Chemical formula: C₆H₈O₄ Molecular mass: 144.125 g/mol PubChem compound: 637568
Dimethyl fumarate interacts in the following cases:
Consumption of large quantities of strong alcoholic drinks (more than 30% alcohol by volume) should be avoided because it may lead to increased dissolution rates of dimethyl fumarate and, therefore, may increase the frequency of gastrointestinal adverse reactions.
Vaccination during treatment with dimethyl fumarate has not been studied. Immunosuppression is a risk factor for the use of live vaccines. The risk of vaccination should be weighed against the benefit.
Limited data are available on the efficacy and safety of dimethyl fumarate in patients who have been previously treated with other immunosuppressive or immunomodulating therapies. When switching patients from such therapies to dimethyl fumarate, the half-life and mode of action of the other therapy should be considered in order to avoid additive effects on the immune system.
No data are available on the efficacy and safety of dimethyl fumarate when taken concomitantly with other immunosuppressive or immunomodulating therapies.
Concurrent therapy with nephrotoxic substances (e.g. methotrexate, ciclosporin, aminoglycosides, diuretics, NSAIDs or lithium) may increase the potential for renal adverse reactions (e.g. proteinuria) in patients taking dimethyl fumarate.
Early diagnosis of Fanconi syndrome and discontinuation of dimethyl fumarate treatment are important to prevent the onset of renal impairment and osteomalacia, as the syndrome is usually reversible. The most important signs are: proteinuria, glucosuria (with normal blood sugar levels), hyperaminoaciduria and phosphaturia (possibly concurrent with hypophosphatemia). Progression might involve symptoms such as polyuria, polydipsia and proximal muscle weakness. In rare cases hypophosphataemic osteomalacia with non-localised bone pain, elevated alkaline phosphatase in serum and stress fractures may occur. Importantly, Fanconi syndrome can occur without elevated creatinine levels or low glomerular filtration rate. In case of unclear symptoms Fanconi syndrome should be considered and appropriate examinations should be performed.
Dimethyl fumarate is an immunomodulator and may affect the way the immune system responds to infection. For patients with pre-existing infections of clinical relevance, the physician should decide if treatment with dimethyl fumarate should only be initiated once the infection has resolved. If a patient develops an infection during treatment with dimethyl fumarate, suspension of treatment should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving dimethyl fumarate should be instructed to report symptoms of infection to a physician.
Cases of opportunistic infections, particularly of progressive multifocal leukoencephalopathy (PML) have been reported with other dimethyl fumarate-containing products. PML is an opportunistic infection caused by the John-Cunningham virus (JCV) that can be fatal or cause severe disabilities. PML is probably caused by a combination of factors.
A previous infection with JCV is considered a prerequisite for the development of PML. Risk factors can include previous immunosuppressive treatment and the existence of certain concomitant disorders (such as some autoimmune disorders or malignant haematological conditions). A modified or weakened immune system as well as genetic or environmental factors can also constitute risk factors.
Persistent moderate or severe lymphopenia during treatment with dimethyl fumarate is also considered a risk factor for PML. Patients who develop lymphopenia should be monitored for signs and symptoms of opportunistic infections, particularly for symptoms indicative of PML. Typical symptoms associated with PML are diverse, become worse over days to weeks and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision and changes in thinking, memory and orientation leading to confusion and personality changes. If PML is suspected, treatment with dimethyl fumarate should be stopped immediately and further appropriate neurological and radiological examinations performed.
Dimethyl fumarate may decrease leukocyte and lymphocyte counts. It has not been studied in patients with pre-existing low leukocyte or lymphocyte counts.
Prior to initiating treatment with dimethyl fumarate, a current complete blood count (including differential blood count and platelet count) should be available. Treatment should not be initiated if leukopenia below 3.0x109/L, lymphopenia below 1.0x109/L or other pathological results are identified.
During treatment a complete blood count with differential should be performed every 3 months. Action is needed in the following circumstances:
Leukopenia: If a marked decrease in the total number of white blood cells is found, the situation should be monitored carefully and treatment with dimethyl fumarate should be discontinued at levels below 3.0x109/L.
Lymphopenia: If the lymphocyte count falls below 1.0x109/L but is ≥0.7 x109/L, blood monitoring should be performed monthly until levels return to 1.0x109/L or higher for two consecutive blood tests at which point monitoring can again be performed every 3 months. If the lymphocyte count falls below 0.7x109/L, the blood test must be repeated and if the levels are confirmed to be below 0.7x109/L, then treatment must be stopped immediately. Patients developing lymphopenia should be monitored after stopping treatment until their lymphocyte count has returned to the normal range.
