Switching-2-fumarates -

Last updated on November 28th, 2024 at 01:44 pm

Possible reasons to switch

Fumarates are licensed in the UK as first-line therapy for people with active MS. Their efficacy is moderate to high.
Although fumarates are not recommended during pregnancy or in women of childbearing potential not using appropriate contraception, they have no known potential to cause foetal abnormalities during pregnancy.
There is no evidence that fumarates affect either male or female fertility.

Reasons for caution

Most people with MS who start taking a fumarate develop gastrointestinal side effects such as cramps, abdominal pain and occasional diarrhoea. These are transient (8 ̶ 12 weeks).
Another common but transient side effect is flushing, or redness of the face and upper body.
The twice-daily dosing regimen can lead to poor adherence in some patients.
PML and other opportunistic infections are rare on fumarates. However, extra vigilance is recommended in patients who are lymphopaenic.

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, a 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.