dimethyl fumarate: prescribing information – dosing, contraindications, interactions, side effects

Skilarence is indicated for the treatment of moderate to severe plaque psoriasis in adults in need of systemic medicinal therapy.

Skilarence is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of psoriasis.

Posology

To improve tolerability of Skilarence, it is recommended to begin treatment with a low initial dose with subsequent gradual increases. In the first week, a 30 mg dose is taken once daily (1 tablet in the evening). In the second week, a 30 mg dose is taken twice daily (1 tablet in the morning and 1 in the evening). In the third week, a 30 mg dose is taken three times daily (1 tablet in the morning, 1 at midday, and 1 in the evening). From the fourth week, treatment is switched to only 1 tablet of

a 120 mg dose in the evening. This dose is then increased by one 120 mg tablet per week at different times of day for the subsequent 5 weeks, as shown in the table below.
The maximum daily dose allowed is 720 mg (six 120 mg tablets).

Week
Number of tablets
Total daily dose (mg)

Morning
Midday
Evening of dimethyl fumarate
Skilarence 30 mg

Skilarence 120 mg

9+

If a particular dose increase is not tolerated, it may be temporarily reduced to the last tolerated dose.

If treatment success is observed before the maximum dose is reached, no further increase of dose is necessary. After clinically relevant improvement of the skin lesions has been achieved, consideration should be given to gradual reduction of the daily dose of Skilarence to the maintenance dose required by the individual.

Dose modifications may also be necessary if abnormalities in laboratory parameters are observed (see section 4.4).

Elderly patients
Clinical studies of Skilarence did not include sufficient numbers of patients aged 65 years and above to determine whether they respond differently compared to patients under 65 years (see section 5.2).
Based on the pharmacology of dimethyl fumarate, a need for dose adjustment in the elderly is not expected.

Renal impairment
No dose adjustment is needed in patients with mild to moderate renal impairment (see section 5.2).
Skilarence has not been studied in patients with severe renal impairment, and use of Skilarence is contraindicated in these patients (see section 4.3).

Hepatic impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment (see section 5.2).
Skilarence has not been studied in patients with severe hepatic impairment, and use of Skilarence is contraindicated in these patients (see section 4.3).

Paediatric population
The safety and efficacy of Skilarence in children below the age of 18 years have not been established.
There are no data available with Skilarence in paediatric population.

Method of administration

For oral use.
Tablets must be swallowed whole with fluid during or immediately after a meal.
The coating of the gastro-resistant tablets is designed to prevent gastric irritation. Therefore, the tablets

should not be crushed, divided, dissolved or chewed.

‒
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
‒
Severe gastrointestinal disorders.
‒
Severe hepatic or renal impairment.
‒
Pregnancy and breast-feeding.

Summary of the safety profile

The most common adverse reactions observed with Skilarence are gastrointestinal events followed by flushing and lymphopenia.

Tabulated list of adverse reactions

The following is a list of adverse reactions experienced by patients treated with Skilarence during the clinical development, post-marketing experience and with Fumaderm, 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).

System organ class
Adverse reactions
Frequency
Infections and infestations
Herpes zoster
Not known**
Blood and lymphatic system disorders
Lymphopenia
Leukopenia
Eosinophilia
Leukocytosis
Acute lymphatic leukaemia*
Irreversible pancytopenia*
Very common
Very common
Common
Common
Very rare
Very rare
Metabolism and nutrition
Decreased appetite
Common

System organ class
Adverse reactions
Frequency disorders
Nervous system disorders
Headache
Paraesthesia
Dizziness*
Progressive multifocal leukoencephalopathy
Common
Common
Uncommon
Not known
Vascular disorders
Flushing
Very common
Gastrointestinal disorders
Diarrhoea
Abdominal distension
Abdominal pain
Nausea
Vomiting
Dyspepsia
Constipation
Abdominal discomfort
Flatulence
Very common
Very common
Very common
Very common
Common
Common
Common
Common
Common
Skin and subcutaneous tissue disorders
Erythema
Skin burning sensation
Pruritus
Allergic skin reaction
Common
Common
Common
Rare
Renal and urinary disorders
Proteinuria
Renal failure
Fanconi syndrome*
Uncommon
Not known
Not known
General disorders and administration site conditions
Fatigue
Feeling hot
Asthenia
Common
Common
Common
Investigations
Hepatic enzymes increased
Serum creatinine increased
Common
Uncommon
*Additional adverse reactions reported with Fumaderm, a related medicinal product containing dimethyl fumarate along with other fumaric acid esters.
**Adverse reactions reported during post marketing experience.

