Tecfidera

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Tecfidera 120 mg gastro-resistant hard capsules 
Tecfidera 240 mg gastro-resistant hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Tecfidera 120 mg gastro-resistant hard capsules 
 
Each gastro-resistant hard capsule contains 120 mg dimethyl fumarate 
 
Tecfidera 240 mg gastro-resistant hard capsules 
 
Each gastro-resistant hard capsule contains 240 mg dimethyl fumarate 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Gastro-resistant hard capsule 
 
Tecfidera 120mg gastro-resistant hard capsules 
 
Green and white gastro-resistant hard capsules, size 0, printed with ‘BG-12 120 mg’ containing 
microtablets. 
 
Tecfidera 240mg gastro-resistant hard capsules 
 
Green gastro-resistant hard capsules, size 0, printed with ‘BG-12 240 mg’ containing microtablets. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Tecfidera is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis 
(see section 5.1 for important information on the populations for which efficacy has been established). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of 
multiple sclerosis.  
 
Posology 
 
The starting dose is 120 mg twice a day. After 7 days, the dose should be increased to the 
recommended maintenance dose of 240 mg twice a day (see section 4.4). 
 
If a patient misses a dose, a double dose should not be taken. The patient may take the missed dose 
only if they leave 4 hours between doses. Otherwise the patient should wait until the next scheduled 
dose.  
 
Temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing and 
gastrointestinal adverse reactions. Within 1 month, the recommended maintenance dose of 240 mg 
twice a day should be resumed. 



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Tecfidera should be taken with food (see section 5.2). For those patients who may experience flushing 
or gastrointestinal adverse reactions, taking Tecfidera with food may improve tolerability (see 
sections 4.4, 4.5 and 4.8). 
 
Special populations 
 
Elderly 
Clinical studies of Tecfidera had limited exposure to patients aged 55 years and above, and did not 
include sufficient numbers of patients aged 65 and over to determine whether they respond differently 
than younger patients (see section 5.2). Based on the mode of action of the active substance there are 
no theoretical reasons for any requirement for dose adjustments in the elderly. 
 
Renal and hepatic impairment 
Tecfidera has not been studied in patients with renal or hepatic impairment. Based on clinical 
pharmacology studies, no dose adjustments are needed (see section 5.2). Caution should be used when 
treating patients with severe renal or severe hepatic impairment (see section 4.4). 
 
Paediatric population 
The safety and efficacy of Tecfidera in children and adolescents aged 10 to 18 years have not yet been 
established. 
Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a 
posology can be made. There is no relevant use of Tecfidera in children aged less than 10 years for the 
indication of relapsing remitting multiple sclerosis. 
 
Method of administration  
 
For oral use. 
 
The capsule should be swallowed whole. The capsule or its contents should not be crushed, divided, 
dissolved, sucked or chewed as the enteric-coating of the microtablets prevents irritant effects on the 
gut.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Suspected or confirmed Progressive Multifocal Leukoencephalopathy (PML) 
 
4.4 Special warnings and precautions for use 
 
Blood/laboratory tests 

Changes in renal laboratory tests have been seen in clinical trials in subjects treated with dimethyl 
fumarate (see section 4.8). The clinical implications of these changes are unknown. Assessment of 
renal function (e.g. creatinine, blood urea nitrogen and urinalysis) is recommended prior to treatment 
initiation, after 3 and 6 months of treatment, every 6 to 12 months thereafter and as clinically 
indicated.  
 
Drug-induced liver injury, including liver enzyme increase (≥ 3 upper limit of normal (ULN)) and 
elevation of total bilirubin levels (≥ 2 ULN) can result from treatment with dimethyl fumarate. The 
time to onset can be directly, several weeks or longer. Resolution of the adverse reactions has been 
observed after treatment was discontinued. Assessment of serum aminotransferases (e.g. alanine 
aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels are 
recommended prior to treatment initiation and during treatment as clinically indicated. 
Patients treated with Tecfidera may develop lymphopenia (see section 4.8). Prior to initiating 
treatment with Tecfidera, a current complete blood count, including lymphocytes, must be performed.  
 



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If lymphocyte count is found to be below the normal range, thorough assessment of possible causes 
should be completed prior to initiation of treatment with Tecfidera. Dimethyl fumarate has not been 
studied in patients with pre-existing low lymphocyte counts and caution should be exercised when 
treating these patients. Tecfidera should not be initiated in patients with severe lymphopenia 
(lymphocyte counts <0.5 x 109/L). 
 
After starting therapy, complete blood counts, including lymphocytes, must be performed every 3 
months.  
 
Enhanced vigilance due to an increased risk for Progressive Multifocal Leukoencephalopathy (PML) 
is recommended in patients with lymphopenia as follows:  

• Tecfidera should be discontinued in patients with prolonged severe lymphopenia (lymphocyte 
counts <0.5 x 109/L) persisting for more than 6 months.  

• In patients with sustained moderate reductions of absolute lymphocyte counts ≥0.5 x 109/L 
and < 0.8 x 109/L for more than six months, the benefit/risk of Tecfidera treatment should be 
re-assessed. 

• In patients with lymphocyte counts below lower limit of normal (LLN) as defined by local 
laboratory reference range, regular monitoring of absolute lymphocyte counts is 
recommended. Additional factors that might further augment the individual PML risk should 
be considered (see subsection on PML below). 
 

Lymphocyte counts should be followed until recovery. Upon recovery and in the absence of 
alternative treatment options, decisions about whether or not to restart Tecfidera after treatment 
discontinuation should be based on clinical judgement. 
 
Magnetic Resonance imaging (MRI) 

Before initiating treatment with Tecfidera, a baseline MRI should be available (usually within 3 
months) as a reference. The need for further MRI scanning should be considered in accordance with 
national and local recommendations. MRI imaging may be considered as part of increased vigilance in 
patients considered at increased risk of PML. In case of clinical suspicion of PML, MRI should be 
performed immediately for diagnostic purposes. 
 
Progressive Multifocal Leukoencephalopathy (PML) 

PML has been reported in patients treated with Tecfidera (see section 4.8). PML is an opportunistic 
infection caused by John-Cunningham virus (JCV), which may be fatal or result in severe disability.  
 
PML cases have occurred with dimethyl fumarate and other medicinal products containing fumarates 
in the setting of lymphopenia (lymphocyte counts below LLN). Prolonged moderate to severe 
lymphopenia appears to increase the risk of PML with Tecfidera, however, risk cannot be excluded in 
patients with mild lymphopenia.  
Additional factors that might contribute to an increased risk for PML in the setting of lymphopenia 
are: 

- duration of Tecfidera therapy. Cases of PML have occurred after approximately1 to 5 years of 
treatment, although the exact relationship with duration of treatment is unknown. 
 

- profound decreases in CD4+ and especially in CD8+ T cell counts, which are important for 
immunological defence (see section 4.8), and 
 

- prior immunosuppressive or immunomodulatory therapy (see below). 
 

Physicians should evaluate their patients to determine if the symptoms are indicative of neurological 
dysfunction and, if so, whether these symptoms are typical of MS or possibly suggestive of PML.  
 
At the first sign or symptom suggestive of PML, Tecfidera should be withheld and appropriate 
diagnostic evaluations, including determination of JCV DNA in cerebrospinal fluid (CSF) by 



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quantitative polymerase chain reaction (PCR) methodology, need to be performed. The symptoms of 
PML may be similar to an MS relapse. Typical symptoms associated with PML are diverse, progress 
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. Physicians should be particularly alert to symptoms suggestive of PML that the 
patient may not notice. Patients should also be advised to inform their partner or caregivers about their 
treatment, since they may notice symptoms that the patient is not aware of. 
 
PML can only occur in the presence of a JCV infection. It should be considered that the influence of 
lymphopenia on the accuracy of serum anti-JCV antibody testing has not been studied in dimethyl 
fumarate treated patients. It should also be noted that a negative anti-JCV antibody test (in the 
presence of normal lymphocyte counts) does not preclude the possibility of subsequent JCV infection.  
 
