Multiple Sclerosis (MS)

Novantrone® (mitoxantrone) is a chemotherapeutic agent that can be used as a disease-modifying drug in multiple sclerosis (MS).1  The brand name Novantrone is discontinued in the US, however, generic forms of the therapy may still be available.

The US Food and Drug Administration approved Novantrone to reduce neurologic disability and/or the frequency of clinical relapses in secondary progressive multiple sclerosis (SPMS), progressive-relapsing MS, and worsening relapsing-remitting multiple sclerosis (RRMS).  Novantrone is not approved for primary progressive multiple sclerosis (PPMS) as it is more effective in SPMS.2 

In the EU, Novantrone may be used to treat patients with highly active relapsing MS when no alternative treatments are available.3 

Novantrone is not licensed in the UK for MS. However, it is sometimes used in some specialist centers to treat patients with highly active relapsing MS whose level of disability is developing rapidly.4

Novantrone should be given as an intravenous infusion at a dose of 12 mg/m2 every 3 months.5 It should never be given subcutaneously, intramuscularly, or intra-arterially. Left ventricular ejection fraction (LVEF) should be evaluated prior to administration of the initial dosage of Novantrone.6

Get Full prescribing information for mitoxantrone at MPR

Mechanism of Action

Novantrone is an antineoplastic agent. In MS, it acts by suppressing the activities of T and B lymphocytes and macrophages that lead to myelin sheath damage.7 It impairs antigen presentation and the secretions of interferon-gamma, tumor necrosis factor-alpha, and interleukin-2, which are overexpressed in MS.

Novantrone intercalates into the DNA through hydrogen bonding and causes crosslinks and strand breaks in DNA. It also inhibits the activity of topoisomerase II, thereby impairing DNA damage repair. Novantrone also interferes with RNA.

Warnings, Precautions, and Adverse Reactions

Novantrone can cause serious long-term and permanent side effects, including cardiac dysfunction with cardiotoxicity and congestive heart disease, therapy-related acute leukemia, and hepatic damage due to changes in liver enzyme levels.4

Other temporary side effects of Novantrone treatment are changes in menstruation patterns and/or temporary or permanent amenorrhea, temporary hair thinning or alopecia, blue-green urine for 24 hours after infusion, upper respiratory and urinary tract infections, headaches, nausea, vomiting, diarrhea, and constipation.

Novantrone may cause birth defects if either parent is being treated.4 Therefore, effective contraception should be used while receiving Novantrone treatment and for 6 months after the last dose of treatment. Novantrone may also pass into breast milk so women should not breastfeed while on Novantrone treatment.

MS patients with a baseline LVEF below the lower limit of normal should not be treated with Novantrone.6

Efficacy in Clinical Trials

The safety and efficacy of Novantrone (mitoxantrone) for the treatment of MS were tested in 5 clinical trials.8 

The first was a randomized, double-blind trial in 25 patients with RRMS. Participants received either 8 mg/m2 of Novantrone or placebo monthly. The results of the trial showed that patients receiving Novantrone had significantly reduced relapse rates at 1 year compared to those given a placebo.9

The second was a 2-year, randomized, partially blinded clinical trial in 51 patients with active RRMS. In this case, patients were also treated with either 8 mg/m2 of Novantrone or a placebo monthly. As in the first trial, patients receiving Novantrone had significantly fewer relapses compared to those receiving placebo.10 Moreover, fewer patients treated with Novantrone had confirmed progression of disability as measured by a 1-point increase in the Expanded Disability Status Scale (EDSS) score. 

The third trial was a randomized, double-blind study including 49 patients with relapsing SPMS. In this trial, patients were given a higher dose of Novantrone (12 mg/m2) or methylprednisolone. The results showed that patients treated with Novantrone had significant improvements in EDSS scores within a year of treatment. Also, significant reductions in the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) were reported compared to those given the corticosteroid. Patients treated with Novantrone also reported nausea, vomiting, and alopecia.11  

Another trial tested the effect of an even higher dose of Novantrone (20 mg monthly) plus 1 g of intravenous methylprednisolone monthly in comparison to methylprednisolone-only treatment. The phase 2 randomized, partially blinded trial recruited 42 patients with either active RRMS or SPMS. Results showed that the patients who also received Novantrone had significantly fewer new gadolinium-enhancing lesions on MRI and significantly fewer relapses at 6 months compared to those who only received methylprednisolone. An increase in the number of patients free of exacerbation was also reported.12 

The fifth trial was a pivotal phase 3 study that included 194 patients with worsening RRMS or SPMS. Participants received either 12 mg/m2 of Novantrone or a placebo for 2 years. The results of this trial showed that those who received Novantrone had significantly fewer relapses and significantly less deterioration in disability compared to those who received the placebo.13 In a nonrandomized subgroup of 110 patients in the study, those who received Novantrone also had a significant reduction in the number of T2-weighted MRI lesions at 24 months.14


  1. Novantrone. National Multiple Sclerosis Society. Accessed June 15, 2021.
  2. NOVANTRONE®: mitoXANTRONE for injection concentrate. Access Data FDA. Accessed June 15, 2021.
  3. Novantrone and associated names. European Medicines Agency. April 29, 2016. Accessed June 15, 2021.
  4. Mitoxantrone (Novantrone). Multiple Sclerosis Trust. Updated June 2017. Accessed June 15, 2021.
  5. Novantrone dosage. Updated September 17, 2020. Accessed June 15, 2021.
  6. MITOXANTRONE injection, solution, concentrate. DailyMed. Updated May 31, 2012. Accessed June 15, 2021.
  7. Mitoxantrone. DrugBank. Accessed June 15, 2021. 
  8. Fox EJ. Management of worsening multiple sclerosis with mitoxantrone: a review. Clin Ther. 2006;28(4):461-474. doi:10.1016/j.clinthera.2006.04.013
  9. 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(3):266-270. doi:10.1017/s0317167100041263
  10. 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(3):153-159. doi:10.1007/s004150050066
  11. van de Wyngaert FA, Beguin C, D’Hooghe MB, et al. A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis. Acta Neurol Belg. 2001;101(4):210-216.
  12. 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(2):112-118. doi:10.1136/jnnp.62.2.112
  13. Hartung HP, Gonsette R, König N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018-2025. doi:10.1016/S0140-6736(02)12023-X
  14. Krapf H, Morrissey SP, Zenker O, et al. Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial. Neurology. 2005;65(5):690-695. doi:10.1212/01.wnl.0000174439.70369.7a

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.