukemias.1 23

Used in combination with other antineoplastic agents in consolidation therapy regimens following induction of complete remission.1 8 10

Prostate Cancer

Used as an alternative regimen for initial palliative treatment of advanced, symptomatic (i.e., painful) hormone-refractory prostate cancer (in combination with prednisone).1 12 13 14 2224 26 Preferred first-line of treatment for hormone-refractory metastatic prostate cancer is docetaxel in combination with prednisone.22

Multiple Sclerosis (MS)

Treatment of secondary (chronic) progressive, progressive-relapsing, or worsening relapsing-remitting MS.1 Used to reduce neurologic disability and/or frequency of relapse.1

Has been studied in patients with the following disease patterns: Gradually increasing disability with or without superimposed clinical relapses (secondary progressive and progressive-relapsing subtypes) and clinical relapses resulting in stepwise increases in disability, with substantially abnormal neurologic status between relapses (worsening relapsing-remitting disease).1

Not recommended for use in patients with primary progressive MS.1

Should not be used for treatment of MS in patients with baseline LVEF <50% (see Myocardial Toxicity in Boxed Warning).1 Generally not recommended for use in those with hepatic impairment (see Hepatic Impairment under Cautions) or in those with neutrophil count <1500/mm3.1

Non-Hodgkin’s Lymphoma

Used as a component of combination chemotherapy regimens for treatment of low-grade non-Hodgkin’s lymphoma†.24

Mitoxantrone Hydrochloride Dosage and AdministrationGeneral

· Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Acute Myeloid Leukemia

· Appropriate hematologic monitoring required; adjunctive therapies (e.g., anti-infectives, blood and blood products) must be available during the expected period of medullary hypoplasia and severe myelosuppression.1 23 Ensure full hematologic recovery before initiating consolidation therapy and monitor closely.1 23 (See Hematologic Effects under Cautions.)

Administration

Administer by IV infusion.1 Do not administer IM or sub-Q.1 Do not administer by intra-arterial or intrathecal injection.1 (See Neurotoxicity under Cautions.)

Safety of administration by routes other than IV not established.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer diluted solution into tubing of a freely running IV solution of 0.9% sodium chloride injection or 5% dextrose injection, preferably via a Butterfly needle or other suitable device inserted into a large vein.1

When possible, do not use veins over joints or in extremities with compromised venous or lymphatic drainage.1

Avoid extravasation.1 If signs or symptoms of extravasation occur, immediately stop the infusion and restart in another vein.1 (See Local Effects under Cautions.) If sub-Q extravasation occurs or is suspected, elevation of the affected extremity and intermittent application of ice to the site may be useful.1 Because of the progressive nature of extravasation reactions, close observation and surgery consultation recommended.1

Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., goggles, gloves, protective gowns).1 Use care to avoid contact of the drug with skin, mucous membranes, and eyes.1 If skin contact occurs, immediately rinse affected areas with copious amounts of warm water; use standard irrigation techniques immediately in the event of eye involvement.1

Dilution

Must be diluted prior to IV infusion.1 2 3

Dilute dose of mitoxantrone hydrochloride in 0.9% sodium chloride injection or 5% dextrose injection to a final volume of ≥50 mL.1 3 Solutions may be further diluted with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection.1

Diluted solutions contain no preservatives; prepare immediately before use.1

Rate of Administration

Administer diluted solution slowly over ≥3 minutes;1 2 3 infusions are typically administered over 15–30 minutes.3 15

In patients with prostate cancer or multiple sclerosis, infuse dose over approximately 5–15 minutes.1

Dosage

Available as mitoxantrone hydrochloride; dosage expressed in terms of mitoxantrone.1

AdultsAcute Myeloid LeukemiaInduction Therapy

IV

12 mg/m2 daily on days 1–3 in combination with cytarabine 100 mg/m2 daily (as a continuous IV infusion over 24 hours) on days 1–7.1 8 10 11

If antileukemic response to the first induction course is incomplete, a second induction course consisting of 2 days of mitoxantrone (12 mg/m2 daily) and 5 days of cytarabine (100 mg/m2 daily) may be given.1 8 10 11

If severe or life-threatening nonhematologic toxicity is observed during the initial induction course, withhold second induction course until toxicity resolves.1

Consolidation Therapy

IV

12 mg/m2 daily on days 1 and 2 in combination with cytarabine 100 mg/m2 daily (as a continuous IV infusion over 24 hours) on days 1–5.1 8 10 Administer initial consolidation course approximately 6 weeks after the final induction course; administer the second consolidation course generally 4 weeks after the initial course.1 8

Prostate CancerIV

12–14 mg/m2 once every 21 days; give as an adjunct to corticosteroid therapy (e.g., prednisone 5 mg orally twice daily, hydrocortisone 40 mg orally daily).1 14 Some clinicians recommend discontinuance of mitoxantrone (and continuation of corticosteroid therapy alone) in patients who are still responding after a cumulative mitoxantrone dose of 140 mg/m2 due to risk of cardiac toxicity.14