Description of selected adverse reactions

Gastrointestinal disturbances
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 Skilarence, leading to medicinal product withdrawal in about 10% of patients. More than 90% of these diarrhoea events were of mild to moderate severity (see section 4.4).
The only adverse reactions that led to discontinuation of treatment in >5% of patients were gastrointestinal reactions. For monitoring recommendations and clinical management of adverse reactions, see section 4.4.

Flushing
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 Skilarence experienced flushing, which was mild in the majority of cases (see section 4.4). 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 Skilarence.

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.

For monitoring recommendations and clinical management of haematological adverse reactions, see section 4.4.

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.

Haematology

Skilarence may decrease leukocyte and lymphocyte counts (see section 4.8). It has not been studied in patients with pre-existing low leukocyte or lymphocyte counts.

Before treatment
Prior to initiating treatment, 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
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 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 (see section 4.8).

Other haematological disorders
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.

Infections

Skilarence 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 should only be initiated once the infection has resolved. If a patient develops an infection during treatment, suspension of treatment should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving this medicinal product should be instructed to report symptoms of infection to a physician.

Opportunistic infections/progressive multifocal leukoencephalopathy (PML)
Cases of opportunistic infections, particularly of progressive multifocal leukoencephalopathy (PML) have been reported with other dimethyl fumarate-containing products (see section 4.8). 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 should be stopped immediately and further appropriate neurological and radiological examinations performed.

Prior and concomitant treatment with immunosuppressive or immunomodulating therapies

Limited data are available on the efficacy and safety of Skilarence in patients who have been previously treated with other immunosuppressive or immunomodulating therapies. When switching patients from such therapies to Skilarence, 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 Skilarence when taken concomitantly with other immunosuppressive or immunomodulating therapies (see section 4.5).

Pre-existing gastrointestinal disease

Skilarence has not been studied in patients with pre-existing gastrointestinal disease. It is contraindicated in patients with severe gastrointestinal disease (see sections 4.3). Gastrointestinal tolerability can be improved by following the dose titration schedule on initiating treatment and by taking the gastro-resistant tablet(s) with food (see sections 4.2 and 4.8).

Renal function

During the Phase III placebo-controlled clinical study, renal function was not seen to deteriorate during therapy across treatment groups. However, Skilarence has not been studied in patients with severe renal impairment, and some cases of renal toxicity have been reported during post-marketing surveillance with fumaric acid esters. Hence, Skilarence is contraindicated in patients with severe renal impairment (see section 4.3).

Renal function (e.g. creatinine, blood urea nitrogen and urinalysis) should be checked prior to initiation of treatment and every 3 months thereafter. In the event of a clinically relevant change in renal function, particularly in the absence of alternative explanations, consideration should be given to dose reduction or treatment discontinuation.

Fanconi syndrome
Early diagnosis of Fanconi syndrome and discontinuation of Skilarence 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) (see section 4.8).
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.

Hepatic function

Skilarence has not been studied in patients with severe hepatic impairment and is contraindicated in these patients (see section 4.3).

It is recommended to monitor hepatic function (SGOT, SGPT, gamma-GT, AP) prior to initiation of treatment and every 3 months thereafter, since elevation of hepatic enzymes has been observed in some patients in the Phase III study (see section 4.8). In the event of a clinically relevant change in hepatic parameters, particularly in the absence of alternative explanations, consideration should be given to dose reduction or treatment discontinuation (see section 4.2).

Flushing

Patients should be made aware that they are likely to experience flushing in the first few weeks of treatment (see section 4.8).

Excipients

Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’.

No interaction studies have been performed.