Therapy should be discontinued and caution is advised if other pathological results occur. In any case blood counts should be monitored until values have returned to the normal range.
There are limited data from the use of dimethyl fumarate in pregnant women. Animal studies have shown reproductive toxicity. Dimethyl fumarate is contraindicated during pregnancy.
It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to newborns or infants cannot be excluded. Therefore, dimethyl fumarate is contraindicated during breastfeeding.
Dimethyl fumarate is not recommended in women of child-bearing potential not using appropriate contraception. In patients experiencing diarrhoea during dimethyl fumarate treatment, the effect of oral contraceptives may be reduced and additional barrier methods of contraception may be necessary.
There are no human or animal data on the effects of dimethyl fumarate on fertility.
No studies on the ability to drive and use machines have been conducted. Dimethyl fumarate may have a minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of dimethyl fumarate.
The most common adverse reactions observed with dimethyl fumarate in the Phase III clinical study (1102) in psoriasis patients were gastrointestinal events (62.7%), flushing (20.8%) and lymphopenia (10.0%). Most adverse reactions were considered mild and did not lead to discontinuation of study treatment. The only adverse reactions that led to discontinuation of treatment in >5% of patients were gastrointestinal reactions.
The following is a list of adverse reactions experienced by patients treated with dimethyl fumarate during the clinical study and with fumaric acid esters, a related medicinal product containing dimethyl fumarate along with other fumaric acid esters.
The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from available data).
Very common: Lymphopenia, Leukopenia
Common: Eosinophilia, Leukocytosis
Very rare: Acute lymphatic leukaemia*, Irreversible pancytopenia*
Common: Decreased appetite
Common: Headache, Paraesthesia
Uncommon: Dizziness*
Not known: Progressive multifocal leukoencephalopathy*
Very common: Flushing
Very common: Diarrhoea, Abdominal distension*, Abdominal pain, Nausea
Common: Vomiting, Dyspepsia, Constipation, Abdominal discomfort, Flatulence
Common: Erythema, Skin burning sensation, Pruritus
Rare: Allergic skin reaction*
Uncommon: Proteinuria*
Not known: Renal failure*, Fanconi syndrome*
Common: Fatigue, Feeling hot, Asthenia
Common: Hepatic enzymes increased
Uncommon: Serum creatinine increased*
* Additional adverse reactions reported with a related medicinal product containing dimethyl fumarate along with other fumaric acid esters.
Data from the Phase III clinical study as well as from the literature show that gastrointestinal disorders with dimethyl fumarate-containing products are most likely to occur during the first 2 to 3 months after starting treatment. No apparent dose relationship and no risk factors for the occurrence of these adverse reactions could be identified. Diarrhoea was a common adverse reaction (36.9%) among patients taking dimethyl fumarate, leading to medicinal product withdrawal in about 10% of patients. More than 90% of these diarrhoea events were of mild to moderate severity.
Based on observations in the Phase III clinical study as well as on literature data, flushing is most likely to occur during the early weeks of treatment and tends to lessen with time. In the clinical study a total of 20.8% of patients receiving dimethyl fumarate experienced flushing, which was mild in the majority of cases. Published clinical experience with dimethyl fumarate-containing products shows that individual episodes of flushing usually begin shortly after taking the tablets and resolve within a few hours. Haematological changes Data from the Phase III clinical study as well as from the literature show that changes in haematological parameters are most likely to occur during the first 3 months after starting treatment with dimethyl fumarate. In particular, in the clinical study there was a slight decrease in mean lymphocyte counts starting between weeks 3 and 5 and reaching a maximum in week 12 where approximately one third of patients had lymphocyte values below 1.0x109/L. The mean and median values of lymphocytes remained within the normal range during the clinical study. At week 16 (end of treatment), there was no further decline in lymphocyte counts. At week 16 of treatment, 13/175 (7.4%) of patients were noted to have lymphocyte levels <0.7x 109/L. Blood sampling for safety clinical laboratory tests at follow-up visits was only performed in case of abnormalities at the preceeding visit. During the treatment free follow up, lymphocyte levels of <0.7x 109/L were observed in 1/29 (3.5%) patient at 6 months and 0/28 (0%) at 12 months after stopping treatment. At 12 months after stopping treatment 3/28 (10.7%) of patients had lymphocyte values below 1.0x109/L, which would represent 3/279 (1.1%) of the patients started on dimethyl fumarate.
For the total leukocyte count, a decline became apparent at week 12 of treatment; it slowly increased again at week 16 (end of treatment); and 12 months after stopping treatment all patients had values above 3.0x109/L.
A transient increase in mean values of eosinophils was noted as early as week 3, reached a maximum at week 5 and 8, and had returned to baseline values at week 16.
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