If a patient develops PML, Tecfidera must be permanently discontinued. 
 
Prior treatment with immunosuppressive or immunomodulating therapies 

No studies have been performed evaluating the efficacy and safety of Tecfidera when switching 
patients from other disease modifying therapies to Tecfidera. The contribution of prior 
immunosuppressive therapy to the development of PML in dimethyl fumarate treated patients is 
possible.  
 
PML cases have occurred in patients who had previously been treated with natalizumab, for which 
PML is an established risk. Physicians should be aware that cases of PML occurring following recent 
discontinuation of natalizumab may not have lymphopenia. 

 
In addition, a majority of confirmed PML cases with Tecfidera occurred in patients with prior 
immunomodulatory treatment.  
 
When switching patients from another disease modifying therapy to Tecfidera, the half-life and mode 
of action of the other therapy should be considered in order to avoid an additive immune effect while 
at the same time, reducing the risk of reactivation of MS. A complete blood count is recommended 
prior to initiating Tecfidera and regularly during treatment (see Blood/laboratory tests above).  
 
Severe renal and hepatic impairment 
 
Tecfidera has not been studied in patients with severe renal or severe hepatic impairment and caution 
should, therefore, be used in these patients (see section 4.2). 
 
Severe active gastrointestinal disease 
 
Tecfidera has not been studied in patients with severe active gastrointestinal disease and caution 
should, therefore, be used in these patients. 
 
Flushing 
 
In clinical trials, 34% of Tecfidera treated patients experienced flushing. In the majority of patients 
who experienced flushing, it was mild or moderate in severity. Data from healthy volunteer studies 
suggest that dimethyl fumarate-associated flushing is likely to be prostaglandin mediated.  A short 
course of treatment with 75 mg non-enteric coated acetylsalicylic acid may be beneficial in patients 
affected by intolerable flushing (see section 4.5).  In two healthy volunteer studies, the occurrence and 
severity of flushing over the dosing period was reduced. 
 
In clinical trials, 3 patients out of a total of 2,560 patients treated with dimethyl fumarate experienced 
serious flushing symptoms that were probable hypersensitivity or anaphylactoid reactions. These 
events were not life-threatening, but led to hospitalisation. Prescribers and patients should be alert to 
this possibility in the event of severe flushing reactions (see sections 4.2, 4.5 and 4.8). 



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Anaphylactic reactions 
 
Cases of anaphylaxis/anaphylactoid reaction have been reported following Tecfidera administration in 
the post-marketing setting. Symptoms may include dyspnoea, hypoxia, hypotension, angioedema, rash 
or urticaria. The mechanism of dimethyl fumarate induced anaphylaxis is unknown. Reactions 
generally occur after the first dose, but may also occur at any time during treatment, and may be 
serious and life threatening. Patients should be instructed to discontinue Tecfidera and seek immediate 
medical care if they experience signs or symptoms of anaphylaxis. Treatment should not be restarted 
(see section 4.8). 
 
Infections 
 
In phase III placebo-controlled studies, the incidence of infections (60% vs 58%) and serious 
infections (2% vs 2%) was similar in patients treated with Tecfidera or placebo, respectively. 
However, due to Tecfidera immunomodulatory properties (see section 5.1), if a patient develops a 
serious infection, suspending treatment with Tecfidera should be considered and the benefits and risks 
should be reassessed prior to re-initiation of therapy. Patients receiving Tecfidera should be instructed 
to report symptoms of infections to a physician. Patients with serious infections should not start 
treatment with Tecfidera until the infection(s) is resolved. 
 
There was no increased incidence of serious infections observed in patients with lymphocyte counts 
<0.8x109/L or <0.5x109/L (see Section 4.8).  If therapy is continued in the presence of moderate to 
severe prolonged lymphopenia, the risk of an opportunistic infection, including PML, cannot be ruled 
out (see section 4.4 subsection PML).  
 
Herpes zoster infections 
 
Cases of herpes zoster have occurred with Tecfidera. The majority of cases were non-serious, 
however, serious cases, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes 
zoster oticus, herpes zoster infection neurological, herpes zoster meningoencephalitis and herpes 
zoster meningomyelitis have been reported. These events may occur at any time during treatment. 
Monitor patients taking Tecfidera for signs and symptoms of herpes zoster especially when concurrent 
lymphocytopenia is reported.  If herpes zoster occurs, appropriate treatment for herpes zoster should 
be administered. Consider withholding Tecfidera treatment in patients with serious infections until the 
infection has resolved (see section 4.8). 
 
Treatment initiation 
 
Tecfidera treatment should be started gradually to reduce the occurrence of flushing and 
gastrointestinal adverse reactions (see section 4.2).  
 
Fanconi syndrome 
 
Cases of Fanconi syndrome have been reported for a medicinal product containing dimethyl fumarate 
in combination with other fumaric acid esters.  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. 
 
 



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4.5 Interaction with other medicinal products and other forms of interaction 
 
Tecfidera has not been studied in combination with anti-neoplastic or immunosuppressive therapies 
and caution should, therefore, be used during concomitant administration. In multiple sclerosis clinical 
studies, the concomitant treatment of relapses with a short course of intravenous corticosteroids was 
not associated with a clinically relevant increase of infection. 
 
Concomitant administration of non-live vaccines according to national vaccination schedules may be 
considered during Tecfidera therapy. In a clinical study involving a total of 71 patients with relapsing 
remitting multiple sclerosis, patients on Tecfidera 240 mg twice daily for at least 6 months (n=38) or 
non-pegylated interferon for at least 3 months (n=33), mounted a comparable immune response 
(defined as ≥2-fold increase from pre- to post-vaccination titer) to tetanus toxoid (recall antigen) and a 
conjugated meningococcal C polysaccharide vaccine (neoantigen), while the immune response to 
different serotypes of an unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell 
independent antigen) varied in both treatment groups. A positive immune response defined as a 
≥4-fold increase in antibody titer to the three vaccines, was achieved by fewer subjects in both 
treatment groups. Small numerical differences in the response to tetanus toxoid and pneumococcal 
serotype 3 polysaccharide were noted in favour of non-pegylated interferon.  
 
No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking 
Tecfidera. Live vaccines might carry an increased risk of clinical infection and should not be given to 
patients treated with Tecfidera unless, in exceptional cases, this potential risk is considered to be 
outweighed by the risk to the individual of not vaccinating. 
 
During treatment with Tecfidera, simultaneous use of other fumaric acid derivatives (topical or 
systemic) should be avoided. 
 
In humans, dimethyl fumarate is extensively metabolised by esterases before it reaches the systemic 
circulation and further metabolism occurs through the tricarboxylic acid cycle, with no involvement of 
the cytochrome P450 (CYP) system. Potential drug interaction risks were not identified from in vitro 
CYP-inhibition and induction studies, a p-glycoprotein study, or studies of the protein binding of 
dimethyl fumarate and monomethyl fumarate (a primary metabolite of dimethyl fumarate). 
  
Commonly used medicinal products in patients with multiple sclerosis, intramuscular interferon 
beta-1a and glatiramer acetate, were clinically tested for potential interactions with dimethyl fumarate 
and did not alter the pharmacokinetic profile of dimethyl fumarate.  
 
Evidence from healthy volunteer studies suggests that Tecfidera-associated flushing is likely to be 
prostaglandin mediated. In two healthy volunteer studies, the administration of 325 mg (or equivalent) 
non-enteric coated acetylsalicylic acid, 30 minutes prior to Tecfidera, dosing over 4 days and over 4 
weeks, respectively, did not alter the pharmacokinetic profile of Tecfidera. Potential risks associated 
with acetylsalicylic acid therapy should be considered prior to co-administration with Tecfidera in 
patients with Relapsing Remitting MS. Long term (> 4 weeks) continuous use of acetylsalicylic acid 
has not been studied (see sections 4.4 and 4.8).  
 