Skilarence should be used cautiously in combination with other systemic antipsoriatic therapy (e.g.
methotrexate, retinoids, psoralens, ciclosporin, immunosuppressants or cytostatics) (see section 4.4).
During treatment, simultaneous use of other fumaric acid derivatives (topical or systemic) should be avoided.

Concurrent therapy with nephrotoxic substances (e.g. methotrexate, ciclosporin, aminoglycosides, diuretics, non-steroidal anti-inflammatory drugs (NSAIDs) or lithium) may increase the potential for renal adverse reactions (e.g. proteinuria) in patients taking Skilarence.

In cases of severe or prolonged diarrhoea during treatment with Skilarence, absorption of other medicinal products may be affected. Caution should be exercised when prescribing medicinal products with a narrow therapeutic index that require absorption in the intestinal tract. The efficacy of oral contraceptives may be reduced and the use of an alternative barrier contraceptive method is recommended to prevent possible failure of contraception (see the prescribing information of the oral contraceptive).

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 Skilarence and, therefore, may increase the frequency of gastrointestinal adverse reactions.

Vaccination during treatment with Skilarence 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.

There is no evidence for interaction with cytochrome P450 and the most common efflux and uptake transporters, thus no interactions are expected with medicinal products metabolised or transported by these systems (see section 5.2).

Women of child-bearing potential

Skilarence is not recommended in women of child-bearing potential not using appropriate contraception. Additional contraceptive methods in case of stomach and intestinal problems that could reduce the effectiveness of oral contraceptives could be necessary (see section 4.5).

Pregnancy

There are limited data from the use of dimethyl fumarate in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Skilarence is contraindicated during pregnancy (see section 4.3).

Breast-feeding

It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to newborns or infants cannot be excluded. Therefore, Skilarence is contraindicated during breast- feeding (see section 4.3).

Fertility

There are no human or animal data on the effects of Skilarence on fertility.

Skilarence may have a minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of Skilarence (see section 4.8).

Symptomatic treatment is indicated in the case of an overdose. No specific antidote is known.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX07

Mechanism of action

The anti-inflammatory and immunomodulating effects of dimethyl fumarate and its metabolite monomethyl fumarate are not fully elucidated but are thought to be mainly due to the interaction with the intracellular reduced glutathione of cells directly involved in the pathogenesis of psoriasis. This interaction with glutathione leads to the inhibition of translocation into the nucleus and the transcriptional activity of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).

The main activity of dimethyl fumarate and monomethyl fumarate is considered to be immunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2 phenotype. The inflammatory cytokine production is reduced with induction of proapoptotic events, inhibition of keratinocyte proliferation, reduced expression of adhesion molecules, and diminished inflammatory infiltrate within psoriatic plaques.

Clinical efficacy and safety

The safety and efficacy of Skilarence was assessed in one double-blind, 3-arm, placebo- and active comparator-controlled Phase III study (1102) in patients with moderate to severe plaque psoriasis (Study 1102). 704 patients were randomised to receive Skilarence, an active comparator (Fumaderm, a combination product with the same content of dimethyl fumarate plus 3 monoethyl fumarate salts) and placebo in a ratio of 2:2:1. Patients began treatment with tablets containing 30 mg/day dimethyl fumarate or placebo, titrating up to a maximum of 720 mg/day in both active treatment arms as described in section 4.2. If treatment success was observed before the maximum dose of 720 mg/day of dimethyl fumarate was reached, no further increase of dose was necessary and the dose was to be steadily reduced to an individual maintenance dose. In case of individual intolerability of the increased dose during weeks 4 to 16, the patient was to return to the last tolerated dose taken since the start of week 4, which was to be maintained until end of the treatment period (week 16). Patients received treatment for up to 16 weeks and follow-up visits were planned for up to 12 months after treatment was stopped.

The demographic and baseline characteristics were well balanced between the treatment groups. Of the 699 patients, most were Caucasian (99%) and male (65%), and the mean age was 44 years. Most patients (91%) were <65 years of age. Most patients had moderate psoriasis based on Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA) scores at baseline: the mean PASI score at baseline was 16.35 and 60% of patients scored as moderate on the PGA. The majority of patients reported a “very large” or “extremely large” effect of psoriasis on their life based on the Dermatology Life Quality Index (DLQI), with a mean DLQI score of 11.5.

