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% of people with MS develop grade 3 (<500/mm³) lymphopaenia and 15% develop grade 2 (<800/mm³); 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

Fumarates are fat soluble, but we don’t know for certain if they enter the brain and spinal cord. Dimethyl fumarate and diroximel fumarate are rapidly broken down in the body to monomethyl fumarate (MMF), which enters cells and activates a cell transcription factor called Nrf2. This pathway stimulates the cell to make antioxidant molecules as part of the programmed cell survival pathway. MMF also inhibits NF-kappa B, the master inflammatory transcription factor. Finally, MMF binds to and activates the nicotinic acid receptor, responsible for the flushing side effect. Apart from these well-known molecular effects on cells, we don’t know exactly how fumarates work in MS.

Efficacy

Moderate to high; fumarates are licensed in the UK as first-line therapy for people with active MS. They are not intended for second-line treatment unless there is intolerance to the first DMT.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, but only high-risk if there is persistent lymphopaenia.

Dosing

Dimethyl fumarate dosing

The starting dose of dimethyl fumarate is 120 mg twice a day for 7 days; if tolerated, the dose is increased to the recommended maintenance dose of 240 mg twice a day. If you miss a dose, do not take two tablets together. You may take a missed dose late, providing you do so at least 4 hours before the next dose; otherwise, wait until the next scheduled dose. A temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing and gastrointestinal symptoms. However, the recommended maintenance dose of 240 mg twice a day should be resumed within the next 4 weeks. Dimethyl fumarate should ideally be taken with food; fatty foods improve its tolerability.

Diroximel fumarate dosing

The starting dose of diroximel fumarate is 231 mg twice a day. After 7 days, the dose should be increased to the recommended maintenance dose of 462 mg twice a day. Temporary dose reductions to 231 mg twice a day may reduce the occurrence of flushing and gastrointestinal adverse reactions. Within one month, the recommended dose of 462 mg twice a day should be resumed. If you miss a dose, a double dose should not be taken. You may take the missed dose only if it leaves 4 hours between doses. Otherwise, you should wait until the next scheduled dose.

Main adverse events

Gastrointestinal events

Most people with MS who start taking a fumarate develop gastrointestinal side effects such as cramps, abdominal pain and occasional diarrhoea. These can be reduced by titrating the dose upwards when starting treatment, taking the drug with fatty foods, and using simple over-the-counter symptomatic therapies such as antispasmodics. Diroximel fumarate is better tolerated than dimethyl fumarate in terms of gastrointestinal side effects.

Flushing

Another common side effect is flushing, or redness of the face and upper body, which typically comes on 20 ̶ 30 minutes after administration and persists for about an hour. All these side effects are transient, improve with time and usually stop after 8 ̶ 12 weeks. Diroximel fumarate is better tolerated than dimethyl fumarate in terms of flushing.

PML and opportunistic infections

Older people with MS who have had prolonged lymphopaenia are at increased risk of progressive multifocal leukoencephalopathy (PML) if they are JC virus (JCV) seropositive. We therefore stop fumarates in patients who become persistently lymphopaenic (i.e. with counts <800/mm³).

Around 1 in 10 people treated with diroximel fumarate get side effects of a cold or chest infection.

Neutralizing antibodies (NAbs)

NAbs are not a problem with this DMT class; fumarates are small molecules or metabolites that do not induce an immune response.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests (LFTs), thyroid function tests, urine protein, pregnancy test.

Follow-up

FBC and urine protein after 3 and 6 months of treatment, every 6 to 12 months thereafter or as clinically indicated.

Rebaselining

A rebaselining MRI needs to be done after a fumarate has had sufficient time to work. I recommend performing an MRI 6 months after starting treatment and including Gd-enhancement as part of the rebaselining.

Women of childbearing potential and pregnancy

Although there is no evidence that fumarates have any reproductive toxicity, they are not recommended during pregnancy or in women of childbearing potential not using appropriate contraception. A fumarate should only be used during pregnancy if needed because the potential treatment benefit justifies the potential undefined risk to the foetus. Most neurologists allow their patients to fall pregnant on fumarates, stop the medication once the patient knows they are pregnant, and reinitiate the medication post-partum.

Breastfeeding

It is unknown whether dimethyl fumarate, MMF or diroximel fumarate is excreted in human milk; if so, it is likely to be in very small amounts. We therefore advise women with MS that it is safe to breastfeed when taking a fumarate.