Concurrent therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics, non-
steroidal anti-inflammatory drugs or lithium) may increase the potential of renal adverse reactions 
(e.g. proteinuria see section 4.8) in patients taking Tecfidera (see section 4.4 Blood/laboratory tests). 
 
Consumption of moderate amounts of alcohol did not alter exposure to dimethyl fumarate and was not 
associated with an increase in adverse reactions. Consumption of large quantities of strong alcoholic 
drinks (more than 30% alcohol by volume) should be avoided within an hour of taking Tecfidera, as 
alcohol may lead to increased frequency of gastrointestinal adverse reactions. 
 
In vitro CYP induction studies did not demonstrate an interaction between Tecfidera and oral 
contraceptives. In an in vivo study, co-administration of Tecfidera with a combined oral contraceptive 
(norgestimate and ethinyl estradiol) did not elicit any relevant change in oral contraceptive exposure. 



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No interaction studies have been performed with oral contraceptives containing other progestogens, 
however an effect of Tecfidera on their exposure is not expected. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited amount of data from the use of dimethyl fumarate in pregnant women. Animal 
studies have shown reproductive toxicity (see section 5.3). Tecfidera is not recommended during 
pregnancy and in women of childbearing potential not using appropriate contraception (see 
section 4.5). Tecfidera should be used during pregnancy only if clearly needed and if the potential 
benefit justifies the potential risk to the foetus. 
 
Breast-feeding 
 
It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding 
or to discontinue Tecfidera therapy. The benefit of breast-feeding for the child and the benefit of 
therapy for the woman should be taken into account. 
  
Fertility 
 
There are no data on the effects of dimethyl fumarate on human fertility. Data from preclinical studies 
do not suggest that dimethyl fumarate would be associated with an increased risk of reduced fertility 
(see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Tecfidera has no or negligible influence on the ability to drive and use machines. No studies on the 
ability to drive and use machines have been conducted but no effects potentially influencing this 
ability were found to be related to dimethyl fumarate in clinical studies. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most common adverse reactions (incidence ≥10%) for patients treated with dimethyl fumarate 
were flushing and gastrointestinal events (i.e. diarrhoea, nausea, abdominal pain, abdominal pain 
upper). Flushing and gastrointestinal events tend to begin early in the course of treatment (primarily 
during the first month) and in patients who experience flushing and gastrointestinal events, these 
events may continue to occur intermittently throughout treatment with Tecfidera. The most commonly 
reported adverse reactions leading to discontinuation (incidence >1%) in patients treated with 
Tecfidera were flushing (3%) and gastrointestinal events (4%). 
In placebo-controlled and uncontrolled clinical studies, a total of 2,468 patients have received 
Tecfidera and been followed for periods up to 4 years with an overall exposure equivalent to 
3,588 person-years. Approximately 1,056 patients have received more than 2 years of treatment with 
Tecfidera. The experience in uncontrolled clinical trials is consistent with the experience in the 
placebo-controlled clinical trials. 
 
Tabulated summary of adverse reactions 
 
Adverse reactions, which were more frequently reported in Tecfidera versus placebo-treated patients, 
are presented in the table below. These data were derived from 2 pivotal Phase 3 placebo-controlled, 



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double-blind clinical trials with a total of 1,529 patients treated with Tecfidera and for up to 24 months 
with an overall exposure of 2,371 person-years (see section 5.1). The frequencies described in the 
table below are based on 769 patients treated with Tecfidera 240 mg twice a day and 771 patients 
treated with placebo 
 
The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ 
Class. The incidence of the adverse reactions below are expressed according to the following 
categories: 
- 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) 
- Not known (frequency cannot be estimated from the available data) 
 

MedDRA System Organ Class Adverse reaction Frequency category 
Infections and infestations Gastroenteritis Common 

Progressive multifocal 
leukoencephalopathy (PML)  Not known  

Herpes zoster1 Not known 
Blood and lymphatic system 
disorders 

Lymphopenia Common 
Leucopenia Common 
Thrombocytopenia Uncommon 

Immune system disorders Hypersensitivity Uncommon 
Anaphylaxis1 Not known 
Dyspnoea1 Not known 
Hypoxia1 Not known 
Hypotension1 Not known 
Angioedema1 Not known 

Nervous system disorders Burning sensation Common 
Vascular disorders Flushing  Very common 

Hot flush Common 
Gastrointestinal disorders Diarrhoea  Very common 

Nausea  Very common 
Abdominal pain upper  Very common 
Abdominal pain Very common 
Vomiting Common 
Dyspepsia Common 
Gastritis Common 
Gastrointestinal disorder Common 

Hepatobiliary disorders Aspartate aminotransferase increased Common 
Alanine aminotransferase increased Common 
Drug-induced liver injury1 Not known 

Skin and subcutaneous tissue 
disorders 

Pruritus Common 
Rash Common 
Erythema Common 

Renal and urinary disorders Proteinuria Common 
General disorders and 
administration site conditions Feeling hot Common 

Investigations Ketones measured in urine Very common 
Albumin urine present  Common 
White blood cell count decreased  Common 

 

1 Adverse reactions derived only during post marketing experience 
 



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Description of selected adverse reactions 
 
Flushing  
 
In the placebo-controlled studies, the incidence of flushing (34% versus 4%) and hot flush 
(7% versus 2%) was increased in patients treated with Tecfidera compared to placebo, respectively. 
Flushing is usually described as flushing or hot flush, but can include other events (e.g. warmth, 
redness, itching, and burning sensation). Flushing events tend to begin early in the course of treatment 
(primarily during the first month) and in patients who experience flushing, these events may continue 
to occur intermittently throughout treatment with Tecfidera. In patients with flushing, the majority had 
flushing events that were mild or moderate in severity. Overall, 3% of patients treated with Tecfidera 
discontinued due to flushing. The incidence of serious flushing, which may be characterised by 
generalised erythema, rash and/or pruritus, was seen in less than 1% of patients treated with Tecfidera 
(see sections 4.2, 4.4 and 4.5).  
 
Gastrointestinal 
 
The incidence of gastrointestinal events (e.g. diarrhoea [14% versus 10%], nausea [12% versus 9%], 
upper abdominal pain [10% versus 6%], abdominal pain [9% versus 4%], vomiting [8% versus 5%] 
and dyspepsia [5% versus 3%]) was increased in patients treated with Tecfidera compared to placebo, 
respectively. Gastrointestinal events tend to begin early in the course of treatment (primarily during 
the first month) and in patients who experience gastrointestinal events, these events may continue to 
occur intermittently throughout treatment with Tecfidera. In the majority of patients who experienced 
gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) of patients treated with 
Tecfidera discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, 
including gastroenteritis and gastritis, was seen in 1% of patients treated with Tecfidera (see 
section 4.2). 
 
Hepatic function  
 
Based on data from placebo-controlled studies, the majority of patients with elevations had hepatic 
transaminases that were <3 times the upper limit of normal (ULN). The increased incidence of 
elevations of hepatic transaminases in patients treated with Tecfidera relative to placebo was primarily 
seen during the first 6 months of treatment. Elevations of alanine aminotransferase and aspartate 
aminotransferase ≥3 times ULN, respectively, were seen in 5% and 2% of patients treated with 
placebo and 6% and 2% of patients treated with Tecfidera. Discontinuations due to elevated hepatic 
transaminases were <1% and similar in patients treated with Tecfidera or placebo. Elevations in 
transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN, were not 
observed in placebo-controlled studies. 
 
Increase of liver enzymes and cases of drug-induced liver injury (elevations in transaminases ≥3 times 
ULN with concomitant elevations in total bilirubin >2 times ULN), have been reported in post 
marketing experience following Tecfidera administration, which resolved upon treatment 
discontinuation.  
 
Lymphopenia  
 
In the placebo-controlled studies most patients (>98%) had normal lymphocyte values prior to 
initiating treatment. Upon treatment with Tecfidera, mean lymphocyte counts decreased over the first 
year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of 
baseline value. Mean and median lymphocyte counts remained within normal limits.  Lymphocyte 
counts <0.5x109/l were observed in <1% of patients treated with placebo and 6% of patients treated 
with Tecfidera.  A lymphocyte count <0.2x109/l was observed in 1 patient treated with Tecfidera and 
in no patients treated with placebo. 
 
