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Novantrone

Generic Name: 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

Warning(s)

  • 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

Uses for Novantrone

Acute 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 24 AML 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

Slideshow: Flashback: FDA Drug Approvals 2013

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 22 24 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

Novantrone Dosage and Administration

General

  • 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

Adults

Acute Myeloid Leukemia
Induction 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 Cancer
IV

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 Sclerosis
IV

12 mg/m2 once every 3 months.1

Prescribing Limits

Adults

Multiple Sclerosis
IV

Maximum cumulative lifetime dose: 140 mg/m2.1

Special Populations

Hepatic 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 Novantrone

Contraindications

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

Warnings/Precautions

Warnings

Hematologic 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 not administer by intra-arterial or intrathecal injection.1

General Precautions

Adequate 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.1 Administer 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 Populations

Pregnancy

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 Novantrone

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

Novantrone Pharmacokinetics

Distribution

Extent

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

Elimination

Metabolism

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 15 Decreased clearance may occur in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).3

Stability

Storage

Parenteral

Injection 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-mcm 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Mitoxantrone Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate, for IV infusion

2 mg (of mitoxantrone) per mL (20, 25, and 30 mg)

Novantrone

OSI Pharmaceuticals (comarketed by Serono)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Novantrone 2MG/ML Concentrate (SERONO): 10/$1,340.70 or 30/$3,980.72

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. EMD Serono. Novantrone (mitoxantrone) for injection concentrate prescribing information. Rockland, MA; 2008 Aug.

2. Dunn CJ, Goa KL. Mitoxantrone: a review of its pharmacological properties and use in acute nonlymphoblastic leukaemia. Drugs Aging. 1996; 9:122-47. [PubMed 8820798]

3. Faulds D, Balfour JA, Chrisp P et al. Mitoxantrone: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs. 1991; 41:400-49. [PubMed 1711446]

4. Chabner BA, Myers CE. Antitumor antibiotics. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:374-84.

5. Capranico G, Zunino F. DNA topoisomerase-trapping antitumour drugs. Eur J Cancer. 1992; 28A:2055-60. [PubMed 1329885]

6. Morrow CS, Cowan KH. Mechanisms of antineoplastic drug resistance. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:340-8.

7. McCauley DL. Treatment of adult acute leukemia. Clin Pharm. 1992; 11:767-96. [IDIS 300402] [PubMed 1521402]

8. Arlin Z, Case DC Jr, Moore J et al. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990; 4:177-83. [PubMed 2179638]

9. Feldman EJ. Acute myelogenous leukemia in the older patient. Semin Oncol. 1995; 22(Suppl 1):21-4. [PubMed 7532322]

10. Pavlovsky S, Gonzalez Llaven J, Garcia Martinez MA et al. A randomized study of mitoxantrone plus cytarabine versus daunomycin versus cytarabine in the treatment of previously untreated adult patients with acute nonlymphocytic leukemia. Ann Hematol. 1994; 69:11-5. [PubMed 8061102]

11. Wahlin A, Hornsten P, Hedenus M et al. Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia. Cancer Chemother Pharmacol. 1991; 28:480-3. [PubMed 1934252]

12. Immunex Corporation. Mitoxantrone for injection concentrate: clinical use in hormone-resistant prostate cancer. Seattle, WA: 1996.

13. Vogelzang NJ. One hundred thirteen men with hormone-refractory prostate cancer died today. J Clin Oncol. 1996; 14:1753-5. [IDIS 369577] [PubMed 8656242]

14. Tannock IF, Osoba D, Stockler MR et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996; 14:1756-64. [IDIS 369578] [PubMed 8656243]

15. Immunex Corporation. Mitoxantrone for injection concentrate: technical monograph. Seattle, WA: 1994.

16. Birchall LA, Bailey NP, Blackledge GRP. An overview of mitozantrone. Br J Clin Pract. 1991; 45:208-11. [IDIS 292197] [PubMed 1805919]

17. Schleyer E, Kamischke A, Kaufmann CC et al. New aspects on the pharmacokinetics of mitoxantrone and its two major metabolites. Leukemia. 1994; 8:435-40. [PubMed 8127148]

18. Crossley RJ. Clinical safety and tolerance of mitoxantrone. Semin Oncol. 1984; 11(Suppl 1):54-8. [PubMed 6385266]

19. Mather FJ, Simon RM, Clark GM et al. Cardiotoxicity in patients treated with mitoxantrone: Southwest Oncology Group phase II studies. Cancer Treat Rep. 1987; 71:609-13. [IDIS 231761] [PubMed 3581099]

20. Posner LE, Dukart G, Goldberg J et al. Mitoxantrone: an overview of safety and toxicity. Invest New Drugs. 1985; 3:123-32. [PubMed 3894276]

21. Prostate Cancer Trialists’ Collaborative Groups. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet. 1995; 346:265-9. [IDIS 352509] [PubMed 7630245]

22. Prostate cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Mar 5.

23. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Mar 3.

24. Anon. Drugs of choice for cancer. Treat Guidelin Med Lett. 2003; 1:41-52.

25. Immunex Corporation, Seattle, WA: Personal communication.

26. Wiseman LR, Spencer CM. Mitoxantrone: a review of its pharmacology and clinical efficacy in the management of hormone-resistant advanced prostate cancer. Drug Aging. 1997; 10:473-85.

27. Goodin DS, Arnason BG, Coyle PK et al. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003; 61:1332-8. [PubMed 14638950]

28. Hartung HP, Gonsette R, König N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002; 360:2018-25. [PubMed 12504397]

29. Edan G, Miller D, Clanet M et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 1997; 62:112-8. [PubMed 9048709]

30. Krapf H, Morrissey SP, Zenker O et al. Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial. Neurology. 2005; 65:690-5. [PubMed 16157900]

31. Bastianello S, Pozzilli C, D’Andrea F et al. A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year. Can J Neurol Sci. 1994; 21:266-70. [PubMed 8000984]

32. Millefiorini E, Gasperini C, Pozzilli C et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol. 1997; 244:153-9. [PubMed 9050955]

33. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004; 351:1502-12. [PubMed 15470213]

34. Kantoff PW, Halabi S, Conaway M et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol. 1999; 17:2506-13. [PubMed 10561316]

35. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:37434-67.

36. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.

37. Meistrich ML, Wilson G, Mathur K et al. Rapid recovery of spermatogenesis after mitoxantrone, vincristine, vinblastine, and prednisone chemotherapy for Hodgkin’s disease. J Clin Oncol. 1997; 15:3488-95. [PubMed 9396402]

38. Cavalla P, Rovei V, Masera S et al. Fertility in patients with multiple sclerosis: current knowledge and future perspectives. Neurol Sci. 2006; 27:231-9. [PubMed 16998725]

39. Azuno Y, Kaku K, Fujita N et al. Mitoxantrone and etoposide in breast milk. Am J Hematol. 1995; 48:131-2. [PubMed 7847330]

40. Food and Drug Administration. MedWatch—Safety alert: mitoxantrone [July 29, 2008]. From FDA web site.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1155-8.

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