Absorption

After oral administration, dimethyl fumarate is not detected in plasma because it is rapidly hydrolysed by esterases to its active metabolite monomethyl fumarate. After oral administration of a single Skilarence 120 mg tablet in healthy subjects, monomethyl fumarate reached plasma peak concentrations of around 1325 ng/mL and 1311 ng/mL under fasted or fed conditions, respectively.
Taking Skilarence with food delayed the tmax of monomethyl fumarate from 3.5 to 9.0 hours.

Distribution

The plasma protein binding of monomethyl fumarate is around 50%. Dimethyl fumarate does not show any binding affinity to serum proteins which may further contribute to its rapid elimination from the circulation.

Biotransformation

The biotransformation of dimethyl fumarate does not involve cytochrome P450 isoenzymes. In vitro studies have shown that monomethyl fumarate at the therapeutic dose does not inhibit or induce any of the cytochrome P450 enzymes, it is not a substrate or inhibitor of P-glycoprotein and is not an inhibitor of the most common efflux and uptake transporters. In vitro studies have shown that dimethyl fumarate at a therapeutic dose does not inhibit CYP3A4/5 and BCRP and is a weak P-glycoprotein inhibitor.

In vitro studies have shown that hydrolysis of dimethyl fumarate to monomethyl fumarate occurs rapidly at pH 8 (pH in the small intestine), but not at pH 1 (pH in the stomach). A part of the total dimethyl fumarate is hydrolysed by esterases and the alkaline milieu of the small intestine, while the remainder enters the portal vein blood. Further studies have shown that dimethyl fumarate (and to a lesser extent monomethyl fumarate) reacts partially with reduced glutathione forming a glutathione- adduct. These adducts were detected in animal studies in the intestinal mucosa of rats and to a smaller extent in portal vein blood. Unconjugated dimethyl fumarate, however, cannot be detected in the

Tecfidera is indicated for the treatment of adult and paediatric patients aged 13 years and older with relapsing remitting multiple sclerosis (RRMS).

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.

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 posology is the same in adults and in paediatric patients aged 13 years and older.
There are limited data available in children between 10 and 12 years old. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.
The safety and efficacy of Tecfidera in children aged less than 10 years have not been established. No data are available.
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 gastrointestinal tract.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Suspected or confirmed progressive multifocal leukoencephalopathy (PML).

Summary of the safety profile
The most common adverse reactions are flushing (35%) and gastrointestinal events (i.e. diarrhoea (14%), nausea (12%), abdominal pain (10%), abdominal pain upper (10%)). 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 treatment discontinuation are flushing (3%) and gastrointestinal events (4%).
In phase 2 and 3 placebo-controlled and uncontrolled clinical studies, a total of 2,513 patients have received Tecfidera for periods of up to 12 years with an overall exposure equivalent to 11,318 person- years. A total of 1,169 patients have received at least 5 years of treatment with Tecfidera, and 426 patients have received at least 10 years of treatment with Tecfidera. The experience in uncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical trials.
Tabulated list of adverse reactions
Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous reports, are presented in the table below.
The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class. The incidence of the adverse reactions below is 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 zoster
Not known
Blood and lymphatic system disorders
Lymphopenia
Common
Leucopenia
Common
Thrombocytopenia
Uncommon
Immune system disorders
Hypersensitivity
Uncommon
Anaphylaxis
Not known
Dyspnoea
Not known
Hypoxia
Not known
Hypotension
Not known
Angioedema
Not known
Nervous system disorders
Burning sensation
Common
Vascular disorders
Flushing
Very common
Hot flush
Common
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea
Not known
Gastrointestinal disorders
Diarrhoea
Very common