In clinical studies (both controlled and uncontrolled), 41% of patients treated with Tecfidera had 
lymphopenia (defined in these studies as <0.91x109/L). Mild lymphopenia (counts ≥0.8x109/L and 



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<0.91 x109/L) was observed in 28% of patients; moderate lymphopenia (counts ≥0.5x109/L and 
<0.8x109/L) persisting for at least six months was observed in 10% of patients; severe lymphopenia 
(counts <0.5x109/L) persisting for at least six months was observed in 2% of patients. In the group 
with severe lymphopenia, the majority of lymphocyte counts remained <0.5x109/L with continued 
therapy.  
 
 
In addition, in an uncontrolled, prospective, post-marketing study, at week 48 of treatment with 
Tecfidera (n=185) CD4+ T cells were moderately (counts ≥0.2x109/L to <0.4x109/L) or severely 
(<0.2x109/L) decreased in up to 37 % or 6 % of patients, respectively, while CD8+ T cells were more 
frequently reduced with up to 59 % of patients at counts <0.2x109/L and 25 % of patients at counts 
<0.1x109/L.Infections, including PML and opportunistic infections 
Cases of infections with John Cunningham virus (JCV) causing Progressive Multifocal 
Leukoencephalopathy (PML) have been reported with Tecfidera (see section 4.4). PML may be fatal 
or result in severe disability. In one of the clinical trials, one patient taking Tecfidera developed PML 
in the setting of prolonged severe lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 
years), with a fatal outcome. In the post-marketing setting, PML has also occurred in the presence of 
moderate and mild lymphopenia (>0.5x109/L to <LLN, as defined by local laboratory reference 
range).  
 
In several PML cases with determination of T cell subsets at the time of diagnosis of PML, CD8+ 
T cell counts were found to be decreased to <0.1x109/L, whereas reductions in CD4+ T cells counts 
were variable (ranging from <0.05 to 0.5x109/L) and correlated more with the overall severity of 
lymphopenia (<0.5 x109/L to <LLN). Consequently, the CD4+/CD8+ ratio was increased in these 
patients. 
 
Prolonged moderate to severe lymphopenia appears to increase the risk of PML with Tecfidera, 
however, PML also occurred in patients with mild lymphopenia. Additionally, the majority of PML 
cases in the post-marketing setting have occurred in patients >50 years. 
 
Herpes zoster infections have been reported with Tecfidera use. In an ongoing long-term extension 
study, in which 1736 MS patients are treated with Tecfidera, approximately 5% experienced one or 
more events of herpes zoster, the majority of which were mild to moderate in severity. Most subjects, 
including those who experienced a serious herpes zoster infection, had lymphocyte counts above the 
lower limit of normal. In a majority of subjects with concurrent lymphocyte counts below the LLN, 
lymphopenia was rated moderate or severe.  In the post-marketing setting, most cases of herpes zoster 
infection were non-serious and resolved with treatment.  Limited data is available on ALC in patients 
with herpes zoster infection in the post-marketing setting. However, when reported, most patients 
experienced moderate (<0.8x109/L to 0.5x109/L) or severe (<0.5x109/L to 0.2x109/L) lymphopenia 
(see section 4.4).  
 
Laboratory abnormalities 
 
In the placebo-controlled studies, measurement of urinary ketones (1+ or greater) was higher in 
patients treated with Tecfidera (45%) compared to placebo (10%). No untoward clinical consequences 
were observed in clinical trials. 
 
Levels of 1,25-dihydroxyvitamin D decreased in Tecfidera treated patients relative to placebo (median 
percentage decrease from baseline at 2 years of 25% versus 15%, respectively) and levels of 
parathyroid hormone (PTH) increased in Tecfidera treated patients relative to placebo (median 
percentage increase from baseline at 2 years of 29% versus 15%, respectively). Mean values for both 
parameters remained within normal range. 
 
A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.  
 
Paediatric population 
 



12 

The safety of Tecfidera in paediatric patients with multiple sclerosis below the age of 18 has not yet 
been established. In a small 24-week open-label uncontrolled study in paediatric patients with RRMS 
aged 13 to 17 years (120 mg twice a day for 7 days followed by 240 mg twice a day for the remainder 
of treatment; safety population, n=22), followed by a 96 week extension study (240mg twice per day ; 
safety population n=20), the safety profile appeared similar to that observed in adult patients.   
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Cases of overdose with Tecfidera have been reported. The symptoms described in these cases were 
consistent with the known adverse reaction profile of Tecfidera. There are no known therapeutic 
interventions to enhance elimination of Tecfidera nor is there a known antidote. In the event of 
overdose, it is recommended that symptomatic supportive treatment be initiated as clinically indicated. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, ATC code: L04AX07 
 
Mechanism of action 
 
The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully 
understood. Preclinical studies indicate that dimethyl fumarate pharmacodynamic responses appear to 
be primarily mediated through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) 
transcriptional pathway. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidant 
genes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]).  
 
Pharmacodynamic effects 
 
Effects on the immune system 
In preclinical and clinical studies, dimethyl fumarate demonstrated anti-inflammatory and 
immunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the primary metabolite 
of dimethyl fumarate, significantly reduced immune cell activation and subsequent release of pro-
inflammatory cytokines in response to inflammatory stimuli in preclinical models. In clinical studies 
with psoriasis patients, dimethyl fumarate affected lymphocyte phenotypes through a down-regulation 
of pro-inflammatory cytokine profiles (TH1, TH17), and biased towards anti-inflammatory production 
(TH2). Dimethyl fumarate demonstrated therapeutic activity in multiple models of inflammatory and 
neuroinflammatory injury. In Phase 3 studies in MS patients, upon treatment with Tecfidera mean 
lymphocyte counts decreased on average by approximately 30% of their baseline value over the first 
year with a subsequent plateau.  
 
Clinical efficacy and safety 
 
Two, 2-year, randomised, double-blind, placebo controlled studies [Study 1 (DEFINE) with 
1234 subjects and Study 2 (CONFIRM) with 1417 subjects] of subjects with relapsing-remitting 
multiple sclerosis (RRMS) were performed. Subjects with progressive forms of MS were not included 
in these studies. Efficacy (see table below) and safety were demonstrated in subjects with Expanded 
Disability Status Scale (EDSS) scores ranging from 0 to 5 inclusive, who had experienced at least 
1 relapse during the year prior to randomisation, or, in the 6 weeks before randomisation had a brain 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


13 

Magnetic Resonance Imaging (MRI) demonstrating at least one gadolinium-enhancing (Gd+) lesion. 
Study 2 contained a rater-blinded (i.e. study physician/ investigator assessing the response to study 
treatment was blinded) reference comparator of glatiramer acetate.  
 
In Study 1, patients had the following median baseline characteristics: age 39 years, disease duration 
7.0 years, EDSS score 2.0. In addition, 16% of patients had an EDSS score >3.5, 28% had ≥2 relapses 
in the prior year and 42% had previously received other approved MS treatments. In the MRI cohort 
36% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 1.4).  
 
In Study 2, patients had the following median baseline characteristics: age 37 years, disease 
duration 6.0 years, EDSS score 2.5. In addition, 17% of patients had an EDSS score >3.5, 32% had 
≥2 relapses in the prior year and 30% had previously received other approved MS treatments. In the 
MRI cohort 45% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ 
lesions 2.4).  
 
Compared to placebo, subjects treated with Tecfidera had a clinically meaningful and statistically 
significant reduction on: the primary endpoint in Study 1, proportion of subjects relapsed at 2 years; 
and the primary endpoint in Study 2, annualised relapse rate at 2 years.  
 
The annualised relapse rate for glatiramer acetate and placebo was 0.286 and 0.401 respectively in 
Study 2, corresponding to a reduction of 29% (p=0.013), which is consistent with approved 
prescribing information. 
 