Multiple SclerosisIV

12 mg/m2 once every 3 months.1

Prescribing LimitsAdultsMultiple SclerosisIV

Maximum cumulative lifetime dose: 140 mg/m2.1

Special PopulationsHepatic Impairment

Decreased clearance; dosage adjustment may be required, however, no specific dosage adjustment recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage reduction not required.15 16

Cautions for Mitoxantrone HydrochlorideContraindications

· Known hypersensitivity to mitoxantrone or any ingredient in the formulation.1

Warnings/PrecautionsWarningsHematologic Effects

Risk of myelosuppression, manifested predominantly as neutropenia;1 may be severe and result in infection.1

Frequent monitoring of hematologic parameters required; monitor CBC, including platelet count, prior to each course of therapy and if signs or symptoms of infection occur.1

Do not initiate mitoxantrone in patients with preexisting drug-induced myelosuppression unless expected treatment benefit warrants risk.1

Except for treatment of AML, use generally not recommended in patients with baseline neutrophil count <1500/mm3.1

Cardiotoxicity

Risk of cardiotoxicity during or months to years after therapy.1 Functional cardiac changes (e.g., decreases in LVEF, irreversible CHF), tachycardia, ECG changes including arrhythmias, and chest pain can occur.1 2 3 18 19 20 26 Risk of cardiotoxicity increases with increasing cumulative dose.2 18 26 (See Myocardial Toxicity in Boxed Warning.)

Probability of developing CHF is 2.6% at a cumulative dosage of 140 mg/m2 in cancer patients; the overall probability of moderate or serious decreases in LVEF was 13% at a cumulative dosage of 140 mg/m2.1 2

Preexisting cardiac disease, prior radiotherapy to the mediastinal or pericardial region, and/or previous anthracycline (e.g., doxorubicin, epirubicin) therapy increase risk of mitoxantrone-induced cardiotoxicity; determine benefit-to-risk ratio before initiating therapy in patients previously treated with anthracyclines (e.g., daunorubicin, doxorubicin).1 2 3 18 19 20 Monitor LVEF regularly following initiation of therapy in patients previously treated with an anthracycline or with mediastinal radiotherapy and in those with preexisting cardiovascular disease.1 2 3 18 19 20 26

Evaluate cardiac function prior to initiation of therapy.1 Discontinue therapy in patients with LVEF <50% or a clinically important reduction in LVEF.1

Monitor LVEF in patients with multiple sclerosis prior to each dose and if signs/symptoms of CHF develop.1 (See Myocardial Toxicity in Boxed Warning.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Potentially teratogenic based on developmental effects of related agents.1

Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Exclude pregnancy with a negative pregnancy test prior to each dose in women of childbearing potential with multiple sclerosis.1

Carcinogenicity

Secondary AML reported in mitoxantrone-treated patients with cancer or multiple sclerosis; risk of refractory AML increases with concomitant use of cytotoxic drugs and/or radiation therapy.1 (See Secondary Acute Myelogenous Leukemia [AML] in Boxed Warning.)

In clinical trials of breast cancer patients receiving mitoxantrone-containing adjuvant therapy, estimated risk of developing treatment-related leukemia at 4, 5, and 10 years was 2.2, 1.1, and 1.6%, respectively.1

In patients with multiple sclerosis receiving mitoxantrone, risk of developing treatment-related leukemia was 0.25% after variable periods of follow up.1

Neurotoxicity

Local or regional neuropathy (sometimes irreversible) has been reported following intra-arterial injection.1 Neurotoxicity (e.g., paralysis with bowel and bladder dysfunction, seizures resulting in coma and severe neurologic sequelae) has been observed following intrathecal injection.1 Do notadminister by intra-arterial or intrathecal injection.1

General PrecautionsAdequate Patient Evaluation and Monitoring

Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.1 27

Closely observe patient and evaluate hematopoietic, hepatic, and cardiac function prior to and at regular intervals during therapy.1 (See Warnings under Cautions.)

Treat systemic infections prior to beginning therapy or concomitantly with therapy.1

Pregnancy test recommended prior to each dose in women of childbearing potential with multiple sclerosis. 1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Tumor Lysis Syndrome

Hyperuricemia may result from rapid lysis of tumor cells; monitor serum uric acid concentration.1Administer hypouricemic therapy (e.g., allopurinol) prior to initiating therapy for leukemia.1

Local Effects

Extravasation may result in tissue necrosis; debridement and skin graft may be required.1 Erythema, swelling, pain, or blue discoloration has been reported following extravasation.1 Phlebitis has been reported at injection site.1

Specific PopulationsPregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Possibility exists of greater sensitivity to the drug and more frequent toxicity in some geriatric individuals.1

Hepatic Impairment

Safety not established; use with caution in patients with cancer.1 Use not recommended in patients with multiple sclerosis who have hepatic impairment (i.e., abnormal liver function test results).1

Decreased clearance reported in patients with severe hepatic impairment (i.e., serum total bilirubin concentration >3.4 mg/dL).1 15 Manufacturer states that drug clearance and required dosage adjustments cannot be predicted from liver function test results; therefore, no specific dosage adjustment recommendations for patients with hepatic impairment.1