MedDRA system organ class
Adverse reaction
Frequency category
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 injury
Rare
Skin and subcutaneous tissue disorders
Pruritus
Common
Rash
Common
Erythema
Common
Alopecia
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
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 adverse reactions
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 adverse reactions 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 adverse reactions. 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 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 counts 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 < 0.5 × 109/L were observed in < 1% of patients treated with placebo and 6% of patients treated with Tecfidera. A lymphocyte count < 0.2 × 109/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 < 0.91 × 109/L). Mild lymphopenia (counts ≥ 0.8 × 109/L to < 0.91 × 109/L) was observed in 28% of patients; moderate lymphopenia (counts ≥ 0.5 × 109/L to < 0.8 × 109/L) persisting for at least six months was observed in 11% of patients; severe lymphopenia (counts < 0.5 × 109/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 < 0.5 × 109/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 ≥ 0.2 × 109/L to < 0.4 × 109/L) or severely (<0.2 × 109/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 < 0.2 × 109/L and 25% of patients at counts < 0.1 × 109/L. In controlled and uncontrolled clinical studies, patients who discontinued Tecfidera therapy with lymphocyte counts below the LLN were monitored for recovery of lymphocyte count to the LLN (see section 5.1).
Progressive multifocal leukoencephalopathy (PML)
Cases of infections with John Cunningham virus (JCV) causing 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, 1 patient taking Tecfidera developed PML in the setting of prolonged severe lymphopenia (lymphocyte counts predominantly < 0.5 × 109/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 (> 0.5 × 109/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 < 0.1 × 109/L, whereas reductions in CD4+ T cells counts were variable (ranging from < 0.05 to 0.5 × 109/L) and correlated more with the overall severity of lymphopenia (< 0.5 × 109/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

Herpes zoster infections have been reported with Tecfidera. In the long-term extension study, in which 1,736 MS patients were treated, approximately 5% experienced one or more events of herpes zoster, of which 42% were mild, 55% were moderate, and 3% were severe. The time to onset from first Tecfidera dose ranged from approximately 3 months to 10 years. Four patients experienced serious events, all of which resolved. 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 are available on absolute lymphocyte count (ALC) in patients with herpes zoster infection in the post-marketing setting. However, when reported, most patients experienced moderate (≥ 0.5 × 109/L to < 0.8 × 109/L) or severe (< 0.5 × 109/L to 0.2 × 109/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
In a 96-week open-label, randomised active controlled trial paediatric patients with RRMS (n=7 aged 10 to less than 13 years and n=71 aged 13 to less than 18 years) were treated with 120 mg twice a day for 7 days followed by 240 mg twice a day for the remainder of treatment. The safety profile in paediatric patients appeared similar to that previously observed in adult patients.
The paediatric clinical trial design differed from the adult placebo-controlled clinical trials. Therefore, a contribution of clinical trial design to numerical differences in adverse events between the paediatric and adult populations, cannot be excluded. Gastrointestinal disorders as well as respiratory, thoracic and mediastinal disorders and the adverse events of headache and dysmenorrhea were more frequently reported (≥10%) in the paediatric population than in the adult population. These adverse events were reported in the following percentages in paediatric patients:

Headache was reported in 28% of patients treated with Tecfidera versus 36% in patients treated with interferon beta-1a.

Gastrointestinal disorders were reported in 74% of patients treated with Tecfidera versus 31% in patients treated with interferon beta-1a. Among them, abdominal pain and vomiting were the most frequently reported with Tecfidera.

Respiratory, thoracic and mediastinal disorders were reported in 32% of patients treated with Tecfidera versus 11% in patients treated with interferon beta-1a. Among them, oropharyngeal pain and cough were the most frequently reported with Tecfidera.

Dysmenorrhea was reported in 17% of patients treated with Tecfidera versus 7% of patients treated with interferon beta-1a.
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; n=22), followed by a 96-week extension study (240 mg twice per day; 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.

Blood/laboratory tests
Renal function
Changes in renal laboratory tests have been seen in clinical trials in patients 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.
Hepatic function
Drug-induced liver injury, including liver enzyme increase (≥ 3 times 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 days, 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.
Lymphocytes
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.
If lymphocyte count is found to be below the normal range, thorough assessment of possible causes should be completed prior to initiation of treatment. Dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts and caution should be exercised when treating these patients. Treatment should not be initiated in patients with severe lymphopenia (lymphocyte counts < 0.5 × 109/L).
After starting therapy, complete blood counts, including lymphocytes, must be performed every 3 months.
Enhanced vigilance due to an increased risk of PML is recommended in patients with lymphopenia as follows:

Treatment should be discontinued in patients with prolonged severe lymphopenia (lymphocyte counts < 0.5 × 109/L) persisting for more than 6 months.