 DEFINE CONFIRM 
 Placebo Tecfidera 

240 mg  
twice a day 

Placebo Tecfidera 
240 mg 
twice a day 

Glatiramer 
acetate 

Clinical Endpointsa      
No. subjects 408 410 363 359 350 
Annualised relapse rate 0.364 0.172*** 0.401 0.224*** 0.286* 

Rate ratio  
(95% CI) 

 0.47  
(0.37, 0.61) 

 0.56 
(0.42, 0.74) 

0.71 
(0.55, 0.93) 

Proportion relapsed 0.461 0.270*** 0.410 0.291** 0.321** 
Hazard ratio 
(95% CI) 

 0.51  
(0.40, 0.66) 

 0.66 
(0.51, 0.86) 

0.71 
(0.55, 0.92) 

Proportion with 12-week 
confirmed disability 
progression 

0.271 0.164** 0.169 0.128# 0.156# 

Hazard ratio  
(95% CI) 

 0.62 
(0.44, 0.87) 

 0.79  
(0.52, 1.19) 

0.93 
(0.63, 1.37) 

Proportion with 24 week 
confirmed disability 
progression 

0.169 0.128# 0.125 0.078# 0.108# 

Hazard ratio  
(95% CI) 

 0.77  
(0.52, 1.14) 

 0.62 
(0.37, 1.03) 

0.87 
(0.55, 1.38) 

MRI Endpointsb      
No. subjects 165 152 144 147 161 
Mean (median) number of 
new or newly enlarging 
T2 lesions over 2 years 

16.5 
(7.0) 

3.2 
(1.0)*** 

19.9 
(11.0) 

5.7 
(2.0)*** 

9.6 
(3.0)*** 

Lesion mean ratio  
(95% CI) 

 0.15 
(0.10, 0.23) 

 0.29 
(0.21, 0.41) 

0.46 
(0.33, 0.63) 

Mean (median) number of 
Gd lesions at 2 years  

1.8 
(0) 

0.1 
(0)***  

2.0 
(0.0) 

0.5 
(0.0)***  

0.7 
(0.0)**  

Odds ratio  
(95% CI) 

 0.10 
(0.05, 0.22) 

 0.26 
(0.15, 0.46) 

0.39 
(0.24, 0.65) 



14 

 DEFINE CONFIRM 
 Placebo Tecfidera 

240 mg  
twice a day 

Placebo Tecfidera 
240 mg 
twice a day 

Glatiramer 
acetate 

Mean (median) number of 
new T1 hypointense 
lesions over 2 years 

5.7 
(2.0) 

2.0 
(1.0)*** 

8.1 
(4.0) 

3.8 
(1.0)*** 

4.5 
(2.0)** 

Lesion mean ratio  
(95% CI) 

 0.28  
(0.20, 0.39) 

 0.43 
(0.30, 0.61) 

0.59 
(0.42, 0.82) 

aAll analyses of clinical endpoints were intent-to-treat; bMRI analysis used MRI cohort 
*P-value < 0.05; **P-value < 0.01; ***P-value < 0.0001; #not statistically significant 
 
Efficacy in patients with high disease activity:  
Consistent treatment effect on relapses in a subgroup of patients with high disease activity was 
observed, whilst the effect on time to 3-month sustained disability progression was not clearly 
established. Due to the design of the studies, high disease activity was defined as follows: 
- Patients with 2 or more relapses in one year, and with one or more Gd-enhancing lesions on 

brain MRI (n=42 in DEFINE; n=51 in CONFIRM) or,  
- Patients who have failed to respond to a full and adequate course (at least one year of treatment) 

of beta-interferon, having had at least 1 relapse in the previous year while on therapy, and at 
least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patients 
having an unchanged or increased relapse rate in the prior year as compared to the previous 2 
years (n=177 in DEFINE; n=141 in CONFIRM). 

 
Paediatric population 
 
Tecfidera was evaluated in a prospective open-label, uncontrolled study in 22 paediatric patients with 
RRMS aged 13 to 17 years (4 patients aged ≤14 years). Subjects received Tecfidera 120 mg twice a 
day for 7 days followed by 240 mg twice a day for 24 weeks. The median number of new or newly 
enlarging T2 hyperintense lesions changed from 2 in the 8 week pre-treatment evaluation period to 0 
in the final 8 weeks of the treatment period (median change -2, n=16).  Patients subsequently entered 
an extension study for a further 96 weeks. Among the 10 patients with MRI data between weeks 64 
and week 72 of the extension study, the median number of subjects with new or newly enlarging T2 
hyperintense lesions was 0 (range 0,2).  Over the full treatment period (120-week), ARR was 0.2 
representing an 84.5% relative reduction in relapses (n=20; 95% CI [66.8, 92.8], p<0.0001), when 
compared to the year prior to treatment initiation.  These data should be considered cautiously 
regarding limitations of the study design (no control arm, pre- versus post-dose comparison) (see 
section 4.2). 
 
5.2 Pharmacokinetic properties 
 
Orally administered dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is 
converted to its primary metabolite, monomethyl fumarate, which is also active. Dimethyl fumarate is 
not quantifiable in plasma following oral administration of Tecfidera. Therefore, all pharmacokinetic 
analyses related to dimethyl fumarate were performed with plasma monomethyl fumarate 
concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy 
volunteers. 
 
Absorption 
 
The Tmax of monomethyl fumarate is 2 to 2.5 hours. As Tecfidera gastro-resistant hard capsules 
contain microtablets, which are protected by an enteric coating, absorption does not commence until 
they leave the stomach (generally less than 1 hour). Following 240 mg twice a day administered with 
food, the median peak (Cmax) was 1.72 mg/l and overall area under the curve (AUC) exposure was 
8.02 h.mg/l in subjects with multiple sclerosis. Overall, Cmax and AUC increased approximately dose- 
proportionally in the dose range studied (120 mg to 360 mg). In subjects with multiple sclerosis, two 
240 mg doses were administered 4 hours apart as part of a three times a day dosing regimen. This 



15 

resulted in a minimal accumulation of exposure yielding an increase in the median Cmax of 12% 
compared to the twice daily dosing (1.72 mg/l for twice daily compared to 1.93 mg/l for three times 
daily) with no safety implications. 
 
Food does not have a clinically significant effect on exposure of dimethyl fumarate. However, 
Tecfidera should be taken with food due to improved tolerability with respect to flushing or 
gastrointestinal adverse events (see section 4.2). 
 
Distribution 
 
The apparent volume of distribution following oral administration of 240 mg dimethyl fumarate varies 
between 60 L and 90 L. Human plasma protein binding of monomethyl fumarate generally ranges 
between 27% and 40%. 
 
Biotransformation 
 
In humans, dimethyl fumarate is extensively metabolised with less than 0.1% of the dose excreted as 
unchanged dimethyl fumarate in urine. It is initially metabolised by esterases, which are ubiquitous in 
the gastrointestinal tract, blood and tissues, before it reaches the systemic circulation. Further 
metabolism occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 
(CYP) system. A single 240 mg 14C-dimethyl fumarate dose study identified glucose as the 
predominant metabolite in human plasma. Other circulating metabolites included fumaric acid, citric 
acid and monomethyl fumarate. The downstream metabolism of fumaric acid occurs through the 
tricarboxylic acid cycle, with exhalation of CO2 serving as a primary route of elimination. 
 
Elimination 
 
Exhalation of CO2 is the primary route of dimethyl fumarate elimination accounting for 60% of the 
dose. Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and 
0.9% of the dose respectively. 
 
The terminal half-life of monomethyl fumarate is short (approximately 1 hour) and no circulating 
monomethyl fumarate is present at 24 hours in the majority of individuals. Accumulation of parent 
drug or monomethyl fumarate does not occur with multiple doses of dimethyl fumarate at the 
therapeutic regimen. 
 
