Dimethyl Fumarate
Summary: Dimethyl fumarate (DMF) is a moderate to high efficacy platform therapy for treating active MS; it reduces the relapse rate by ~45-50% and slows the acquisition of disability. It reduces MRI activity by over 80%. It has little effect on brain volume loss in the first 2 years of treatment. DMF is licensed as a first-line therapy in the UK and it is not recommended to be used 2nd-line unless it it is being prescribed because another DMT is not tolerated. It is taken as a daily 240 mg tablet twice a day, which is a problem for some people because of poor adherence. DMF has a complex and interesting dual mode of action. Firstly, it activates anti-oxidant and cell survival pathways and secondly it works as an anti-inflammatory medication targeting a key pathway in the inflammatory cascade inside cells. DMF reduces the circulating lymphocyte count by about ~30%, which is not a problem for the majority of MSers. However, about 5% and 15% of MSers develop grade 3 (<500/mm3) or grade 2 lymphopaenia (<800/mm3) that if prolonged (> 6 months) can increase their risk of developing opportunistic infections. In older MSers who have had prolonged lymphopaenia there is an increased risk of PML in MSers who are JCV seropositive and we therefore stop DMF in MSers who become persistently lymphopaenic, i.e. in those who have counts below 800/mm3. Most MSers when they start taking DMF develop gastrointestinal side effects such cramps, abdominal pain and occasional diarrhoea. This can be reduced by titrating the dose upwards when starting DMF, taking DMF with fatty foods and my using simple over-the-counter symptomatic therapies, for example antispasmodics. Another common side effect is flushing, or redness of the face and upper body, that typically comes on 20-30 minutes after taking DMF and persists for about an hour. All these side effects get better with time and typically last for 8-12 weeks. You need to be aware of this so don't give up if you develop these symptoms as they are transient. Blood and urine monitoring are done 3 monthly for the first 12 months and if there are no problems we then switch our patients to 6 monthly monitoring. DMF is not teratogenic, i.e. has no known potential to cause foetal abnormalities when women fall pregnant on the drug, and the decision to stop the drug to fall pregnant or during pregnancy is based on a personal benefit-risk assessment.
Trade Names: Tecfidera
Mode of action: DMF is a fat soluble, but we don't know for certain if it gets into the brain and spinal cord. DMF is 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 a programmed cell survival pathway. MMF also inhibits the master inflammatory transcription factor called NF-kappa B. Finally, MMF binds to the nicotinic acid receptor and activates it, which is responsible for the flushing side effect. Despite these well known molecular effects on cells we don't really know how DMF actually works in MS.
Efficacy: Moderate to high, it is licensed in the UK as a platform or 1st-line therapy for MSers with active MS. We are not meant to use it 2nd-line unless the switch is due to intolerance to the other DMT.
Class: Maintenance, immunosuppressive
Immunosuppression: Yes, but only high-risk if there is a persistent lymphopaenia.
Posology: The starting dose of DMF is 120 mg twice a day for 7 days and if you are tolerating DMF the dose should be increased to the recommended maintenance dose of 240 mg twice a day. If you miss a dose, a double dose should not be taken. You may take a missed dose late if it leaves at least 4 hours before the next dose otherwise you should wait until the next scheduled dose. We have found that 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. DMF should ideally be taken with food. Fatty foods, in particular, improve the tolerability of DMF.
Main adverse events: The most common side effect on DMF are flushing and gastrointestinal events, i.e. diarrhoea, nausea and abdominal pain. Flushing and gastrointestinal side effects tend to begin early in the course of treatment (primarily during the first month) and may continue to occur intermittently, particularly the flushing. About 1 in 10 MSers discontinues DMF due to side effects.
Neutralizing Antibodies (NAbs): NAbs are not a problem on DMF as DMF is small molecule or metabolite that does not induce an immune response.
Pharmacovigilance monitoring requirements:
- Baseline: FBC, U&E, LFTs, FBC, urine protein and pregnancy test.
- Follow-up: FBC and urine protein 3 monthly for a year, then 6-monthly after that.
Rebaselining: A rebaseline MRI needs to be done after DMF has had sufficient time to work. I would recommend that an MRI is done 6 months after starting treatment and to include Gd-enhancement as part of the rebaselining MRI.
Women of childbearing potential and pregnancy: Although there is no evidence that DMF has any reproductive toxicity, DMF is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception. DMF should only be used during pregnancy only if clearly needed and if the potential benefit justifies the potential undefined risk to the foetus.
Breast-feeding: It is not whether DMF or MMF is excreted in human milk, but if it is is likely to be in very small amounts. We are therefore advising women with MS that it is safe to breastfeed on DMF.
Fertility: There is no evidence that DMF affects either male or female fertility.
Vaccination: Two clinical studies have shown that vaccinations to component or inactivated vaccines were safe and effective whilst on teriflunomide. However, the use of live attenuated vaccines may carry a risk of infections and the current recommendation is that these should therefore be avoided.
Concomitant administration of non-live or component vaccines are safe and can be administered whilst on DMF. Patients with relapsing remitting MS mounted a good immune response to tetanus toxoid and a meningococcal C polysaccharide vaccine. However, the immune response to a pneumococcal polysaccharide vaccine was blunted. There is no clinical data are available on the efficacy and safety of live attenuated vaccines in MSers on DMF. Live vaccines might carry an increased risk of clinical infection in MSers on DMF and therefore should not be given to MSers on DMF unless the potential risk of getting the infection is considered to be outweighed by the risk to the individual of not receiving the vaccine.
Travel: MSers need to be aware that travel may be affected by being on DMF, for example some countries require you to be vaccinated against yellow fever, which is a live attenuated vaccine and is not recommended on DMF.
Summary of Product Characteristics (SmPC): Tecfidera