Renal Impairment

Not studied in patients with renal impairment.1

Common Adverse Effects

Nausea, diarrhea, anorexia, alopecia, menstrual disorders, amenorrhea, myelosuppression, infection, fever, stomatitis, asthenia, fatigue, edema, dyspnea.1

Interactions for Mitoxantrone Hydrochloride

Does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; may be a weak inducer of CYP2E1.1

No formal pharmacokinetic drug interaction studies to date.1 Clinically important drug interactions not reported; information on interactions in patients with multiple sclerosis is limited.1

Specific Drugs

Drug	Interaction
Aspirin	Plasma protein binding of mitoxantrone not altered1
Corticosteroids	Interaction not observed1 Plasma protein binding of mitoxantrone not altered by prednisone or prednisolone1
Doxorubicin	Plasma protein binding of mitoxantrone not altered1
Heparin	Plasma protein binding of mitoxantrone not altered1
Methotrexate	Plasma protein binding of mitoxantrone not altered1
Phenytoin	Plasma protein binding of mitoxantrone not altered1

Mitoxantrone Hydrochloride PharmacokineticsDistributionExtent

Extensively distributed into tissues.1 Distributed into milk.1 Low concentrations attained in brain, spinal cord, eye, and CSF in monkeys.1

Plasma Protein Binding

78%.1

Special Populations

Increased tissue penetration and protein binding in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).3

EliminationMetabolism

Metabolic pathways not elucidated.1

Elimination Route

Eliminated in feces (25%) by the hepatobiliary system1 and to a lesser extent in urine (approximately 10%)1 2 16 17 as unchanged drug or inactive metabolites.1

Half-life

Triphasic; terminal half-life is approximately 23–215 hours (median: approximately 75 hours).1

Special Populations

Severe hepatic impairment (serum total bilirubin concentration >3.4 mg/dL) decreases clearance.1 15Decreased clearance may occur in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).3

StabilityStorageParenteralInjection Concentrate

15–25°C.1 Do not freeze.1

Undiluted concentrate may be stored for 7 days at 15–25°C or 14 days under refrigeration after puncture of the vial stopper.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Compatible with filters; during the manufacturing process, drug solution is passed through a 0.22-µm filter without loss of potency.15

Solution CompatibilityHID

Compatible

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility

Do not mix in the same infusion as heparin; precipitation may occur.1

Admixture CompatibilityHID

Compatible

Cyclophosphamide

Cytarabine

Etoposide

Fluorouracil

Hydrocortisone sodium succinate

Potassium chloride

Variable

Hydrocortisone sodium phosphate

Y-Site CompatibilityHID

Compatible

Allopurinol sodium

Amifostine

Cladribine

Etoposide

Etoposide phosphate

Filgrastim

Fludarabine phosphate

Gemcitabine HCl

Granisetron HCl

Linezolid

Melphalan HCl

Ondansetron HCl

Oxaliplatin

Sargramostim

Teniposide

Thiotepa

Vinorelbine tartrate

Incompatible

Amphotericin B cholesteryl sulfate complex

Aztreonam

Cefepime HCl

Doxorubicin HCl liposome injection

Lansoprazole

Paclitaxel

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Propofol

Actions

· A DNA-reactive agent1 that interferes with the function of topoisomerase II, thereby preventing religation of DNA strand breaks.2 5 26

· Cytotoxic activity also may result from the aggregation and compaction of DNA via electrostatic cross-linking, generation of free radicals (which may cause breaks in DNA strands), inhibition of protein kinase C activity, and induction of apoptosis in leukemic cells.2 26

· Exerts a cytocidal effect on both proliferating and nonproliferating cultured human cells.1

· Produces concentration- and time-proportional delays in cell-cycle progression.3 Not considered cell-cycle specific; however, mitoxantrone is most cytotoxic to cells in late S phase.3

· Possible additive or synergistic effects with other antineoplastic agents (e.g., cytarabine, amsacrine, cisplatin, doxorubicin, etoposide).2

· Tumor resistance may occur as a result of increased P-glycoprotein expression, alteration of the levels or activity of topoisomerase II, enhanced DNA repair mechanisms, or a combination of these and other mechanisms.2 3 26

· Incomplete cross-resistance with anthracyclines has been demonstrated in vitro.2 3 7

· Inhibits B-cell, T-cell, and macrophage proliferation; impairs antigen presentation; and inhibits secretion of cytokines (interferon gamma, tumor necrosis factor, interleukin-2) in vitro.1

Advice to Patients

· Importance of providing patients who have multiple sclerosis with a copy of the manufacturer’s patient information prior to initiation of therapy and before each dose of the drug.1

· Importance of recognizing and reporting adverse effects of mitoxantrone, including myelosuppressive effects (and related precautions), CHF symptoms, and injection site pain.1

· Risk of irreversible myocardial toxicity and secondary leukemia.1

· Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.1

· Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1

· Possible blue-green appearance of urine for 24 hours after administration; the white part of the eyes also may appear blue.1

· Importance of informing patients of other important precautionary information.1 (See Cautions.)