Linearity 
 
Dimethyl fumarate exposure increases in an approximately dose proportional manner with single and 
multiple doses in the 120 mg to 360 mg dose range studied. 
 
Pharmacokinetics in special patient groups 
 
Based on the results of Analysis of Variance (ANOVA), body weight is the main covariate of 
exposure (by Cmax and AUC) in RRMS subjects, but did not affect safety and efficacy measures 
evaluated in the clinical studies.  
 
Gender and age did not have a clinically significant impact on the pharmacokinetics of dimethyl 
fumarate. The pharmacokinetics in patients aged 65 and over has not been studied. 
 
Paediatric population 
The pharmacokinetic profile of 240 mg dimethyl fumarate twice a day was evaluated in a small, open-
label, uncontrolled study in patients with RRMS aged 13 to 17 years (n=21). The pharmacokinetics of 
Tecfidera in these adolescent patients was consistent with that previously observed in adult patients 
(Cmax: 2.00±1.29 mg/l; AUC0-12hr: 3.62±1.16 h.mg/l, which corresponds to an overall daily AUC of 
7.24 h.mg/l). 
 



16 

Renal impairment 
Since the renal pathway is a secondary route of elimination for dimethyl fumarate accounting for less 
than 16% of the dose administered, evaluation of pharmacokinetics in individuals with renal 
impairment was not conducted. 
  
Hepatic impairment 
As dimethyl fumarate and monomethyl fumarate are metabolised by esterases, without the 
involvement of the CYP450 system, evaluation of pharmacokinetics in individuals with hepatic 
impairment was not conducted. 
 
5.3 Preclinical safety data 
 
The adverse reactions described in the Toxicology and Reproduction toxicity sections below were not 
observed in clinical studies, but were seen in animals at exposure levels similar to clinical exposure 
levels. 
 
Mutagenesis  
 
Dimethyl fumarate and mono-methylfumarate were negative in a battery of in vitro assays (Ames, 
chromosomal aberration in mammalian cells). Dimethyl fumarate was negative in the in vivo 
micronucleus assay in the rat. 
 
Carcinogenesis 
 
Carcinogenicity studies of dimethyl fumarate were conducted for up to 2 years in mice and rats. 
Dimethyl fumarate was administered orally at doses of 25, 75, 200 and 400 mg/kg/day in mice, and at 
doses of 25, 50, 100, and 150 mg/kg/day in rats. In mice, the incidence of renal tubular carcinoma was 
increased at 75 mg/kg/day, at equivalent exposure (AUC) to the recommended human dose. In rats, 
the incidence of renal tubular carcinoma was increased at 100 mg/kg/day, approximately 2 times 
higher exposure than the recommended human dose. The relevance of these findings to human risk is 
unknown. 
 
The incidence of squamous cell papilloma and carcinoma in the nonglandular stomach (forestomach) 
was increased at equivalent exposure to the recommended human dose in mice and below exposure to 
the recommended human dose in rats (based on AUC). The forestomach in rodents does not have a 
human counterpart.  
 
Toxicology 
 
Nonclinical studies in rodent, rabbits, and monkeys were conducted with a dimethyl fumarate 
suspension (dimethyl fumarate in 0.8% hydroxypropyl methylcellulose) administered by oral gavage. 
The chronic dog study was conducted with oral administration of the dimethyl fumarate capsule.  
 
Kidney changes were observed after repeated oral administration of dimethyl fumarate in mice, rats, 
dogs, and monkeys. Renal tubule epithelial regeneration, suggestive of injury, was observed in all 
species. Renal tubular hyperplasia was observed in rats with life time dosing (2-year study). In dogs 
that received daily oral doses of dimethyl fumarate for 11 months, the margin calculated for cortical 
atrophy was observed at 3 times the recommended dose based on AUC. In monkeys that received 
daily oral doses of dimethyl fumarate for 12 months, single cell necrosis was observed at 2 times the 
recommended dose based on AUC. Interstitial fibrosis and cortical atrophy were observed at 6 times 
the recommended dose based on AUC. The relevance of these findings to humans is not known.  
 
In the testes, degeneration of the seminiferous epithelium was seen in rats and dogs. The findings were 
observed at approximately the recommended dose in rats and 3 times the recommended dose in dogs 
(AUC basis). The relevance of these findings to humans is not known. 
 
Findings in the forestomach of mice and rats consisted of squamous epithelial hyperplasia and 



17 

hyperkeratosis; inflammation; and squamous cell papilloma and carcinoma in studies of 3 months or 
longer in duration. The forestomach of mice and rats does not have a human counterpart. 
 
Reproduction toxicity 
 
Oral administration of dimethyl fumarate to male rats at 75, 250, and 375 mg/kg/day prior to and 
during mating had no effects on male fertility up to the highest dose tested (at least 2 times the 
recommended dose on an AUC basis). Oral administration of dimethyl fumarate to female rats at 
25, 100, and 250 mg/kg/day prior to and during mating, and continuing to Day 7 of gestation, induced 
reduction in the number of estrous stages per 14 days and increased the number of animals with 
prolonged diestrus at the highest dose tested (11 times the recommended dose on an AUC basis). 
However, these changes did not affect fertility or the number of viable fetuses produced. 
 
Dimethyl fumarate has been shown to cross the placental membrane into fetal blood in rats and 
rabbits, with ratios of fetal to maternal plasma concentrations of 0.48 to 0.64 and 0.1 respectively. No 
malformations were observed at any dose of dimethyl fumarate in rats or rabbits. Administration of 
dimethyl fumarate at oral doses of 25, 100, and 250 mg/kg/day to pregnant rats during the period of 
organogenesis resulted in maternal adverse effects at 4 times the recommended dose on an AUC basis, 
and low fetal weight and delayed ossification (metatarsals and hindlimb phalanges) at 11 times the 
recommended dose on an AUC basis. The lower fetal weight and delayed ossification were considered 
secondary to maternal toxicity (reduced body weight and food consumption).  
 
Oral administration of dimethyl fumarate at 25, 75, and 150 mg/kg/day to pregnant rabbits during 
organogenesis had no effect on embryo-fetal development and resulted in reduced maternal body 
weight at 7 times the recommended dose and increased abortion at 16 times the recommended dose, 
on an AUC basis. 
 
Oral administration of dimethyl fumarate at 25, 100, and 250 mg/kg/day to rats during pregnancy and 
lactation resulted in lower body weights in the F1 offspring, and delays in sexual maturation in F1 
males at 11 times the recommended dose on an AUC basis. There were no effects on fertility in the F1 
offspring. The lower offspring body weight was considered secondary to maternal toxicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule contents (enteric-coated microtablets) 
  
Microcrystalline cellulose  
Croscarmellose sodium  
Talc 
Silica, colloidal anhydrous  
Magnesium stearate 
Triethyl citrate 
Methacrylic acid – methyl methacrylate copolymer (1:1) 
Methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30% 
Simeticone 
Sodium laurilsulfate 
Polysorbate 80 
 
Capsule shell 
 
Gelatin 
Titanium dioxide (E171) 
Brilliant Blue FCF (E133) 
Yellow iron oxide (E172) 



18 

 
Capsule print (black ink) 
 
Shellac 
Potassium hydroxide 
Black iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
4 years 
 
6.4 Special precautions for storage 
 
Do not store above 30ºC.  
Keep the blisters in the outer carton in order to protect from light. 
 
