Last updated on October 3rd, 2023 at 10:33 am
Summary
Fumarates (dimethyl fumarate and diroximel fumarate) are moderate- to high-efficacy platform therapies for treating active MS; they reduce the relapse rate by ~45 ̶ 50% and slow the acquisition of disability. They reduce magnetic resonance imaging (MRI) activity by over 80% but have little effect on brain volume loss in the first 2 years of treatment.
The fumarates are licensed as first-line therapies in the UK but are not recommended for second-line use unless they are being prescribed because another DMT is not tolerated. After the first 7 days, they are taken twice daily; this dosing regimen can lead to poor adherence in some people with MS. Fumarates have a complex and interesting dual mode of action. Firstly, they activate antioxidant and cell survival pathways; secondly, they are anti-inflammatory medications targeting a critical pathway in the inflammatory cascade inside cells. They reduce the circulating lymphocyte count by about 30%, which is not a problem for most people with MS. However, about 5% or 15% of people with MS, respectively, develop grade 3 (<500/mm3) or grade 2 (<800/mm3) lymphopaenia; if prolonged (>6 months) this can increase their risk of opportunistic infections. Progressive multifocal leukoencephalopathy (PML) and other opportunistic infections are rare on fumarates. However, extra vigilance is recommended in patients who are lymphopaenic.
The most common side effects of fumarates are flushing and gastrointestinal events, i.e. diarrhoea, nausea and abdominal pain, all of which tend to begin early (primarily during the first month) and may continue intermittently, particularly the flushing. About one in 10 people with MS discontinues a fumarate due to side effects. Diroximel fumarate is better tolerated than dimethyl fumarate regarding gastrointestinal side effects and flushing.
Blood and urine monitoring is done 3-monthly for the first 12 months; if there are no problems, we switch to 6-monthly monitoring. Fumarates have no known potential to cause foetal abnormalities when women fall pregnant on the drug or during pregnancy; however, they are not recommended in women of childbearing potential not using appropriate contraception. The decision to stop the drug to fall pregnant or to continue during pregnancy is based on a personal benefit ̶ risk assessment.
Trade names
Tecfidera (dimethyl fumarate), Vumerity (diroximel fumarate).
Mode of action
Dimethyl and diroximel fumarate are both broken down in the body into monomethyl fumarate. They activate antioxidant and cell survival pathways and have anti-inflammatory effects; their exact mode of action in MS is not known.
Efficacy
Moderate to high; intended as first-line therapy only (in the UK).
Class
Maintenance, immunosuppressive.
Immunosuppression
Yes, but only high-risk if there is persistent lymphopaenia.
Dosing
Dimethyl fumarate dosing
Starting dose: 120 mg twice a day for 7 days; if tolerated, increase to 240 mg twice daily.
Diroximel fumarate dosing
Starting dose: 231 mg twice a day; after 7 days, increase to 462 mg twice daily.
Dose reduction and missed doses
If you miss a dose, do not take a double dose. You may take the missed dose only if it leaves 4 hours between doses. Otherwise, wait until the next scheduled dose. A temporary reduction to the starting dose may reduce flushing and gastrointestinal symptoms. This guidance applies to both fumarates.
Main adverse events
- Gastrointestinal side effects (cramps, abdominal pain and occasional diarrhoea).
- Transient flushing, or redness of the face and upper body.
- Increased risk of PML in older people with MS with prolonged lymphopaenia who are JC virus seropositive.
Pharmacovigilance monitoring requirements
- Tests for liver function, urine protein and pregnancy.
- A rebaselining MRI 6 months after starting treatment and including Gd-enhancement.
- Not recommended for use during pregnancy unless the potential treatment benefit justifies the potential undefined risk to the foetus.
- Avoid live attenuated vaccines unless the risk of not being vaccinated could outweigh the potential risk of infection.