Fertility

There is no evidence that fumarates affect either male or female fertility.

Vaccination

Clinical studies have shown that vaccinations of component or inactivated vaccines were safe and effective whilst on fumarates. However, live attenuated vaccines may carry a risk of infection, so the current recommendation is to avoid them unless the risk of not being vaccinated is likely to outweigh the potential risk of infection.

Travel

Being on a fumarate may affect travel; for example, some countries require vaccination against yellow fever, a live attenuated vaccine that is not recommended while taking a fumarate.

Summaries of Product Characteristics (SmPC)

Tecfidera, Vumerity.

Switching-2-fumarates

Please note that fumarates are not recommended as second-line therapy on the UK National Health Service. The following advice is for people with MS who are considering switching to a fumarate because of tolerance or safety issues with other DMTs.

Interferon and glatiramer acetate

In general, a fumarate can be started immediately after discontinuation of interferon or glatiramer acetate. All the recommended baseline screening tests and reviews must be done before starting a fumarate.

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended before starting a fumarate. Most often, the reason for switching from natalizumab to a fumarate (or another DMT) is to reduce the risk of carry-over PML from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JCV-DNA on polymerase chain reaction. Provided these two tests are clear, we typically initiate a fumarate as soon as possible after the last natalizumab infusion. However, we tend not to use a fumarate post-natalizumab because the evidence that this drug class can prevent rebound activity is not as strong as for S1P modulators or anti-CD20 therapies. All the recommended baseline screening tests and reviews must be done before starting a fumarate.

S1P modulators

Some neurologists recommend a short washout period before switching from an S1P modulator (e.g. 4 ̶ 6 weeks in the case of fingolimod), because of the long half-life of this drug class. I recommend waiting for the total peripheral lymphocyte count to go above 800/mm³ to exclude the uncommon occurrence of persistent lymphopaenia post-fingolimod and other S1P modulators. It is important that all the recommended baseline screening tests and necessary reviews are done before starting a fumarate. If the switch is because of abnormal LFTs on an S1P modulator, the liver enzymes ideally need to normalise or at least drop to below three times the upper limit of normal before starting a fumarate.

Teriflunomide

It is important that all the recommended baseline screening tests and necessary reviews are done before starting a fumarate. If the main reason for switching from teriflunomide is leukopaenia or abnormal LFTs, I recommend waiting for the lymphocyte counts to go above 800/mm³ and for the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting a fumarate.

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting a fumarate. I would recommend first waiting for the total peripheral lymphocyte counts to go above 800/mm³. A switch should be considered only if there are tolerance or safety issues with the current DMT. On the UK National Health Service (NHS), fumarates are not recommended after alemtuzumab, but this does not necessarily apply to other healthcare systems.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting a fumarate. On the NHS switch should be considered only if there are tolerance or safety issues with the current DMT. However, this does not necessarily apply to other healthcare systems.

Cladribine (selective cell depleting DMT)

Mitoxantrone

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting a fumarate. I recommend first waiting for the neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively. A switch should be considered only if there are tolerance or safety issues with the current DMT.

HSCT

It Is important that all the recommended baseline screening tests are done before starting a fumarate. I recommend first waiting for the neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively. A switch should be considered only if there are tolerance or safety issues with the current DMT.

Fumarate: maintenance to starting dose reduction

The starting dose of dimethyl fumarate, 120 mg twice a day for 7 days, is increased to the recommended maintenance dose of 240 mg twice a day after induction if well tolerated.
Likewise, the starting dose of diroximel fumarate, 231 mg twice a day for 7 days, is increased to the recommended maintenance dose of 462 mg twice a day if well tolerated.

A temporary dose reduction to 120 mg twice a day (dimethyl fumarate) or 231 mg twice a day (diroximel fumarate) may reduce the occurrence of flushing and gastrointestinal symptoms. However, the recommended maintenance dose of 240 mg twice a day or 462 mg twice a day for dimethyl fumarate or diroximel fumarate, respectively, should be resumed within the next 4 weeks. Fumarates should ideally be taken with food, particularly fatty foods, to improve their tolerability.

If you miss a dose, do not take a double dose. You may take the missed dose only if you leave 4 hours between doses. Otherwise, you should wait until the next scheduled dose.