6.5 Nature and contents of container  
 
120 mg capsules: 14 capsules in PVC/PE/PVDC-PVC aluminium blister packs. 
240 mg capsules: 56 or 168 capsules in PVC/PE/PVDC-PVC aluminium blister packs. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Biogen Netherlands B.V. 
Prins Mauritslaan 13 
1171 LP Badhoevedorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/837/001 
EU/1/13/837/002  
EU/1/13/837/003  
  
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 January 2014 
Date of latest renewal: 20 September 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 



19 

Agency http://www.ema.europa.eu. 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



21 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
DK-3400 Hillerod 
Denmark 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 
  



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tecfidera 120 mg gastro-resistant hard capsules  
dimethyl fumarate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each gastro-resistant hard capsule contains 120 mg dimethyl fumarate 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 gastro-resistant hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
  
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC 
Keep the blisters in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 



25 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Biogen Netherlands B.V. 
Prins Mauritslaan 13 
1171 LP Badhoevedorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/837/001  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Tecfidera 120 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
  
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC  
SN  
NN 
 
  



26 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
HEAT SEALED BLISTER CARD 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tecfidera 120 mg gastro-resistant hard capsules  
dimethyl fumarate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Biogen Netherlands B.V. 
  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. OTHER 
 
Morning 
Evening 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 
Sun as a symbol  
Moon as a symbol 
 
14 gastro-resistant hard capsules 
Oral use 
Each capsule contains 120 mg dimethyl fumarate 
Read the package leaflet before use 
Keep out of the sight and reach of children 
Do not store above 30ºC 
Keep the blisters in the outer carton in order to protect from light 
  



27 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOIL  
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tecfidera 120 mg 
dimethyl fumarate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



28 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tecfidera 240 mg gastro-resistant hard capsules  
dimethyl fumarate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each gastro-resistant hard capsule contains 240 mg dimethyl fumarate 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 gastro-resistant hard capsules 
168 gastro-resistant hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC 
Keep the blisters in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 



29 

APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Biogen Netherlands B.V. 
Prins Mauritslaan 13 
1171 LP Badhoevedorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/837/002 
EU/1/13/837/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Tecfidera 240 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
  
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC  
SN  
NN 
  



30 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
HEAT SEALED BLISTER CARD 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tecfidera 240 mg gastro-resistant hard capsules  
dimethyl fumarate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Biogen Netherlands B.V. 
  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. OTHER 
 
Morning 
Evening 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 
Sun as a symbol  
Moon as a symbol 
 
  



31 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOIL  
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tecfidera 240 mg 
dimethyl fumarate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 

  



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
  



33 

 
Package leaflet: Information for the patient 

 
Tecfidera 120 mg gastro-resistant hard capsules 
Tecfidera 240 mg gastro-resistant hard capsules 

dimethyl fumarate 
 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Tecfidera is and what it is used for  
2. What you need to know before you take Tecfidera  
3. How to take Tecfidera 
4. Possible side effects  
5. How to store Tecfidera  
6. Contents of the pack and other information 
 
 
1. What Tecfidera is and what it is used for 
 
What Tecfidera is 
 
Tecfidera is a medicine that contains the active substance dimethyl fumarate. 
 
What Tecfidera is used for 
 
Tecfidera is used to treat relapsing-remitting multiple sclerosis (MS) in adult patients.  
MS is a long-term condition that affects the central nervous system (CNS), including the brain and the 
spinal cord. Relapsing-remitting MS is characterised by repeated attacks (relapses) of nervous system 
symptoms. Symptoms vary from patient to patient, but typically include walking difficulties, feeling 
off balance and visual difficulties (e.g. blurred or double vision). These symptoms may disappear 
completely when the relapse is over, but some problems may remain. 
 
How Tecfidera works 
 
Tecfidera seems to work by stopping the body’s defence system from damaging your brain and spinal 
cord. This may also help to delay future worsening of your MS.  
 
 
2. What you need to know before you take Tecfidera 
 
Do not take Tecfidera 
 
- if you are allergic to dimethyl fumarate or any of the other ingredients of this medicine (listed 

in section 6). 
- If you are suspected to suffer from a rare brain infection called progressive multifocal 

leukoencephalopathy (PML) or if PML has been confirmed. 
 



34 

Warnings and precautions 
 
Tecfidera may affect your white blood cell counts, your kidneys and liver. Before you start 
Tecfidera, your doctor will do a blood test to count the number of your white blood cells and will 
check that your kidneys and liver are working properly. Your doctor will test these periodically during 
treatment. If your number of white blood cells decreases during treatment, your doctor may consider 
additional analytic measures or discontinue your treatment. 
 
Talk to your doctor before taking Tecfidera if you have: 
- severe kidney disease 
- severe liver disease 
- a disease of the stomach or bowel 
- a serious infection (such as pneumonia) 
 
Herpes zoster (shingles) may occur with Tecfidera treatment.  In some cases, serious complications 
have occurred. You should inform your doctor immediately if you suspect you have any symptoms 
of shingles. 
 
If you believe your MS is getting worse (e.g. weakness or visual changes) or if you notice any new 
symptoms, talk to your doctor straight away because these may be the symptoms of a rare brain 
infection called progressive multifocal leukoencephalopathy (PML). PML is a serious condition that 
may lead to severe disability or death. 
 
A rare but serious kidney disorder (Fanconi Syndrome) has been reported for a medicine containing 
dimethyl fumarate, in combination with other fumaric acid esters, used to treat psoriasis (a skin 
disease). If you notice you are passing more urine, are more thirsty and drinking more than normal, 
your muscles seem weaker, you break a bone, or just have aches and pains, talk to your doctor as soon 
as possible so that this can be investigated further. 
 
Children and adolescents 
 
Tecfidera is not recommended for use in children and adolescents because there is limited experience 
in the use of Tecfidera in this population. 
 
Other medicines and Tecfidera 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any medicines, in 
particular:  
- medicines that contain fumaric acid esters (fumarates) used to treat psoriasis 
- medicines that affect the body’s immune system including other medicines used to treat 

MS, such as fingolimod, natalizumab, teriflunomide, alemtuzumab, ocrelizumab or cladribine, 
or some commonly used cancer treatments (rituximab or mitoxantrone). 

- medicines that affect the kidneys including some antibiotics (used to treat infections), “water 
tablets” (diuretics), certain types of painkillers (such as ibuprofen and other similar anti-
inflammatories and medicines purchased without a doctor’s prescription) and medicines that 
contain lithium  

- Taking Tecfidera with certain types of vaccines (live vaccines) may cause you to get an 
infection and should, therefore, be avoided. Your doctor will advise whether other types of 
vaccines (non-live vaccines) should be given.  

 
Tecfidera with alcohol 
 
Consumption of more than a small quantity (more than 50 ml) of strong alcoholic drinks (more than 
30% alcohol by volume, e.g. spirits) should be avoided within an hour of taking Tecfidera, as alcohol 
can interact with this medicine. This could cause inflammation of the stomach (gastritis), especially in 
people already prone to gastritis. 
 



35 

Pregnancy and breast-feeding  
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Pregnancy 
 
Do not use Tecfidera if you are pregnant unless you have discussed this with your doctor. 
 
Breast-feeding 
 
It is not known whether the active substance of Tecfidera passes into breast milk. Tecfidera should not 
be used during breast-feeding. Your doctor will help you decide whether you should stop breast-
feeding, or stop using Tecfidera. This involves balancing the benefit of breast-feeding for your child, 
and the benefit of therapy for you. 
 
Driving and using machines 
 
The effect of Tecfidera on the ability to drive or use machines is not known.  Tecfidera is not expected 
to affect your ability to drive and use machines. 
 
 
3. How to take Tecfidera 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Starting dose 
 
120 mg twice a day. 
Take this starting dose for the first 7 days, then take the regular dose.  
 
Regular dose 
 
240 mg twice a day. 
 
Tecfidera is for oral use 
 
Swallow each capsule whole, with some water. Do not divide, crush, dissolve, suck or chew the 
capsule as this may increase some side effects. 
 
Take Tecfidera with food – it may help to reduce some of the very common side effects (listed in 
section 4). 
 
If you take more Tecfidera than you should 
 
If you have taken too many capsules, talk to your doctor straight away. You may experience side 
effects similar to those described below in section 4. 
 
If you forget to take Tecfidera 
 
If you forget or miss a dose, do not take a double dose.  
 