In patients with sustained moderate reductions of absolute lymphocyte counts ≥ 0.5 × 109/L to < 0.8 × 109/L for more than 6 months, the benefit/risk balance of treatment with Tecfidera 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 (see section 5.1). 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 of PML in the setting of lymphopenia are:
- duration of Tecfidera therapy. Cases of PML have occurred after approximately 1 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 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 been reported 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 or 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 adverse reactions 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).
Anaphylactic reactions
Cases of anaphylaxis/anaphylactoid reaction have been reported following Tecfidera administration in the post-marketing setting (see section 4.8). 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 3 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(are) resolved.
There was no increased incidence of serious infections observed in patients with lymphocyte counts < 0.8 × 109/L or < 0.5 × 109/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 been reported with Tecfidera (see section 4.8). 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 adverse reactions may occur at any time during the treatment. Patients should be monitored 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. Withholding treatment should be considered in patients with serious infections until the infection has resolved (see section 4.8).
Treatment initiation
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 with 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.
Excipients
This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium free’.

Anti-neoplastic, immunosuppressive or corticosteroid therapies
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.
Vaccines
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 RRMS, 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 titre) 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 titre 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.
Other fumaric acid derivatives
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 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 (the primary metabolite of dimethyl fumarate).
Effects of other substances on 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 RRMS. 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 amounts 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.
Effects of dimethyl fumarate on other substances
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 oestradiol) did not elicit any relevant change in oral contraceptive exposure.
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.

Pregnancy
A moderate amount of data on pregnant women are available (between 300-1,000 pregnancy outcomes), based on a pregnancy registry and post-marketing spontaneous reports. In the Tecfidera pregnancy registry, 289 prospectively collected pregnancy outcomes were documented in patients with MS who were exposed to dimethyl fumarate. The median duration of exposure to dimethyl fumarate was 4.6 gestational weeks with limited exposure after the sixth gestational week (44 pregnancy outcomes). Exposure to dimethyl fumarate during such early pregnancy indicates no malformative or foeto/neonatal toxicity compared to the general population. The risk of longer dimethyl fumarate exposure or exposure in later stages of pregnancy is not known.
Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Tecfidera during pregnancy. 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 taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
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).

Tecfidera has no or negligible influence on the ability to drive and use machines.

Cases of overdose with Tecfidera have been reported. The symptoms described in these cases were consistent with the known safety 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

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, 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 (DEFINE, CONFIRM and ENDORSE), 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. In these studies, patients who discontinued treatment with lymphocyte counts below the lower limit of normal (LLN, 0.9 × 109/L) were monitored for recovery of lymphocyte counts to the LLN.
Figure 1 shows the proportion of patients estimated to reach the LLN based on the Kaplan-Meier method without prolonged severe lymphopenia. The recovery baseline (RBL) was defined as the last on-treatment ALC prior to treatment discontinuation. The estimated proportion of patients recovering to LLN (ALC ≥ 0.9 × 109/L) at Week 12 and Week 24, who had mild, moderate, or severe lymphopenia at RBL are presented in Table 1, Table 2, and Table 3 with 95% pointwise confidence intervals. The standard error of the Kaplan-Meier estimator of the survival function is computed using Greenwood’s formula.

Figure 1: Kaplan-Meier method; proportion of patients with recovery to ≥ 910 cells/mm3 (0.9 × 109/L) LLN from the recovery baseline (RBL) Note: 500 cells/mm3, 800 cells/mm3, 910 cells/mm3 correspond to 0.5 × 109/L, 0.8 × 109/L and 0.9 × 109/L respectively.
Table 1: Kaplan-Meier method; proportion of patients estimated to reach LLN, mild lymphopenia at the recovery baseline (RBL), excluding patients with prolonged severe lymphopenia Number of patients with mild lymphopeniaa at risk Baseline N=86 Week 12 N=12 Week 24 N=4 Proportion reaching LLN (95% CI)

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 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