You may take the missed dose if you leave at least 4 hours between the doses. Otherwise wait until 
your next planned dose.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 



36 

 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious effects 
 
Tecfidera may lower lymphocyte counts (a type of white blood cell). Having a low white blood cell 
count can increase your risk of infection, including the risk of a rare brain infection called progressive 
multifocal leukoencephalopathy (PML). PML may lead to severe disability or death. PML has 
occurred after 1 to 5 years of treatment and so your physician should continue to monitor your white 
blood cells throughout your treatment, and you should remain observant of any potential symptoms of 
PML as described below. The risk of PML may be higher if you have previously taken a medicine 
impairing the functionality of your body’s immune system. 
 
The symptoms of PML may be similar to an MS relapse. Symptoms may include new or worsening 
weakness on one side of the body; clumsiness; changes in vision, thinking, or memory; or confusion or 
personality changes, or speech and communication difficulties lasting for more than several days. 
Therefore, if you believe your MS is getting worse or if you notice any new symptoms while you are 
on Tecfidera treatment, it is very important that you speak to your doctor as soon as possible. Also 
speak with your partner or caregivers and inform them about your treatment. Symptoms might arise 
that you might not become aware of by yourself. 
 
 Call your doctor straight away if you experience any of these symptoms  
 
Severe Allergic reactions 
 
The frequency of severe allergic reactions cannot be estimated from the available data (not known).  
 
Reddening of the face or body (flushing) is a very common side effect. However, should flushing be 
accompanied by a red rash or hives and you get any of these symptoms: 
 
- swelling of the face, lips, mouth or tongue (angioedema) 
- wheezing, difficulty breathing or shortness of breath (dyspnoea, hypoxia) 
- dizziness or loss of consciousness (hypotension) 
 
then this may represent a severe allergic reaction (anaphylaxis) 
 
 Stop taking Tecfidera and call a doctor straight away   
 
Very common side effects  
 
These may affect more than 1 in 10 people: 
- reddening of the face or body feeling warm, hot, burning or itchy (flushing) 
- loose stools (diarrhoea) 
- feeling sick (nausea)  
- stomach pain or stomach cramps 
 
 Taking your medicine with food can help to reduce the side effects above 
 
Substances called ketones, which are naturally produced in the body, very commonly show up in urine 
tests while taking Tecfidera. 
 
Talk to your doctor about how to manage these side effects. Your doctor may reduce your dose. Do 
not reduce your dose unless your doctor tells you to. 
 



37 

Common side effects 
 
These may affect up to 1 in 10 people: 
- inflammation of the lining of the intestines (gastroenteritis) 
- being sick (vomiting) 
- indigestion (dyspepsia) 
- inflammation of the lining of the stomach (gastritis) 
- gastrointestinal disorder 
- burning sensation 
- hot flush, feeling hot 
- itchy skin (pruritus) 
- rash 
- pink or red blotches on the skin (erythema) 
 
Side effects which may show up in your blood or urine tests 

- low levels of white blood cells (lymphopenia, leucopenia) in the blood. Reduced white 
blood cells could mean your body is less able to fight an infection. If you have a serious 
infection (such as pneumonia), talk to your doctor immediately 

- proteins (albumin) in urine 
- increase in levels of liver enzymes (ALT, AST) in the blood 

 
Uncommon side effects 
 
These may affect up to 1 in 100 people: 
- Allergic reactions (hypersensitivity) 
- reduction in blood platelets 
 
Not known (frequency cannot be estimated from the available data) 
 
- liver inflammation and increase in levels of liver enzymes (ALT or AST in combination with 

bilirubin) 
- herpes zoster (shingles) with symptoms such as blisters, burning, itching or pain of the skin, 

typically on one side of the upper body or the face, and other symptoms, like fever and 
weakness in the early stages of infection, followed by numbness, itching or red patches with 
severe pain 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
5. How to store Tecfidera 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the blister and the carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
Do not store above 30ºC. 
Keep the blisters in the outer carton in order to protect from light. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


38 

 
What Tecfidera contains  
 
The active substance is dimethyl fumarate.  
Tecfidera 120 mg: Each capsule contains 120 mg of dimethyl fumarate. 
Tecfidera 240 mg: Each capsule contains 240 mg of dimethyl fumarate. 
 
The other ingredients are microcrystalline cellulose, croscarmellose sodium, talc, silica colloidal 
anhydrous, magnesium stearate, triethyl citrate, methacrylic acid – methyl methacrylate copolymer 
(1:1), methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30%, simeticone, sodium 
laurilsulfate , polysorbate 80, gelatin, titanium dioxide (E171), brilliant blue FCF (E133), yellow iron 
oxide (E172), shellac, potassium hydroxide and black iron oxide (E172). 
 
What Tecfidera looks like and contents of the pack 
 
Tecfidera 120 mg gastro-resistant hard capsules are green and white and printed with ‘BG-12 120 mg’ 
and are available in packs containing 14 capsules. 
 
Tecfidera 240 mg gastro-resistant hard capsules are green and printed with ‘BG-12 240 mg’ and are 
available in packs containing 56 or 168 capsules.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Biogen Netherlands B.V. 
Prins Mauritslaan 13 
1171 LP Badhoevedorp 
The Netherlands 
 
Manufacturer 
 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
DK - 3400 Hillerød 
Denmark  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder 
 
België/Belgique/Belgien 
Biogen Belgium NV/SA 
Tél/Tel: +32 2 2191218 

Lietuva 
Biogen Lithuania UAB 
Tel: +370 5 259 6176 
 

България 
ТП ЕВОФАРМА  
Teл: +359 2 962 12 00  

Luxembourg/Luxemburg 
Biogen Belgium NV/SA 
Tél/Tel: +32 2 2191218 
 

Česká republika 
Biogen (Czech Republic) s.r.o. 
Tel: +420 255 706 200 
 

Magyarország 
Biogen Hungary Kft. 
Tel: + 36 1 899 9883 
 

Danmark 
Biogen (Denmark) A/S 
Tlf: +45 77 41 57 57 
 

Malta 
Pharma. MT Ltd.  
Tel: +356 21337008  



39 

Deutschland 
Biogen GmbH 
Tel: +49 (0) 89 99 6170 
 

Nederland 
Biogen Netherlands B.V. 
Tel: +31 20 542 2000 
 

Eesti 
Biogen Estonia OÜ 
Tel: +372 618 9551 
 

Norge 
Biogen Norway AS 
Tlf: +47 23 40 01 00 

Ελλάδα 
Genesis Pharma SA  
Tηλ: +30 210 8771500  

Österreich 
Biogen Austria GmbH 
Tel: +43 1 484 46 13 
 

España 
Biogen Spain, S.L. 
Tel: +34 91 310 7110 
 

Polska 
Biogen Poland Sp. z o.o.  
Tel: +48 22 351 51 00 
 

France 
Biogen France SAS 
Tél: +33 (0)1 41 37 95 95 
 

Portugal 
Biogen Portugal Sociedade Farmacêutica, 
Unipessoal, Lda. 
Tel: +351 21 318 8450 
 

Hrvatska 
Biogen Pharma d.o.o. 
Tel: +385 (0) 1 775 73 22 
 

România 
Johnson & Johnson Romania S.R.L.  
Tel: +40 21 207 18 00 
 
 

Ireland 
Biogen Idec (Ireland) Ltd. 
Tel: +353 (0)1 463 7799 
 

Slovenija 
Biogen Pharma d.o.o. 
Tel: +386 1 511 02 90 

Ísland 
Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika 
Biogen Slovakia s.r.o. 
Tel: +421 2 323 340 08  
 

Italia 
Biogen Italia s.r.l. 
Tel: +39 02 5849901 

Suomi/Finland 
Biogen Finland Oy 
Puh/Tel: +358 207 401 200 
 

Κύπρος 
Genesis Pharma Cyprus Ltd  
Tηλ: +3572 2 765740  

Sverige 
Biogen Sweden AB 
Tel: +46 8 594 113 60 
 

Latvija 
Biogen Latvia SIA 
Tel: +371 68 688 158 

United Kingdom 
Biogen Idec Limited 
Tel: +44 (0) 1628 50 1000 
 

 
This leaflet was last revised in {MM YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET

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